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WO2018160855A1 - Inhibiteurs sélectifs de la protéine arginine méthyltransférase 5 (prmt5) - Google Patents

Inhibiteurs sélectifs de la protéine arginine méthyltransférase 5 (prmt5) Download PDF

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Publication number
WO2018160855A1
WO2018160855A1 PCT/US2018/020483 US2018020483W WO2018160855A1 WO 2018160855 A1 WO2018160855 A1 WO 2018160855A1 US 2018020483 W US2018020483 W US 2018020483W WO 2018160855 A1 WO2018160855 A1 WO 2018160855A1
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Prior art keywords
cealk
compound
cealkyl
chlorophenyl
difluorophenyl
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PCT/US2018/020483
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English (en)
Inventor
Juan Luengo
Hong Lin
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Prelude Therapeutics, Incorporated
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Publication of WO2018160855A1 publication Critical patent/WO2018160855A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

Definitions

  • the disclosure is directed to PRMTS 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.
  • ADMA ⁇ NG.N'G symmetric dimethylarginine
  • SDMA ⁇ NG.N'G symmetric dimethylarginine
  • PRMT1 methyltransferases
  • 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
  • PRMTS is as a general transcriptional repressor that functions with numerous transcription factors and repressor complexes, including BRG1 and hBRM, Blimp 1, and Snail.
  • This enzyme once recruited to a promoter, symmetrically dimethylates H3R8 and H4R3.
  • the H4R3 site is a major target for PRMT1 methylation (ADMA) and is generally regarded as a transcriptional activating mark.
  • ADMA PRMT1 methylation
  • both H4R3me2s repressive; me2s indicates SDMA modification
  • H4R3me2a active; me2a indicates ADMA modification
  • 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.
  • PRMTs Aberrant expression of PRMTs has been identified in human cancers, and PRMTs are considered to be therapeutic targets.
  • Global analysis of hi stone modifications in prostate cancer has shown that the dimethylation of hi stone H4R3 is positively correlated with increasing grade, and these changes are predictive of clinical outcome.
  • PRMT5 levels have been shown to be elevated in a panel of lymphoid cancer cell lines as well as mantle cell lymphoma clinical samples.
  • PRMT5 interacts with a number of substrates that are involved in a variety of cellular processes, including RNA processing, signal transduction, and transcriptional regulation.
  • PRMT5 can directly modify hi stone H3 and H4, resulting in the repression of gene expression.
  • PRMTS overexpression can stimulate cell growth and induce transformation by directly repressing tumor suppressor genes. Pal et al., Mol. Ceil. Biol. 2003, 7475; Pal et al. Mol. Ceil. Biol. 2004, 9630; Wang et al. Mol. Ceil. Biol. 2008, 6262; Chung et al.
  • 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.
  • MTAP methylthioadenosine phosphorylase
  • 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.
  • PRMT5 induces the repressive histone mark, H4R3me2s, which serves as a template for direct binding of DNMT3A, and subsequent DNA methylation. Loss of PRMT 5 binding or its enzymatic activity leads to demethyiation of the CpG dinucleotides and gene activation.
  • 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.
  • A is CH or N
  • R 1 is -Co-Cealk-Ci-Cealkyl, -Co-Cealk-Ci-Cehaloalkyl, -Co-C 6 alk-C ⁇ H, -Co-C6alk-C ⁇ C-Ci- Cealkyl, -Co-C6alk-C ⁇ C-C 3 -C6cycloalkyl, -Ci-Cealk- aryl, -Co-Cealk-heteroaryl , -Ci-Cealk-O-heteroaryl, -Ci-Cealk-S-heteroaryl, or -Ci- Ceal k-NH-heteroaryl ;
  • R 2 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH, -Co-Ceal k-O-Ci-Cealkyl, -Co-Cealk-NHi, -Co-Cealk-NH-Ci-Cealkyl, -Co-Cealk-NiCi-CealkylVCi-Cealkyl, -Co-Cealk-NH-Cs-Cecycloalkyl,
  • R 3 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-CB-Ceeycloalkyl, -Co-Cealk-OH,
  • R 4 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH,
  • R J and R 4 together with the atom to which they are attached, form a Cs-Cecycloalkyl ring or a heterocycloal ky] ring;
  • R 5 is I I, halo, NFfc, or Ci-Cealkyl
  • R 6 is H, halo, Ci-Cealkyl, -Ci-Cehaloalkyl, or -Co-C6alk-C 3 -C6cycloalkyl,
  • R' is halo, -Ci-G alkyl, -C 1 -C 4 haloalkyl, -C3-C&cycloalkyl, -Oj-Cehaloeyeloalkyl, -C 2 -
  • R 8 and R 8' are each independently H, Ci-Cealkyl, or -Co-Cealk-OCi-Cealkyl;
  • R 8 and R 8 together with the atom to which they are attached, form a Cs-Cecycloalkyl ring or a five or six membered heterocyclic ring;
  • R 9 is -Ci-Cealkyl, or Co-Cealk-Cs-Cecycloal kyl .
  • Stereoisomers of the compounds of Formula I, Formula II, Formula III, or Formula IV, and the pharmaceutical salts and solvates thereof, are al so descri bed. Methods of using compounds of Formula I, Formula II, Formula III, or Formula IV are described, as well as pharmaceutical compositions including the compounds of Formula I, Formula II, Formula III, or Formula IV.
  • 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, C j alkyl), ethyl (Et, dalkyl), n-propyl (dalkyl), isopropyi (C 3 alkyl), butyl (C 4 alkyl), isobutyl (dalkyl), sec-butyl (C 4 alkyl), tert-butyl (dalkyl), pentyl (dalkyl), isopentyl (Csalkyl), tert-pentyl (dalkyl), hexyl (dalkyl), isohexyl (dalkyl), and the like.
  • halo when used alone or as part of a substituent group refers to chloro, fiuoro, 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, triftuorom ethyl (-CF3), chlorom ethyl (- CH2CI), and the like.
  • cycloalkyl when used alone or as part of a substituent group refers to cyclic-containing, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms ("C 3 -C 10 "), preferably from 3 to 6 carbon atoms ("C3-C6").
  • Examples of cycloalkyl groups include, for example, cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopropylmethyl (C 4 ), cyclopentyi (C5), cyclohexyl (d), 1- methylcyclopropyl (C 4 ), 2-methylcyclopentyl (C 4 ), adamantanyl (do), and the like.
  • halocycloalkyl when used alone or as part of a substituent group refers to a cycloalkyl group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms.
  • Halogen atoms include chlorine, fluorine, bromine, and iodine.
  • Examples of cycloalkyl groups include, for example, chiorocyclopropyl (C 3 ), fluorocyciobutyi (C 4 ),
  • heterocycloaikyi when used alone or as part of a substituent group refers to any three to ten membered monocyclic or bicyclic, saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S.
  • the heterocycloaikyi group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
  • heterocycloaikyi groups include, but are not limited to, azepanyl, aziridinyi, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazoiidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, and the like.
  • oxo-substituted-heterocycloalkyl when used alone or as part of a substituent group refers to a heterocycloalkvl group wherein at least one of the carbon atoms in the ring is substituted with an oxo group.
  • oxo-substituted heterocycloalkvl groups include, but are not limited to, 2-aziridinonyi, 2-azetidinonyl, pyrrolidinonyl, dioxoianonyi,
  • alkenyl when used alone or as part of a substituent group refers to a straight- or branched-chain group having from 2 to 12 carbon atoms (“C2-C12”), preferably 2 to 4 carbons atoms ("C2-C "), in the group, wherein the group includes at least one carbon-carbon double bond.
  • 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 (“C3-C10”), preferably from 3 to 6 carbon atoms (“C3-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.
  • substituents include a halogen atom, a -C1-C3 alky! group, or a -C1-C3 aiky! group that is substituted with a hydroxy group, an amino group (i.e., -NH2), or an alky-substituted amino group.
  • Halogen atoms include chlorine, fluorine, bromine, and iodine.
  • aryi groups substituted and unsubstituted
  • aryi groups include phenyl, naphtvl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, methyl chlorophenyl, (hydroxymethyl)chlorophenyl, (hydroxymethyl)fluorophenyl,
  • 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.
  • substituents include a halogen atom; an amino group; a substituted amino group, including an amino group substituted with a -d-Ce cycloalkyl group or a -Ci-Ce alkyl group; or a -Ci-Cs alkyl group.
  • Halogen atoms include chlorine, fluorine, bromine, and iodine.
  • heteroaryl groups include but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyi, imidazoiyl, purazolyl, isoxazolyi, isothiazolyl, triazolyl, thiadiazoiyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, turazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuranyi, benzothiophenyl, benzimidazolyl, benzthiazolyl, purinyl, quinoiizinyl, quinolinyi, 2- amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, 2-
  • C1-C3 includes C1-C3, C1.C2, C2-C3, Ci, C2, and C 3 .
  • Ci-Cealk when used alone or as part of a substituent group refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, -CH2-, -CH(CH 3 )-, -CH(CH3)-CH2-, and -C(CH 3 )2-.
  • -Coalk- refers to a bond.
  • the Ci-Cealk can be substituted with one or more -OH, -Nth, 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-naphthalenesulfonie acid, 4-toluene
  • tetraalkyl ammonium and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • 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, or Formula IV 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.
  • isotopic variant refers to a compound that contains proportions of isotopes at one or more of the atoms that constitute such compound that is greater than natural abundance.
  • an "isotopic variant" of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non-radioactive isotopes such as for example, deuterium ( I or D), carbon- 13 ( ! C), nitrogen- 5 ( 15 N), or the like.
  • any hydrogen may be H/D
  • any carbon may be 13 C
  • any nitrogen may be l5 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • the disclosure is directed to compounds of Formula I, Formula II, Formula III, and Formula IV. In some aspects, the disclosure is directed to com ounds of Formula I:
  • a in Formula I or Formula II is N or CH.
  • A is N and the compoun f Formula I are of Formula IA:
  • A is N and the compounds of Formula II are of Forniu
  • A is CH and the compounds of Formula I are of Formula IB :
  • A is CH and the com ounds of Formula II are of Formula IIB:
  • R 1 in Formula I, Formula II, Formula III, and Formula is -Co-Cealk-Ci-Cealkyl, -Co-Cealk-Ci-Cehaloalkyl, -Co-Cealk-C-CIl -Co-C6alk-C ⁇ C-Ci- Cealkyl, -Co-C6alk-C ⁇ C-Ci-C6haloalkyl, -Co-C6alk-C ⁇ C-C 3 -C6cycloalkyl, -Ci-Cealk-aryl, -C 0 - Cealk-heteroaryl, -d-Cealk-O-heteroaryl, -Ci-Cealk-S-heteroaryl, or -Ci-Cealk-NH-heteroaryl.
  • R f i s -Co-Cealk-C i-Cealkyl for example, -Coalk-Cialkyl, -Cialk- Cialkyl, -C 2 alk-Cj.alkyl, -C 3 alk-Cj.alkyl, -C 4 alk-Cialkyl, -Csalk-Cialkyl, -Cealk-Cialkyl, -Coalk- C 2 alkyl, -Cialk-Csalkyl, -C 2 alk-C 2 alkyl, -C 3 alk-C 2 alkyl, -C 4 alk-C 2 alkyl, -Csalk-C 2 alkyl J -Ce.alk- C alkyl, -Coalk-Csalkyl, -Cialk-Csalkyl, -Cialk-Csalkyl, -Cialk-
  • R 1 is -Co-Cealk-Ci-Cehaloalkyl, for example, -Coalk-Cihaloalkyl, - Cialk-Cihaloa!kyl, -C alk-Cihaloalkyl, -Csalk-Cihaloalkyl, -Gialk-dhaloalkyl, -Csalk-dhaloalkyl, - dalk-Cihaloalkyl, -Coalk-C 2 haloalkyl, -Cialk-dhaloalkyl, -C 2 alk-C 2 haloalkyl, -dalk-Ohaloalkyl, - C 4 alk-C 2 haloalkyl, -dalk-dhaloalkyl, -C6alk-C 2 haloalkyl, -Coalk-dhaloalkyl, -dalkyl, -dal
  • R 1 is chloromethyl (i.e., -CH2-CI .) In some embodiments, R 1 is -CH(OH)d- C4haloalkyl. [0048] In some aspects, R 1 is -Co-C6alk-C ⁇ CH, for example, -Coalk-C ⁇ CH, -Cialk-C ⁇ CH , -C 2 alk-C ⁇ CH , -C 3 alk-C ⁇ CH , -C 4 alk-C ⁇ CH , -C 5 alk-C ⁇ CH , -Cealk-C ⁇ CH, ethynyl, propargyl, - CH(OH)-C ⁇ CH, -CH(F)-C ⁇ CH, -CH(NH 2 )-C-CH, -CH ⁇ Me)-C O i, -C(Me)(OH)-C ⁇ CH, and the like.
  • R 1 is for example, -Coalk-0 ⁇ €-Ciaikyl, -Cialk-C ⁇ C-Cialkyl, -C 2 alk-C ⁇ C-Cialkyl, -C 3 alk-C ⁇ C-Cialkyl, -C4alk-C ⁇ C-Ciafkyf, -Csalk-C ⁇ C- Cialkyl, -C6alk-C ⁇ C-Cialkyl, -Coalk-C-C-C 2 alkyl, -Cialk-C ⁇ C-C2alkyl, -C 2 alk-C ⁇ -C 2 alkyl, - C3alk-C ⁇ C-C 2 alkyl, -C4alk-C ⁇ C-C2alkyl, -C5alk-C ⁇ C-C 2 alkyl , -C6alk-C ⁇ C-C?.aikyi,
  • R 1 is -CH(OH)-C ⁇ C-CH 3 , -CH(F)-C ⁇ C-CH 3 , -CH( H 2 )-C ⁇ C-CH 3 , -CH(Me)-C ⁇ C-CH 3 , or -C(Me)(OH)-C ⁇ C-CH 3 .
  • R 1 is -CH(OH)-C ⁇ C-CH 3 .
  • R 1 is -CH(F)-C ⁇ C-CH 3 .
  • R 1 is -CH(NH 2 )-C ⁇ C-CH 3 . In some embodiments, R 1 is -CH(Me)-C ⁇ C-CH 3 . In other embodiments, R 1 is C! !(()[ i )(Me)-C C-C! h
  • R 1 is -Co-Cealk-C ⁇ -d-Cehaloalkyl, for example, -Coalk-C ⁇ C- Cihaloalkyl, -Cialk-C ⁇ C-Cihaloalkyl, -C 2 alk-C ⁇ -Cihaloalkyl, -C 3 alk-C ⁇ C-Cihaloalkyl, -C 4 alk- C ⁇ C-Cihaloalkyl, -C5alk-C ⁇ C-Cihaloalkyl, -C&alk-C ⁇ C-Cihaloafkyf, -Coalk-C ⁇ C-C 2 haloaikyi, - Cialk-C ⁇ -C 2 haloalkyi, - a!k-C C-dhaioa!kv!, -C 3 alk-C ⁇ -C 2 haloalkyl, -C 4 alk-C
  • oalkyl -Cialk-C ⁇ C- C4haioalkyl, -C2alk-C ⁇ C-C 4 haloalkyl, -C 3 alk-C ⁇ C-C4haloalkyl, -C4alk-C ⁇ C-C4haloalkyl, -Csalk- C ⁇ C-C 4 haloalkyl s -C6alk-C ⁇ C-C haloalkyl, -Coalk-C ⁇ C-C5haloalkyl, -C alk-GOCshaloalkyl, - C 2 alk-C ⁇ C-C5haioalkyl, -C 3 alk-C ⁇ C-C 5 haloalkyl, -C 4 alk-C ⁇ C-C5haloaikyI, -C 5 aik-C ⁇ C- Cshaloalkyl, -C6alk-C ⁇ C-C5haloalky
  • R 1 is - ( ' l i(Ol i )-( ' C-C ⁇ ( ⁇ ! ]( ) ⁇ (- C ' -( -CH(NH?.)-C ⁇ C-CF3, -CH(Me)-C ⁇ C-CF 3 , -C(Me)(OH)-C ⁇ C- CPs, and the like.
  • R 1 is -CH(OH)-C ⁇ C-CF3.
  • R 1 is -Co-C6alk-C ⁇ C-C 3 -C6cycloalkyl, for example, -Coalk-C ⁇ C- C 3 cycloalkyl, -Coalk-C ⁇ C-C4cycloalkyl, -Coalk-C ⁇ C-C5cycloalkyl, -Coalk-C ⁇ C-C6cycloalkyl, - Cialk-C ⁇ C-C 3 cycloalkyl, -Cialk-C ⁇ C-C4cycloal kyl , -Cial k-C ⁇ C-Cs-cycloalkyl, -Cialk-C ⁇ C- Cecycloalkyl, -C 2 alk-C ⁇ C-C 3 cycloalkyl, -C2alk-C ⁇ C-C4cycloalkyl, -C2alk-C ⁇ C-C5cycloalkyl, - C2alk
  • R 1 is -CH(OH)-C ⁇ C-cyclopropyl , -CH(F)-C ⁇ C- cyclopropyl, -CH(NH2)-C ⁇ C-cyclopropyl, -CH(Me)-C ⁇ C-cyclopropyl, -C(Me)(OH)-C ⁇ C- cyclopropyl, and the like.
  • R 1 is -CH(OH)-C ⁇ C-cyclopropyl.
  • R 1 is -Ci-Cealk-aryl, for example, -Cialk-aryl, -C 2 alk-aryl, -C alk- aiyl, -C salk-arvl, -Csalk-aryl, -Cealk-aryl, -CHzaryl, -CH(OH)-aryl, -C]T(F)-aryl, -CH(Nil2)-aryl, - CH(Me)-aryl, -C(Me)(OH)-aryl, -C(CF 3 )(OH)-aryl and the like.
  • R 1 is -Ci-Cealk-aryl
  • the -aryi is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, ⁇ 3-ffuoro-4 ⁇ chlorophenyl, -3-chloro-4-fluorophenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3- methylphenyl, 2,4-difluorophenyl, 2-hydroxymethyl-4-chlorophenyl, 2-hydroxymethyl-5- chlorophenyl, 2-aminomethy 1 -4-chl oropheny!, 2-(methy 1 aminomethy 1 )-4-chl oropheny!, 2- hydroxymethyl-4,5-difluorophenyl, 2-aminomethyl-4,5-difluorophenyl, or 2-(methylaminomethyl)- 4,5-difluorophenyl
  • R 1 is -CH -di fluorophenyl, -CHb-3,4- difluorophenyl, -CH2-4-chlorophenyl, -CH 2 -3-chloro-4-fluorophenyl, -CH2-4-chloro-3 -fluorophenyl, -CH 2 -dichlorophenyl, -CH 2 -3,4-dichlorophenyl, -CH 2 -3-fluoro-4-(trifluoromethyl)phenyl, or -CH 2 - 4-chloro-3 -methylphenyl, -CH2-2,4-difluorophenyl, -CH2-2-hydroxymethyl-4-chlorophenyl, -CH?-2- hydroxymethyl-5-chlorophenyl, -CH 2 -2-aminomethyl-4-chlorophenyl, -CFfe-2- (methylaminomethyl)-4-chlorophenyl,
  • R 1 is -Co-Ceaik-heteroaryl, for example, -Coalk-heteroaryl, -Cialk- heteroaryl, -C 2 alk-heteroaryl, -C 3 alk-heteroaryl, -C 4 alk-heteroaryl, -Csalk-heteroaryl, and -Cealk- heteroaiyl.
  • R 1 is 2-(2-amino-3-bromoquinolin-7-yl)ethyl, 2-(2-amino-3- chloroquinolin-7-yl)ethyl, 2-(2-((cyclopropylmethyl)amino)quinolin-7-yl)ethyl, 2-(2- (methylamino)quinolin-7-yl)ethyl, or 2-(2-aminoquinolin-7-yl)ethyl.
  • R 1 is -Ci-Cealk-O-heteroaryl, for example, -Cialk-O-heteroaryl , - C 2 alk-0-heteroaryl, -Csaik-Q-heteroaryl, -C 4 alk-0-heteroaryl, -Csalk-O-heteroaryl, and -Cealk-O- heteroaryl.
  • R 1 is ((2-amino-3-bromoquinolin-7-yl)oxy)methyl.
  • R 1 is -Ci-Cealk-S-heteroaryl, for example, -Cialk-S-heteroaryl, - C 2 alk-S-heteroaryl, -C3alk-S-heteroaryl, -C4alk-S-heteroaryl, -Csalk-S-heteroaryl, and -Cealk-S- heteroaryi.
  • R ! is ((2-amino-3-bromoquinolin-7-yl)thio)methyl.
  • R 1 is -C ⁇ -Cealk- H-heteroaryl , for example, -Cialk-NH-heteroaryl, -C 2 alk-NH-heteroaryl, -C 3 alk- H-heteroaryl, -C4alk-NH-heteroaryl, -Csalk- H-heteroarj'l, and - C6alk- H-heteroaryl.
  • R 1 is ((2-amino-3-bromoquinolin-7-yl)amino)methyl.
  • R 5 is H, halo, -Ci-Cealkyl, or NFb.
  • R 5 is H.
  • R 5 is halo, for example F, Ci, Br, or I, with -CI being preferred.
  • R s is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, i sobutyl, s-butyl, t-butyl, pentyl, and the like.
  • R 5 is methyl (Me).
  • R 5 is H 2 .
  • R b is H, halo, -Ci-Cealkyl, -Ci-C 6 haloalkyl, or -Co-Cealk-Cj-Cecycioalkyl,
  • R b is H.
  • R 6 is halo, for example F, CI, Br, or I. In some embodiments,
  • R 6 is F.
  • R 6 is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. In some embodiments, R 6 is methyl.
  • R b is -Ci-Cehaloalkyl, for example, -CF 3 or -CHF 2 .
  • R 6 is -Co-C6alk-C 3 -C6cycloalkyl, for example, for example, for example -Coalk-Cjcycloalkyl, -Cialk-Cscycloalkyl, -C 2 alk-C 3 cycloal kyl, -C 3 alk-C 3 cycloalkyl, -C 4 alk- C3cycioalkyl, -Csaik-Cscycloalkyl, -Cealk-Cscycloalkyl, -Coalk-C 4 cycloalkyl, -Ciaik-C4cycloaikyl, - C 2 alk-C 4 cycloalkyl, -C 3 alk-C4cycloalkyl, -C 4 alk-C 4 cycloalkyl, -Csalk-C4cycloalkyl , -Cealk- C 4
  • R 2 is H, halo, -CJ - Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-C 3 -C6cycloalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Cealky , -Co- Cealk-Mfc, -Co-Cealk- H-C i -Cealkyl, -Co-C 6 alk-N(C i-Cealky -Ci-Cealkyi, -Co-Cealk-NH-Cs- Cecycloalkyl, -Co-Cealk-NCCi-Cealkylj-Cs-Cecycloalkyl, -Co-Cealk-heteroeycloalkyl, heteroaryl, or - CN.
  • R 2 is H.
  • R 2 is halo, for example, F, CI, Br, or I, with F, CI, and Br being preferred and F and CI being more preferred.
  • R 2 is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.
  • z is methyl.
  • R 2 is -Ci-Cehaloalkyl, for example, -CF 3 or -CHF 2 .
  • R 2 is -Co-C&alk-Cs-Cecyeloalkyl, for example, -Coalk- Cscycloalkyl, -Cialk-Cscycloalkyl, -C2.alk-C3cycloalkyl, -C 3 alk-C3cycloalkyl, -C 4 alk-C 3 cycloalkyl, - Csal k-Cscycloalkyl s -Ceal k-C 3 cycloalkyl, -Coalk-C 4 cycloal ky] , -Gal k-C 4 cycloalkyl, -C 2 alk- C 4 cycloalkyl, -C 3 alk-C 4 cycloalkyl, -C 4 al
  • R 2 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-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OG-Gsalkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyl), and halo (e.g., F or CI).
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OG-Gsalkyl e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -
  • R 2 is -Co-Cealk-OH, for example, -Coalk-OH, -dalk-OH, -C 2 alk- OII, -Csalk-OH, -C4alk-OH, -Csalk-OH, or -Cealk-OH.
  • R 2 is -Co-C&alk-O-Ci-C&alkyl, for example, -Coalk-O-Cialkyl, - Cialk-O-Cialkyl, -C 2 alk-0-Cialkyl, -Csalk-O-Cialkyl, -C4alk-0-Cialkyl, -Csalk-O-Cialkyl, -Cealk- O-Cialkyl, -Coalk-O-Galkyl, -Cialk-0-C2alkyl, -Gmlk-O-Galkyl, -C 3 alk-0-C2alkyl, -C 4 alk-0- C 2 alkyl, -Csalk-0-C2alkyl, -Cealk-O-Gmlkyl, -Coalk-O-Csalkyl, -Cialk-O
  • R 2 is -Co-Cealk-NH-Ci-Cealkyl, for example, -Coalk-NH- alkyl, - Cialk-NFI-Cialkyl, -C2aik-NFI-Ciaikyi, -Csalk-NH-Cialkyl, -C 4 aik-NH-Ciafkyf, -Csalk-NH-Cialkyl , -Cealk- H-Cialkyl, -Coalk- H-C2alkyl, -Galk-NH-Gialkyl, -C ⁇ -aik- ⁇ ! l-C-aikvi.
  • R 2 is - €VC6alk-N(Ci-C6alkyl)-C --Cealkyl, for example, -Coalk- N(Ci-C6alkyl)-Cialkyl, -Cialk-N(Ci-C6alkyl)-Cialkyl, -C2alk-N(Ci-C6alkyl)-Cialkyl, ⁇ C u;i k- ⁇ iCV Cealky -Cialkyl, -C4alk-N(Ci-C6alkyl)-Cialkyl, -C5alk-N(Ci-C6alkyl)-Cialkyl , -Cealk- N(Ci- Cealky -Cialkyl, -Coalk- N(Ci-C6alkyl)-C 2 alkyl, -Cialk-N(Ci-C6alkyl)
  • R 2 is -Co-Cealk-NH-CB-Cecycloalkyl, for example, -Coalk-NH- C 3 cycloalkyl, -Cialk-NH-C3cycloalkyl, -C 2 alk-NH-C 3 cycloalkyl, -C 3 alk-NH-C 3 cycloalkyl, -C4aik- NH-C3cycloalkyl, -Csalk- H-Cscycloalkyl t -C 6 alk-NH-C3cycloalkyl, -Coalk-NH-C4cycloalkyl, - Cialk- H-C4cycloalkyl, -C2alk-NH-C4cycloalkyl, -C3alk-NH-C 4 cycloaikyi, -C 4 aik-NH- C icycioa!kyL -C5alk
  • R 2 is -Co-Ceaik- NH-Cs-Cficycloal kyl
  • the cycloalkyl is unsubstituted.
  • the cycloalkyl is substituted with one, two, or three R substituents independently selected from d-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -Od-dalkyl (e.g., - Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).
  • d-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -Od-dalkyl e.g., - Omethyl, -Oethyl, -Opropyl, -Oiso
  • R 2 is -( j-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, for example, - Coalk-N(Ci -C6alkyl)-C3cycIoalkyl, -Cialk-N(d-C6alkyl)-C3cycloalkyl, -dalk- Ci-Cealkyl)- C3cycloalkyl, -C3al k-N(Ci-C6alkyl)-C3cycloalkyl, -C4alk-N(Ci-C6alkyl)-C3cycloalkyl, -Csalk-N(Ci- C6alkyl)-C3cycloalkyl , -C&alk-N(Ci-C6alkyl)-C3cycloalkyl, -Coalk-N(Ci-C6alkyl)-
  • R 2 is -Co- C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl
  • the cycloalkyl is unsubstituted.
  • R 2 is -Co-Cealk-NiCi-Cealkylj-C -Cecycloalkyl
  • the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-dalkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), - Od-dalkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).
  • Ci-dalkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • R 2 is -Co-Ceal k-heterocycloalkyl, for example, -Coal k- heterocycloalkyl, -C i -Cealk-heterocycloaikyi, -C j -dalk-heterocy cl oalkyl, -C i-C alk- heterocycloal ky] , -d-dalk-heterocycl oalkyl, -d-dalk-heterocycloalkyl, or -Cial k- heterocycloalkyl.
  • heterocvloalkyl moieties include, for example piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and oxetanyl .
  • R 2 is -Co-Cealk-heterocycloaikyl
  • the heterocycloalkyl is unsubstituted.
  • R 2 is -Co-Cealk-heterocyeloalkyl
  • the heterocycloalkyl is substituted with one, two, or three R substituents independently selected from d-dalkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -Gd-daikyi (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or Cl ),
  • d-dalkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -Gd-daikyi e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl
  • halo e.g.,
  • R 2 is heteroaryi, for example furanyl, imidazolyi, and pyrazoiyl. In some aspects wherein R 2 is heteroaryi, the heteroaryi is unsubstituted. In other aspects wherein R 2 is heteroaryi, the heteroaryi is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., - Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-Cealkyl e.g., - Omethyl, -Oethy
  • R 2 is -CN.
  • R 3 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cj-Cecycloalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Cealkyl, -Co-Cealk-NEb, -Co-Cealk-NH-Ci-Cealkyl, -Co-C 6 alk-N(Ci-C6alkyl)-Ci- Cealkyl, -Co-Cealk-NH-C ⁇ Cecycloalkyl, -Co-Cealk-NCCi-Cealky -Ci-Cecycloalk l, -Co-Cealk- heterocycioalkyl, heteroaryl, or -CN.
  • R 3 is H.
  • R 3 is halo, for example, F, CI, Br, or I, with F, CI , and Br being preferred and F and CI being more preferred.
  • R 3 is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl , butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.
  • R 3 is -Ci-Cehaloalkyl, for example, -CF 3 or ( ⁇ If ⁇
  • R J is -Co-C&alk-Cs-Cecyeioalkyl, for example, -Coalk- CjCycloalkyl, -Cialk-Cscycloalkyl, -C 2 alk-C 3 cycloalkyl, -C 3 alk-C 3 cycloalkyl, -C 4 alk-C 3 cycloalkyl, Csalk-C3cycloalkyl s -Cealk-Cscycloalkyl, -Coalk-C 4 cycloalkyl, -Cialk-C4cycloalkyl, -C 2 alk- C 4 cycloalkyl, -C 3 alk-C 4 cycloalkyl, -C 4 alk-C 4 cycloalkyl, -Csalk-Ocycloalkyl, -Cealk-Ocycloalkyl, Coalk-C
  • R 3 is -Co-C6alk-C3-C6cycloaikyi
  • the cycloalkyl is unsubstituted.
  • the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyl), and halo (e.g., F or CI).
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-Cealkyl e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl,
  • R 3 is -Co-Cealk-OH, for example, -Coalk-OH, -Cialk-OH, -C 2 alk- OH, -Csalk-OH, -C+alk-OH, -Csalk-OH, or -Cealk-OH.
  • R J is -Co-Cealk-O-Ci-Cealkyl, for example, -C 0 alk-O-Cj.alkyl, - Cial k-O-Cialkyl, -Cialk-O-Cialkyl, -Csalk-O-Cialkyl, -C 4 alk-0-Cialkyl, -Csalk-O-Cialkyl , -Cealk- O-Cialkyl, -Coalk-0-C 2 alkyl, -Cialk-0-C?.alkyl, -Czalk-O-C aikyi, -C 3 alk-0-C2alkyl, -C 4 alk-0- Cialkyl, -Csalk-O-Cialkyl, -Cealk-O-Cialkyl, -Coalk-O-Csalkyl
  • R 3 is Co-Cealk-Ntk, for example, -Coalk-NHb, -Cialk-NHi, -C 2 alk- -I2, -Csalk-NIfc, -C ;a! k- ⁇ ! ! -. -C 5 alk-NH 2 , or (V.ai k-Xl f
  • R 3 is -Co-Cealk-NH-Ci-Cealkyl, for example, -Coal k-NH-Cial kyl, - Cialk- H-Cialkyl, -C 2 alk-NH-Cialkyl, -Csalk- H-Cialkyl, -C4alk-NH-Ciaikyi, -Csalk- H-Cialkyl, -Cealk-NH-C lalkyl, -Coalk-NH-CSalkyl, -C lalk-NI-I-CSalkyl, -CSalk-NI-I-CSalkyl, -Csalk-NH- C 2 alkyl, -C4alk-NH-C2alkyl, -Csalk-NH-Cialkyl, -Cealk-NH-Cimlkyl, -Coalk- H-Csalkyl, -Coal
  • R 3 is -Co-C6alk-N(Ci-C6alkyl)-Ci-C6alkyl, for example, -Coaik- N(Ci-C6al ky])-Cialkyl, -Cialk-N(Ci-C6alkyl)-Cialkyl, -C2alk-N(Ci-C6alkyl)-Cialkyl, -Csalk-N(Ci- C-.alkvD-C ialkvl.
  • R J is -Co-Cealk- H-Cs-Cecycloalkyl, for example, -Coalk- H- Cjcycloalkyl, -Cialk-NH-Cscycloalkyl, -Cialk-NH-C cycloalkyl, -C 3 alk-NH-C 3 cycloalkyl, -Csalk- H-C3cycloalkyl, -Csalk-NH-Cscycloalkyl, -Ceaik-NH-Cscycioalkyl, -Coalk-NH-C4cycloalkyl, - Cialk- H-C4cycloalkyl, -Caalk-NH-C ⁇ cycloalkyl, -C 3 alk- H-C4cycloalkyl, -C ⁇ alk-NH- C4cycloalkyl, -C5alk- H-C4cyclo
  • R 3 is -Co-Ce.alk- NH-Cs-Cecycloalkyl
  • the cycioalkyl is unsubstituted.
  • the cvcloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Ceaikyi, (e.g., methyl, ethyl, propyl, isopropyi, butyl), -OCi-Cealkyl (e.g., - Om ethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).
  • Ci-Ceaikyi e.g., methyl, ethyl, propyl, isopropyi, butyl
  • -OCi-Cealkyl e.g., - Om ethyl, -Oethyl
  • R 3 is -Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloaikyi, for example, - Coalk-N(Ci-C6alkyl)-C3cycloalkyl, -Cialk-N(Ci-C 6 alkyl)-C3cycioalkyl, -C2aik-N(Ci-C 6 alkyl)- C3cycloalkyl, -C3al k-N(Ci-C6alkyl)-C3cycloalkyl, -C4alk-N(Ci-C6alkyl)-C3cycloalkyl, -Csalk-N(Ci- C6alkyl)-C3cycloalkyl , -C6alk-N(Ci-C6alkyl)-C3cycloalkyl, -Coalk-N(Ci-C6alkyl)-C3cycl
  • R 3 is -Co- C6alk-N(Ci-C6alkyl)-C 3 -C6cycloalkyl
  • the cycioalkyl is unsubstituted.
  • W is -Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloarkyl
  • the cycioalkyl is substituted with one, two, or three R substituents independently selected from d-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), - OCi-Cealkyl (e.g., -Omethyl, -Oethyi, -Opropyl, -Oisopropyi, -Obutyi), and halo (e.g., F or Ci).
  • d-Cealkyl e.g., methyl, ethyl, propyl, is
  • R 3 is -Co-Cealk-heterocycloalkyl, for example, -Coalk- heterocycloalkyl, -Ci-Ceaik-heterocycloalkyl, -C i-Csalk-heterocy cioalkyl, -Ci-C 4 alk- heterocycloalkyl, -C 1 -C 3 alk-heterocycloalkyl, -C 1 -C 2 alk-heterocycloalkyl, or -Cialk- heterocycloalkyl.
  • Preferred heterocyioalkyl moieties include, for example piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanvl, pyrrolidinyl, tetrahydroturanyl, tetrahydropyranyl, and oxetanvl.
  • R 3 is -Co-Cealk-heterocycloalkyl
  • the heterocycloalkyl is unsubstituted.
  • R 3 is -Co-Cealk-heterocycloalkyl
  • the heterocycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Ce.alkyi, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyi, -Opropyl, -Oisopropyi, -Obutyi), and halo
  • R 3 is heteroaryi, for example furanyl, imidazolyi, and pyrazoiyl.
  • the heteroaryi is unsub tituted.
  • the heteroaryi is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., - Omethyl, -Oethyi, -Opropyl, -Oisopropyi, -Obutyi), and halo (e.g., F or CI).
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-Cealkyl e.g., - Omethyl, -Oethyi, -Opropyl, -Oisopropyi,
  • R 3 is -CN.
  • R 4 is H, halo, -Ci-Cealkyl, -Ci-Cehaloaikyi, -Co-Cealk-Cs-Cecycioalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Cealkyl, -Co-Cealk-NIfc, -Co-Cealk-NH-Ci-Cealkyl, -Co-Cealk-NiCi-Cealky -Ci- Cealkyl, -Co-Cealk- H-Cs-Cecycloalkyl, -Co-Cealk-NCCi-Cealky -Cs-Cecycloalkyl, -Co-Cealk- heterocycloalkyl, heteroaryi, or -CN.
  • R 4 is H.
  • R 4 is halo, for example, F, CI, Br, or I, with F, CI, and Br being preferred and F and CI being more preferred.
  • R 4 is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.
  • R 4 is -Ci-Cehaloaikyi, for example, -CF 3 or -CHF?..
  • R 4 is -Co-Cealk-C -Cocycloalkyl, for example, -Coalk- C 3 cycloalkyl, -Cialk-C cycloalkyl, -C 2 alk-C 3 cycloalkyl, -C 3 alk-C3cycloalkyl, -C4alk-C 3 cycloalkyl, - Cialk-C- cycloalkyl, -Cealk-O cycloalkyl, -Coalk-C4cycloalkyl, -Cialk-C4cycloalkyl, -C?.alk- C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk-C4cyc!oalkyl, -C5alk-C4cycloalkyl ( -C6alk ⁇ C4cycloalkyl, - Coal k-
  • R 4 is -Co-Cealk-Cs-Cecycloalkyl
  • the cycloalkyl is unsubstituted.
  • the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyl), and halo (e.g., F or CI).
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-Cealkyl e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl,
  • R 4 is -Co-Cealk-OH, for example, -Coalk-OH, -Cialk-OH, -C 2 alk- OH, -Csalk-OH, -Qalk-OH, -Csalk-OH, or -Cealk-OH.
  • R 4 is -Co-Cealk-O-Ci-Cealkyl, for example, -Coalk-O-Cialkyl, - Cialk-O-Cialkyl, -C 2 alk-0-Cialkyl, -Csalk-O-Cialkyl, -C 4 alk-0-Cialkyl, -Csalk-O-Cialkyl, -Cealk- O-Cialkyl, -Coalk-0-C2alkyl, -Cialk-0-C 2 alkyl, -C 2 alk-0-C2alkyl, -C 3 alk-0-C2alkyl, -C 4 alk-0- C 2 alkyl, -C5alk-0-C2alkyl, -C6alk-0-C2alkyl, -Coalk-O-Csalkyl, -Cialk-O-Csalkyl,
  • R 4 is -Ci-Cealk-Nft, for example, -Coalk-Ntb, -Cialk-NH 2 , - C 2 alk-NH2, -Csalk-NIfe, -C 4 alk-NH2, -C 5 aik-NH 2 , r - ( ⁇ .aik-M l.v
  • R 4 is -Co-Cealk-NI-I-Ci-Cealkyl, for example, -Coalk-NH-Cialkyl, - Cialk-NH-Cialkyl, -C2alk-NH-Cialkyl, -Csalk-NH-Cialkyl, -C4alk-NH-Cialkyl, -Csalk-NH-Cialkyl, -Cealk-NH-Cialkyl, -Coalk- H-C2alkyl, -Cialk- H-C2alkyl, -C2alk- H-C2alkyl, -Oak- M i- C 2 alkyl, -O u)lk-NM-0 *lkyl, -0 ⁇ alk-NM-C *lkyl , -Cealk-NH-iialkyl, -Coalk-NH-NH-NH-NH-Ci
  • -C4alk-NH-C4alkyl -Csalk-NH ⁇ alkyl, -Cealk-NH-Cialkyl, -Coalk-NH-Csalkyl, -Ciaik-NH- Csalkyl, -Cialk-NH-Csalkyl, -C3alk-NH-C 5 alkyl, -Csalk-NH-Csalkyl , -C V.al k- H-Csalkyl, -Coalk- H-Cealkyl, -Cialk- H-Cealkyl, •• C -al k- ⁇ ! l-(Vai kvi. -Csalk- H-Cealkyl, - -Csalk-NH-Cealkyl, and -Cealk-N -Cealkyl.
  • R 4 is -Co-C6alk-N(Ci-C6alkyl) ⁇ Ci-C6alkyl, for example, -Coalk- N(Ci-C6alkyl)-Cialkyl, -Cialk-N(Ci-C6alkyl)-Cialkyl, -(ialk-NiCi-Cealkylj-Cialkyl, -C 3 alk-N(Ci- Cealky -Cialkyl, -C4alk-N(Ci-C6alkyl)-Cialkyl, -C5alk-N(Ci-C6alkyl)-Cialkyl, -Cealk- N(Ci- Cealky -Cialkyl, -Coalk- N(Ci-C6alkyl)-C2alkyl, -Cialk-N(Ci-C6alkyl)-C2alkyl
  • ks i -Coalk-NiCi-Cealkylj-Cealkyl, -Cialk-N(Ci- C&alkyl)-C&alkyl, -C2alk-N(Ci-C6alkyl)-C6alkyl, -C3alk-N(Ci-C6alkyl)-C6alkyl, -C4alk-N(Ci- ( ' .-.alkvl ) -C.-.alkvk -C 5 dk-N(Ci-C6alkyl)-C6alkyl , -Cealk-NCCi-Cealky -Cealkyl and the like.
  • R 4 is -Co-Cealk-NH-Cs-Cficyeloalky], for example, -Coal k-NH- Cscycloalkyl, -Cialk-NH-Cscycloalkyl, -C 2 alk ⁇ H-C3cycloalkyL -Csalk-NH-Cscycloalkyl, -C 4 aik- NH-C3cycloalkyl, -C5alk-NH-C 3 cycloalkyl 1 -Cealk-NH-Cscycloalkyl, -Coalk-NH-C 4 cycloalkyl, - Cialk-NH-C4cycloalkyl, -C 2 alk ⁇ NH-C4cycloalkyL -C3alk-NH-C4cycloalkyl, -C 4 aik- H- C 4 cycloalkyl, -C5alk-NH-C 4
  • aikyi - Csalk-NH-Cscycloalkyl , -Cealk-NH-Cscycloalkyl, -Coalk-NH-Cecycloalkyl, -Cialk-NH- C&cycloalkyl, -C2alk-NH-C6cycloalkyi, -Csalk-NH-Cecycloalkyl, -C4alk-NH-C6cycloalkyl, -Csalk- NH-Cecycloalkyl , -Cealk- H-Cecycloalkyl, and the like.
  • R 4 is -Co-Cealk- NH-C3-C 6 cy cl oalkyl
  • the cycloalkyl is unsubstituted.
  • R 4 is -Co-Cealk-NH- C3-C6cycioalkyl
  • the cycloalkyl is substituted with one, two, or three R substituents independently- selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -Od-Cealkyl (e.g., - Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyi), and halo (e.g., F or Cl).
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • R 4 is -Co-C&alk-N(Ci-C&alkyl)-C3-C6cycloalkyl, for example, - Coalk-N(Ci-C6alkyl)-C3cycloalkyl, -Cialk-N(Ci-C 6 alkyl)-C3cycloalkyl, -C 2 alk-N(Ci-C6alkyl)- Cscycloalkyl, -C3alk-N(Ci-C6alkyl)-C3cycloalkyl, -C4alk-N(Ci-C6alkyl)-C3cycloalkyl, -Csalk-NiCi- Cealky -Cscycloalkyl , -Cealk-NCCi-Cealky -Cscycloalkyl, -Coaik-N(Ci-C6aikyi)-C4cycloalkyl
  • R 4 is -Co- C6aik-N(Ci-C6alkyl)-C3-C6cycioalkyl
  • the cycloalkyl is unsubstitirted.
  • R 4 is ⁇ Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyi
  • the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Ceaikyi, (e.g., methyl, ethyl, propyl, isopropyl, butyl), - OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).
  • Ci-Ceaikyi e.g., methyl, ethyl, propyl, iso
  • R 4 is -Co-Cealk-heterocycloalkyl, for example, -Coalk- heterocycloalkyl, -Ci-Ceaik-heterocycloalkyl, -C i-Csalk-heterocy cioalkyl, -Ci-C4alk- heterocycloalkyl, -C 1 -C 3 alk-heterocycloalkyl, -C 1 -C 2 alk-heterocycloalkyl, or -Cialk- heterocycioalkyl.
  • Preferred heterocyloalkyl moieties include, for example, piperidinyi, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrrolidinyl, tetrahydrofurany], tetrahydropyranyl, or oxetanyl.
  • R 4 is -Co-Cealk-heterocycloalkyl
  • the heterocycloalkyl is unsubstituted.
  • R 4 is -Co-Cealk-heterocycloalkyl
  • the heterocycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-Cealkyl e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl
  • halo e.g., F or
  • R 4 is heteroaryi, for example furanyl, imidazolyl, and pyrazoiyl. In some aspects wherein R 4 is heteroaryi, the heteroaryi is unsubstituted. In other aspects wherein R 4 is heteroaryi, the heteroaryi is substituted with one, two, or three R substituents independently- selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., - Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).
  • R 2 , R 3 , and R 4 are each H.
  • R 2 and R 3 together with the atoms to which they are attached, form a C3- Ceeycloalkenyl ring, for example, cyciopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.
  • R 2 and R 3 together form a triple bond.
  • R 3 and R 4 together with the atom to which they are attached, form a Cs-Cecycloalkyl ring or a heterocvcloalkyl ring.
  • R J and R 4 together with the atom to which they are attached, form a Cs-Ce.cyeloalkyl ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexvl.
  • R 3 and R 4 together with the atom to which they are attached, form a heterocvcloalkyl ring, for example, piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyi, or oxetanyi.
  • a heterocvcloalkyl ring for example, piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyi, or oxetanyi.
  • R 7 is halo, -Ci-Cealkyl, -Ci-C4haloalkyl, -Cs-Cecycloaikyi, -Cs-Cehalocycloalkyi, -C2- C4alkenyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-C6alk-C(0)-Ci-C 6 alkyl, -CVC ⁇ alk-N((V( V.alkyl )R s .
  • R' is halo, for example, F, CI, Br, or I.
  • R'' is -CI.
  • R 7 is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl and the like.
  • R'' is methyl.
  • R 7 is -d-CAaloalkyl, for example, -CF3 or -CHF2, - CH2CH2CI, -CH2CH2F, or -CH2CHF2.
  • R 7 is -CH2CH2C.
  • R'' is -CH2CH2F
  • R 7 is -CH2CHF2.
  • R 7 is -Cs-Cecycloalkyl, for example, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyciohexyi.
  • R 7 is cyclopropyl.
  • R is -Cj-Cehalocycloalkyl, for example chlorocyclopropyl, fluorocyclobutyl, bromocyciopentyl, iodocyciohexyi, and the like.
  • R 7 is ---Ci-Cealk-O-Ci-Cealkyl, for example, -Cialk-O- Cialkyl, -C 2 alk-0-Cialkyl, -Csalk-O-Cialkyl, -C4alk-0-Cialkyl, -Csalk-O-Cialkyl, -Cealk-O- Cialkyl, -Cialk-O-Cialkyl, -C2alk-0-C2alkyl, -Csalk-O-C i alkyl, -C4alk-0-C 2 alkyl, -Csalk-O- C 2 alkyl > -Cealk-O-Cialkyl, -Cialk-O-Csalkyl, - alk-O-Csalkyl, -Csalk-O-Csalkyl, - alk-O-Cs
  • R'' is ⁇ Ci-C6alk-C(0)-Ci-C6alkyl, for example, -Cialk-C(O)- Cialkyl, -C 2 a]k-C(0)-Cialkyl, -C 3 alk-C(0)-Cialkyl, -C4alk-C(0)-Cialkyl, -C 5 alk-C(0)-Cialkyl, - C.-.alk-( ' ⁇ ( ))-C ialkvl.
  • R 7 is -Ci-C6ark-N(Ci-C6alkyl)R 8 , for example, -Cialk- N(Cialkyl)R 8 , -C 2 alk-N(Cialkyl)R 8 , -C 3 alk-N(Cialkyl)R 8 , -C4alk-N(Ciaikyi)R 8 , -Csalk- N(Cialkyl)R 8 s -C&alk-N(Cialkyl)R 8 , -Cialk-N(C 2 alkyl)R 8 , -C 2 alk-N(C 2 alkyl)R 8 , -C 3 alk- N(C 2 alkyl)R 8 , -C4alk-N(C 2 alkyl)R 8 , ⁇ ( " : ⁇ a 1 k - ⁇ ⁇ ( ' 2 a 1 )
  • R 8 is methyl
  • R' is -CH 2 CH 2 -N(CH 3 ) 2 .
  • R 7 is -Ci-Cealk-S-Ci-Cealkyl, for example, -Cialk-S- Cialkyl, -C 2 alk-S-Cialkyl, -Csalk-S-Cialkyl, -C4alk-S-Cialkyl, -Csalk-S-Cialkyl, -Cealk-S-Cialkyl, - Cialk-S-C 2 alkyl, -C 2 alk-S-C 2 alkyl, -C 3 alk-S-C 2 alkyl, -C4alk-S-C 2 alkyl, -Csalk-S-Qalkyl, -Cealk-S- C 2 alkyl, -Cialk-S-C 3 alkyl, -C 2 alk-S-C 3 alkyl, -Oalk-S-Oa!k
  • R' is -Ci-Cealk-SfOVCi-Cealkyl, for example, -Cialk-S(O)- Cialkyl, -C 2 alk-S(0)-Cialkyl, -C 3 alk-S(0)-Cialkyl, -C4alk-S(0)-Cialkyl, -C 5 alk-S(0)-Cialkyl s - C6alk-S(0)-Ciaikyi, -Cialk-S(0)-C 2 alkyl, -C 2 alk-S(0)-C 2 alkyl, -C 3 alk-S(0)-C 2 alkyl, -C 4 alk-S(0)- C 2 alkyl, -C 5 alk-S(0)-C 2 alkyl s -C6alk-S(0)-C 2 alkyl, -Cialk-S(0)-C 3 alkyl, -C 2 a
  • R 7 is -Ci-C6alk-S(()) 2 -Ci-C6arkyl, for example, -Cialk- S(0) 2 -Cialkyl, -C 2 alk-S(0) 2 -Cialkyl, -C 3 alk-S(0) 2 -Cialkyl, -C4alk-S(0) 2 -Cialkyl, -Csalk-S(0) 2 - Cialkyl , -C6alk-S(0) 2 -Cialkyl, -Cialk-S(0) 2 -C 2 alkyl, -C 2 alk-S(0) 2 -C 2 alkyl, -C 3 alk-S(0) 2 -C 2 alkyl, - C4alk-S(0) 2 -C 2 alkyl, -C5alk-S(0) 2 -C 2 alkyl, -C6alk-S(0) 2 -C 2 alkyl
  • 11 is -CR 8 R 8 CN.
  • R is cyanomethyl (i.e., -C i K ' X ).
  • R' is -Nli-Ci-Cealk-S-Ci-Cealkyl, for example, ⁇ NH-Cialk S-Cialkyl, - H-C 2 alk-S-Cialkyl, -NH-C 3 alk-S-Cialkyl, -NH-C 4 alk-S-Cialkyl, -NH-Csalk-S- Cialkyl , -NH-Cealk-S-Cialkyl, - H-Cialk-S-C2alkyl, -XI l-C -aik -S-C.uiikyL -NH-C 3 alk-S-C 2 alkyl, H-C4alk-S-C 2 alkyl, -NH-C 5 alk-S ⁇ C 2 alkyl , -NH-Ceal k-S-Cialkyl, -NH-NH-Nli-Ceal
  • kyl -NH-C 3 alk-S ⁇ C4alkyl, - ⁇ 1 l-C iai k-S-C iai kyL NH-C 5 aik-S-C4alkyi, -NH-Cealk-S-Cialkyl, -NH-Cialk-S-Csalkyl, - i-Caalk-S-Csalkyl, -NH- Csaik-S-Csalkyl, -NH-C4alk-S-C 5 alkyl, - H-Csalk-S-Csalkyl , - H-Cealk-S-Csalkyl, -NH-Cialk-S- C&alkyl, -NH-C2alk-S-C6alkyl, -NH-Csalk-S-Cealkyl, -NH-Ciaik-S-Ceafkyl
  • R'' is -NH-Ci-C6alk-S(0)-Ci-C6alkyl, for example, -NH- Cial k-S(0)-Cialkyl, -NH-C2alk-S(0)-Cialkyl, -NH-C 3 alk-S(0)-Cialkyl, -NH-C4alk-S(0)-Cial kyl , NH-C 5 alk-S(0)-Cialkyl .
  • R 7 is - H-CH2CH_S(0)Me.
  • R 7 is -NH-Ci-C6alk-S(0)2-Ci-C6alkyl, for example, -NH- Cialk-S(0) 2 -Cialkyl, -NH-C2alk-S(0)2-Cialkyl, -NH-C 3 alk-S(0)2-Cialkyl, -NH-C 4 alk-S(0) 2 - Cial kyl , - H-Csalk-S(0)2-Cialkyl , -NH-Ceal k-S(0)2-Cialkyl, -NH-C ialk-S(0)2-C 2 alkyl, -NH- C2alk-S(0)2-C 2 aikyi, - H-C 3 alk-S(0)2-C2alkyl, -NH-C 4 aik-S(Q)2-C2alkyl, - H-C 5 alk-S(0) 2 - C 2 alkyl s -
  • R is -X H-C i -CXai k ⁇ X(( ' i -G.ai k ! )R K , for example, -NH- Cialk-N(Cialkyl)R 8 , -NH-C2alk-N(Cialkyl)R 8 , -NH-C3alk-N(Cialkyl)R 8 , -NH-C 4 alk-N(Cialkyl)R 8 , -NH ⁇ C 5 alk ⁇ N(Cialkyl)R 8 s -NH-C6alk-N(Cialkyl)R 8 , -NH-Cialk-N(C2alkyl)R 8 , -NH-C2alk- N(C 2 alkyl)R s , -NH-C3alk-N(C 2 alkyl)R s , -NH-C 4 alk-N(
  • R 7 is -NR 8 R 8 .
  • R 8 and R 8' are both H, R 7 is -NH2.
  • R'' is -NHCR 8 R 8 CN.
  • R 7 is -NHCH2CN.
  • R is - HCONR 8 R 8' .
  • R 7 is -NHCO H2.
  • R 8 and R 8 are both methyl
  • R 7 is -NHCON(CH 3 ) 2 .
  • R 8 i s H and R 8' is methyl
  • R 7 is -NHCO HCH3.
  • R 8 and R 8 together with the atom to which they are attached, form a or a five
  • R ? is - HC(S) R 8 R 8' .
  • 7 is -NHC(S)NH 2 .
  • R' is M fC( S)N(CI f ⁇ ) ⁇ .
  • R 8 is H and 8' is methyl, is M fC( S)M ⁇ k
  • R 7 i s - HC(0)OR 9 In some embodiments, R 7 i s - HC(0)OR 9 . Thus, in some embodiments wherein R 9 is methyl, R 7 is -NHC(0)OCH 3 .
  • R 7 is -NHC(S)OR y .
  • R 9 is methyl
  • R 7 is -NHC(S)OCH3.
  • R 7 is - HC(0)-Ci-C6alkyl, for example, -NHC(0)-Cialkyl, NHC(0)-C 2 al ky] , NHC(0)-C 3 alkyl, NHC(0)-C 4 alkyl, NHC(0)-C 5 alkyl, NHC(0)-C6alkyl,
  • R ? is -NHC(0)-m ethyl.
  • R is NHC(0) ⁇ Ci-C6haloalkyl, for example, -NHC(0)-Cihaloalkyl, NHC(0)-C 2 haloalkyl, NHC(Q)-C 3 haloalkyl, NHC(0)-C4haioalkyl, NHC(0)-C 5 haloalkyl, - NITC(0)-C0haloalkyl, -NHC(0)-chloromethyl, ⁇ NHC(0) ⁇ chloroethyl, -NHC(0)-fiuoromethyl, - NHC(0)-fluoroethyl and the like,
  • R 7 is for example, -NH-Cialk- C(0)-Ci-Cealkyl, -NH-C 2 alk-C(0)-Ci-C6alkyl, -X I I-C " 3 ⁇ 4ai k-C ( ⁇ >)- ⁇ ' i ⁇ c.alks i, -NH-C4alk-C(0)-Ci- Cealkyl, - H-C 5 alk-C(0)-Ci-C6alkyl, - H-C 6 alk-C(0)-Ci-C 6 alkyl, - H-Ci-C6alk-C(0)-Cialkyl, - NIT-Ci-C6alk-C(0)-C2alkyl, -NH-Ci-C6alk-C(0)-C 3 alkyl, - H-Ci-C6alk-C(0)-C4alkyl, -NH-Ci- Cealk-C(0)
  • R 7 i s -N-(3-Ci-C6alkyl)iniidazolidir!-2-one that is:
  • Ci-Cealkyl is methyl, ethyl, propyl, and the like. In some embodiments, Ci -Cealkyl is methyl, and R' is
  • R 8 and R 8 are each independently H, Ci-Cealkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, i sobutyl, s-butyl, t-butyl, pentyl, and the like), or -Co-Cealk-OCi-Cealkyl (e.g., Coalk-OCi- Cealkyl, Ci-Cealk-OCi-Cealkyl, Ci-Csalk-OCi-Cealkyl, Ci-C4aik-QCi-Cealkyl, Ci-Csalk-OCi- Cealkyl, Ci-Cialk-OCi-Cealkyl, Cialk-OCi-Cealkyl, Co-Cealk-OCi-Csalkyl, Co-C6alk-OCi-C4
  • R 8 is H or Ci-Cealkyl . In some embodiments, R 8 is H or Ci-Cealkyl.
  • R 8 and R 8 are each H.
  • R 8 and R 8 are each independently Ci-Cealkyl .
  • R 8 is methyl and R 8' is methyl.
  • R 8 is Ci-Cealkyl and R 8 is H.
  • R 8 is methyl and R 8 is H.
  • R 8 and R 8 are each independently -Co-Cealk-OCi -Cealkyl.
  • R s is -Co-Ceaik-OCi-Cealkyl and R 8 is H.
  • R 8 and R 8 together with the atom to which they are attached, form a Cs-Cecycloalkyl, for example, cyciopropyi, cyciobutyi, cyciopentyl, or cyclohexyl.
  • R 8 and R 8' together with the atom to which they are attached, form a or a five or six membered heterocyclic ring, for example, pyrrolidine, piperidine, morpholine, piperazine, or 4-methylpiperizine.
  • R 9 is -Ci-Ceal ky] , or -Co-Ceal k-Cs-Cecycloalkyl .
  • R 9 is Ci- Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyi, t-butyl, pentyi, and the like. Thus, in some embodiments, R 9 is methyl.
  • R 9 is Co-Cealk-Cs-Cecyeioalkyl, for example, -Coalk-Cscycloalkyl, -Cialk-C.3cycloalkyl, -C 2 alk-C3cycloalkyl, -C 3 alk-C 3 cycloalkyl, -C 4 alk-C 3 cycloalkyl, -Csalk- CiCycloalkyl , -Cealk-Cjcyc!oal ky] , -Coal k-C 4 cycloalkyl, -Cialk-C-tcycloal ky] , -C 2 al k-C 4 cycloalkyl, - C 3 alk-C 4 cycloalkyl, -C 4 alk-C 4 cycloalkyl, -Csalk-Ocycloalkyl, -C6alk-C 4 cycl
  • R 2 is -Co-Cealk-Cs-Cecycloalkyl
  • the cycloalkyl is unsubstituted.
  • the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyi, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI),
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-Cealkyl e.g., -Omethyi, -Oethyl, -Opropyl, -Ois
  • R 1 is -CH(OH)-Ci-C 6 al kyl , -CH(F)-Ci-C6alkyl, -CH( H 2 )-Ci-C6al kyl , -CH(Me)- Ci-Cealkyl, -C(Me)(OH)-Ci-C 6 alkyl, -CH(OH)-Ci-C6 haloalkyl, -CH(F)-Ci-C6 haloalkyl, - Cf [ , ⁇ -( ⁇ , -( ' ,, haloalkyl, ⁇ CH(Me)-Ci-C 6 haloalkyl, -C( e)(OH)-Ci-C6 haloalkyl, -CI [( ( )!
  • the disclosure is directed to compounds of Formula II or IV wherein R f is -Co-Cealk-heteroaryi, -Ci-Cealk-O-heteroaryl, -Ci-Cfialk-S-heteroaryl, or -Ci-Cealk- H-heteroaryl, and R 7 , is -Ci-Cealk-O-Ci-Cealkyl, -Ci-C6alk-C(0)-Ci-C 6 alkyl, -Ci-C6alk-N(Ci- Ceal kyl)R 8 , -Ci-Ceaik-S-Ci-Cealkyl, -Ci-C6alk-S(0)-Ci-C6alkyl, -Ci-C6alk-S(0)2-Ci-C6alkyl, - CR 8 R S' C , -NH-Ci
  • R 1 is -Co-Cealk-C-C-Ci-Cealkyl, -Co-Cealk-C-C-Cs- Cecycloalkyl, or -Ci-Ceaik-aryl;
  • R 7 is halo, -Ci-CAaloalkyl, -C 3 -C6cycloalkyl, -C2-C4alkenyl, -Ci Cealk-O-Ci-Cealkyl, -Ci-C6alk-C(0)-Ci-C6alkyl, -Ci-C6alk-N(Ci-C6alkyl)R 8 , -Ci-Cealk-S-Ci- C&alkyl, -NH-Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-C6alk-S(0)2-Ci-C6alkyl, -NHCR 8 R 8' CN,
  • the compounds of Formula IIB-1 are those wherein R 1 is - Co-C 6 alk-C ⁇ C-C3-C6cycloalkyl; R ? is halo, -Ci-Cihaloalkyl, -C3-C6cycloalkyl, -C2-C 4 alkenyl, -Ci Cealk-O-Ci-Cealkyl, -Ci-Ceafk-CCOVCi-Cealkyl, -Ci-C6alk-N(Ci-C6alkyl)R 8 , -Ci-Cealk-S-Ci- Cealkyl, - H-Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-C6alk-S(0)2-Ci-C6alkyl, -NHCR R 8' CN, - NIiCONR3 ⁇ 4 8' , -NIIC
  • the compounds of Formula IIB-1 are those wherein R 1 is - Ci-Ce.alk-aryl, and R is halo, -Ci-Cmaloalkyl, -C 3 -C6cycloalkyl, -C 2 -C 4 alkenyl, -Ci-Cealk-O-Ci- Cealkyl, -Ci-C6alk-C(0)-Ci-C 6 alkyl, -C!-C6alk-N(Ci-C6aikyi)R 8 , -Ci-Cealk-S-Ci-Cealkyl, - H-C G.alk-S-( ' i-G.alkyi.
  • R 1 is - Ci-Cealk-aryl wherein the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3- fluoro-4-chlorophenyl, -3-chloro-4-fluorophenyL 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3- methylphenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3-methylphenyl, 2,4-difluorophenyl, ' hydroxymethyl-4-chlorophenyl, 2-hydroxymethyl-5-chlorophenyl, 2-aminomethyl-4-chlorophenyl,
  • R is halo, -C 1 -C 4 haloalkyl, -C 3 - Cecycloalkyl, -C 2 -C4alkenyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-C6alk-C(0)-Ci-C 6 alkyl, -Ci-Ceaik-NfCi- Cealkyl)R 8 , -Ci-Cealk-S-Ci-Ceal kyl , - H-Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-C6alk-S(0)2-Ci-C6alkyl,
  • the compounds of Formula IDS-1 are those wherein R l is -CH 2 -difluorophenyl, -CH 2 -3,4-difiuorophenyl, -CH 2 -4-chlorophenyl, -CH -3-chloro-4- fluorophenyl, -CH? ⁇ 4-chloro-3-fluorophenyl, -CFb-dichlorophenyl, -CH2-3,4-dichiorophenyl, -CH2
  • compounds of Formula IIB-1 are those wherein R 1 is -CH(OH)-4-chl orophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)- 3-fIuoro-4-chlorophenyl, -CH(OH)-3-chloro-4-fluorophenyl, -CH(OH)-3-fluoro-4- (trifluoromethyl)phenyl, -CH(OH)-4-chloro-3-methylphenyl, -C(CF 3 )(OH)-4-chlorophenyl; and R 7 i s -halo, -Ci-C haloalkyl, -Cs-Cecycloalkyl, -C 2 -C 4 alkenyl, -Ci-Cealk-O-Ci-Cealkyl, -C
  • R 7 is -CI, -CH2CH2CI, cyclopropyl, vinyl, -CH2CH2-O-CH3, - ⁇ WI KC « ) )-CI h, -CI ⁇ !.
  • R l is -CH(OH)-4-cMorophenyl
  • R 7 is -CI, -CH2CH2CI, cyclopropyl, vinyl, -CH2CH2-O- C! h.
  • the disclosure is directed to compounds of formula ⁇ -!
  • R f is -Ci-Cealk-aryl
  • R 7 is halo, -Ci-C'Jhaloaikyi, -C 3 -C6cycloalkyl, -Ci-Cealk-O-Ci- Cealkyl, - HCR S
  • R 8' CN, -NH-CN, -NHCONR 8 R 8 , - HC(0)OR 9 , -NHC(G)-C!-C 6 alkyl, NHCfOV Ci-Cehaioalkyl, -NH-Ci-C6alk-C(0)-Ci-C6alkyl; and R 8 , R 8' , and R 9 have any of the values described above.
  • R 1 is - Ci-Cealk-aryf wherein the -aryl is -4-chlorophenyl, -3 ,4-dichl orophenyl, -3,4-difluorophenyi, -3- fluoro-4-chl orophenyl, -3-chloro-4-fluorophenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3- methylphenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3-methylphenyl, 2,4-difluorophenyl, 2- hydroxymethyl-4-chlorophenyl, 2-hydroxymethyl-5-chlorophenyl, 2-aminomethyl-4-chlorophenyl,
  • R'' is halo, -Ci-C 4 haloalkyl, -C 3 - Cecycloalkyl, -Ci-Cealk-O-Ci-Ceaikyi, -NHCR 8 R 8' CN, -NH-CN, -NHC()NR 8 R 8' , -NHC(0)()R 9 , - NHC(0)-Ci-C6alkyl, HC(0)-Ci-C 6 haloalkyl, -NH-Ci-C6alk-C(0)-Ci-C6alkyl; and R 8 , R 8' , and R 9 have any of the values described above,
  • compounds of Formula IIA-1 are those wherein R 1 is -CH(OH)-4-chl orophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, ⁇ CH(OH) ⁇
  • R 7 is halo, -Ci-C 4 haloalkyl, -C 3 - Cecycloalkyl, -Ci-Cealk-O-Ci-Cealkyl, -NHCR 8 R ' CN, - H-CN, -NHCO R 8 R 8' , -NHC(0)QR 9 , - NHC(0)-Ci-C 6 alkyl, NHC(0)-Ci-C6haloalkyl, -NH-Ci-C6alk-C(0)-Ci-C6al kyl ; and R 8 , R 8' , and R 9
  • R 1 is -Ci-Cealk-aryl
  • R 2 is H or -Ci-Cealkyl
  • the compounds of Formula IB-1 are those wherein R 1 is -Ci-Cealk-aryl, and R 2 is H.
  • the compounds of Formula IB-1 are those wherein R 1 is -Ci-Cealk-aryl, and R 2 is -Ci-Cealkyl.
  • R ! is -Ci - Cealk-aryl wherein the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro- 4-chlorophenyl, -3-chloro-4-fluorophenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3- methylphenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3-methylphenyl, 2,4-difluorophenyl, 2- hydroxymethyl -4-chlorophenyl, 2-hydroxymethyl-5-chlorophenyl, 2-aminomethyl -4-chlorophenyl, 2-(methylaminomethyl)-4-chlorophenyl, 2-hydroxymethyl-4,5-difluorophenyl, 2-amin
  • the compounds of Formula IB-1 are those wherein R ! is - CH 2 -difluorophenyl, -CH 2 -3,4-difluorophenyl, -CH 2 -4-chlorophenyl, -CH 2 -3-c-hloro-4-fluorophenyl, -CH 2 -4-chloro-3 -fluorophenyl, -CH 2 -dichlorophenyl, -CH_-3,4-dichlorophenyl, -CH2-3-fluoro-4- (trifluoromethyl)phenyl, or -C3 ⁇ 4-4-chloro-3-methylphenyl, -CH 2 -2,4-difluorophenyl, -CHi-2- hydroxymethyl -4-chlorophenyl, -CH 2 -2-aminomethyl -4-chlorophenyl, -CHb-2- (methylaminomethyl)-4-chloroph
  • compounds of Formula IB-1 are those wherein R f is -CH(OH)-4-cMorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)-
  • R 2 is H or methyl.
  • compounds of Formula IB-1 are those wherein R 1 is -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, or -CH(OH)-3-chloro-4- fluorophenyl, and R 2 is H or methyl.
  • R 1 is -Ci-Cealk-aryl
  • R 2 is H or -Ci-Cealkyl
  • the compounds of Formula IIIA are those wherein R 1 is -Ci-Ceafk-aryl, and R 2 is H.
  • the compounds of Formula IIIA are those wherein R 1 is -Ci-Cealk-aryl, and R 2 is -Ci-Cealkyl.
  • R 1 is -Ci- C 6 alk-aryl wherein the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro- 4-chlorophenyl, -3-chloro-4-fluorophenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3- methylphenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3-methylphenyl, 2,4-difluorophenyl, 2- hydroxymethyl -4-chlorophenyl, 2-hydroxymethyl-5-chlorophenyl, 2-aminomethyl -4-chlorophenyl, 2-(methylaminomethyl)-4-chlorophenyl, 2-hydroxymethyl-4,5-difluorophenyl, 2-aminomethyl
  • the compounds of Formula IIIA are those wherein R 1 is - CH 2 -difluorophenyl, -CH 2 -3,4-difluorophenyl, -CH 2 -4-chlorophenyl, -CH 2 -3-c-hloro-4-fluorophenyl, -CH 2 -4-chloro-3 -fluorophenyl, -CH 2 -dichlorophenyl, -CH2-3,4-dichiorophenyl, -CH2-3-fluoro-4- (trifluoromethyl)phenyl, or -CH 2 -4-chloro-3-methylphenyl, -CH 2 -2,4-difluorophenyl, -CH 2 -2- hydroxymethyl-4-chlorophenyl, -CH 2 -2-aminomethyl-4-chlorophenyl, -CHb-2- (methylaminomethyl)-4-ch
  • compounds of Formula ⁇ are those wherein R 1 is -CH(OH)-4-cMorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)-
  • compounds of Formula IIIA are those wherein R 1 is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, - CH(OH)-3 -fluoro-4-cMorophenyl, -CH(OH)-3 -cMoro-4-fluorophenyl, -CH(OH)-3 -fluoro-4- (trifluoromethyl)phenyl, -CH(OH)-4-chloro-3 -methyl phenyl , -C(CF 3 )(OH)-4-chlorophenyl ; and R 2 is H or methyl.
  • R f is -Co-Cealk-C-C-Ci-Cealkyl, -Co-Cealk-C-C-Cs- Cecycloalkyl, or -Ci-Cealk-aryl; and R 2 is H or -Ct-Cealkyl.
  • the compounds of Formula IA-1 are those wherein R 1 is and R 2 is H or -Ci-Cealkyl.
  • the compounds of Formula IA-1 are those wherein R 1 is -Co-C6alk-C ⁇ C-Ci- Cehaloaikyi, and R 2 is H or -Ci-Cealkyl.
  • the compounds of Formula IA-1 are those wherein R 1 is -Co-C6alk-C ⁇ C-C3-C6cycloalkyl, and R 2 is H or -Ci-Cealkyl.
  • the compounds of Formula IA-1 are those wherein R 1 is -Ci- ( ' •-.alk-aryl. and R 2 is H. In other embodiments, the compounds of Formula IA-1 are those wherein R 1 is -Ci-Cealk-aryl, and R 2 is -Ci-Cealkyl.
  • the disclosure is directed to compounds of formula IV- A
  • R 1 is -Ci-Cealk-aryl
  • R 7 is halo, -d-Ohaloalkyl, -C 3 -C6cycloalkyl, -C 2 -C 4 alkenyl, -Ci- Ceal k-O-Ci-Cealkyl, -Ci-C6alk-C(0)-Ci-C6alkyl, -Ci-Ceaik-NrCi-Cealkyl)]!
  • the compounds of Formula IV- A are those wherein R 1 is - Ci-Cealk-aryl, and R' is halo, -Ci-C4haloalkyl, -Cs-Cecycloaikyi, -C 2 -C 4 alkenyl, -Ci-Cealk-O-Ci- Cealkyl, -Ci-C6alk-C(0)-Ci-C 6 alkyl, -Ci ⁇ C6aik-N(C] ⁇ C6alkyl)R 8 , -Ci-Cealk-S-Ci-Cealkyl, -NH-Ci- Cealk-S-Ci-Cealkyl, - H-Ci-C6alk-S(0)2-Ci-C6alkyl, - HCR 8 R ' CN, -NHCONR 8 R 8' , - HC(S)NR 8 R 8' ,
  • R 1 is - Ci-Cealk-aryl wherein the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3- fluoro-4-chlorophenyl, -3-chloro-4-fluorophenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3- methylphenyl, 3 -fluoro-4-(trifluoromethyl)phenyl , 4-chl oro-3 -methylphenyl , 2,4-difluoropheny 1, 2- hydroxymethyl -4-chlorophenyl, 2-aminomethyl -4-chlorophenyl, 2-(methylaminomethyl)-4- chlorophenyi, 2-hydroxymethyl-4,5-difluorophenyl, 2-aminomethyl-4,5-difluoroph
  • the compounds of Formula IV- A are those wherein R is -CHb-difluorophenyl, -CH? ⁇ 3,4 ⁇ difluorophenyl, -CH?-4-chlorophenyl, -CH 2 -3-chloro-4- fl uorophenyl , -CH 2 -4-chl oro-3 -fluorophenyl , -CFb-di chloropheny 1 , -CH 2 -3 ,4-dichlorophenyl, -CH 2 3-fluoro-4-(trifluoromethyl)phenyl, or -CH 2 -4-chloro-3-methylphenyl, -CH2-2,4-difluorophenyl, - C3 ⁇ 4-2-hydroxymethyl-4-chlorophenyl, -CH 2 -2-aminomethyl-4-chlorophenyl, -Clh-2- (methylaminomethyl)-4
  • compounds of Formula IV- A are those wherein R 1 is -CH(OH)-4-chl orophenyl, -CH(OH)-3,4-dichlorophenyl , -CH(OH)-3,4-difluorophenyl, -CH(OH)-
  • R ' is -halo, -C --C4haloalkyl, -Cs-Cecycloaikyi, -C 2 -C 4 alkenyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-Cealk- C(0)-Ci-C6alkyl, -Ci-C6alk-N(Ci-C6alkyl)R 8 , -Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-Cealk-S-Ci-Ci-
  • R 1 is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichl orophenyl, -CH(OH)-3,4- difluorophenyl, -CH(OH)-3-fluoro-4-chl orophenyl, -CH(OH)-3-chloro-4-fluorophenyl, -CH(OH)-3- fluoro-4-(trifluoromethyl)phenyl, or -CH(OH)-4-chloro-3-methylphenyl; and R 7 is -CI, -CH2CH2CI, cyclopropyl, vinyl, -CH2CH2-O-CH3, ⁇ CH 2 CH 2 -C(0)-CH3, - ⁇ W!
  • R 1 is -CH(OH)-4-chlorophenyl
  • R 7 is -CI, -CH2CH2CI, cyclopropyl, vinyl, - CH2CH2-O-CH3, -CH 2 CH 2 -C(0)-CH3, -CH 2 CH2-N(CH 3 ) 2 , -CH2CH2-S-CH3, -NH-CH2CH2-S-CH3, -NH-CH2Ce2-S(())2-CH3, -NHCH2CN, -NHCON(CH 3 ) 2 , -NHCO H2, -NHC(S)N(CH 3 )2, - HC(S)NH(C3 ⁇ 4), - HC(0)OCH3, -M !C ( S )OCl h , -NHC(0)-CH 3 , -NH-CH2-C(0)-CH 3 ,
  • the disclosure is directed to compounds of formula IIB
  • R f is -Ci-Cealk-aryl wherein the aryl is (hydroxymethyl)chlorophenyl
  • R (methylaminomethyl)dichlorophenyl; and R is -NR 8 R 8 or -Ci-Cealkyl; and R 8 and R 8 are independently H or Ci-Cealkyl.
  • the compounds of Formula ⁇ -2 are those wherein R 1 is - CH(OH)-2-hydroxymethyl-4-c-hlorophenyl, -CH(OH)-2-hydroxymethyl-5-chlorophenyl, -CH(OH)- 2-aminomethyl-4-chlorophenyl, -CH(OH)-2-(methylaminomethyl)-4-chlorophenyl, -CH(OH)-2- (methylaminomethyl)-5-chlorophenyl, -CH(OH)-2-hydroxymethyl-4,5-difluorophenyl, -CH(OH)-2- aminomethyl-4,5-difluorophenyl, -CH(OH)-2-(methylaminomethyl)-4,5-difluorophenyl , and R ' is NH 2 or methyl.
  • Preferred embodiments of the compounds of Formula IIB-2 are those wherein R 1 is -CH(OH)-2-hydroxymethyl-4-chlorophenyl, -CH(OFf)-2-hydroxymethyl-5-chlorophenyl, -CH(OH)- 2-hydroxymethyl-4,5-difluorophenyl, -CH(OH)-2-aminomethyl-4,5-difluorophenyl, -CH(OH)-2- (methylaminomethyl)-4,5-difluorophenyl; and R 7 is NH 2 or methyl.
  • references to Formula I, Formula II, Formula III, or Formula IV herein include all subgenera described herein, including, for example, IA-1, EB-1, IIA-1, IIB-1, IIB-2, IIIA, and IV- 1.
  • compositions and methods of administration 0188 . 1 The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • 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.
  • 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 any two
  • the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18,75%, 18.50%, 18.25% 18%, 17,75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16,25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 1 1 .50%, 11 ,25% 1 1%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%,
  • 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.
  • the concentration of one or more compounds of the invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0,02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2,5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately !%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.
  • the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 , 3.5 g, 3.0 g, 2.5 g, 2,0 g, 1 .5 g, 1.0 g, 0,95 g, 0.9 g, 0.85 g, 0,8 g, 0,75 g, 0.7 g, 0,65 g, 0.6 g, 0.55 g 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0,01 g,
  • the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 0.03 g, 0,035 g, 0,04 g, 0.045 g, 0.05 g, 0.055 g, 0,06 g, 0,065 g, 0,07 g, 0.075
  • 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 exemplar ⁇ ' dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • 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.
  • compositions for oral administration are provided.
  • 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 nonaqueous 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 ail 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 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 administration.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and
  • disi tegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • 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 pyrrol idone, 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 pyr
  • 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.
  • talc calcium carbonate (e.g., granules or powder)
  • microcrystalline cellulose e.g., powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form
  • compositions and dosage forms of the invention include, but are not limited to, agar- agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacriiin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oi l, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryi sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof.
  • a lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.
  • 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 lipophi lic surfactants may generally have an HLB value of or less than about 10.
  • An empirical parameter used to characterize the relative hydrophilicity and hvdrophobicitv of non-ionic amphophi lic compounds is the hy drophili c-lipophili c balance (" HLB" value).
  • HLB hy drophili c-lipophili c balance
  • 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-g
  • ionic surfactants include, by way of example: lecithins, iysoiecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts, sodium docusate, acylactylates; mono- and di- acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
  • Ionic surfactants may be the ionized forms of lecithin, Iysoiecithin,
  • phosphatidylcholine phosphatidyl ethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidyl serine, lysophosphatidyl choline, lysophosphatidylethanolamine,
  • lysophosphatidylglycerol lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, iactylic esters of fatty acids, stearoyl-2- lactylate, stearoyl lactyiate, succinylated monoglycerides, niono/diacetyiated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, iaurate, myri state, palmitate, oieate, ricinoieate, iinoleate, iinolenate, stearate, iauiyl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoy
  • Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alky!
  • ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkyl phenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids raonoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterifi cation products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; poiyoxy ethylene sterols, derivatives, and analogues thereof, polyoxyethylated vitamins and derivatives thereof; polyoxy ethyl ene- poiyoxypropylene block copolymers; and mixtures thereof
  • hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG-20 iaurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oieate, PEG- 15 oieate, PEG-20 oieate, PEG-20 dioieate, PEG-32 oieate, PEG-200 oieate, PEG-400 oieate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioieate, PEG-20 glyceryl laurate, PEG-30 glyceryl iaurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oieate, PEG-30
  • 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, mannitoi, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methyicelluiose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG ; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-
  • esters such as ethyl propionate, tributyl citrate, acetyl tri ethyl citrate, acetyl tributyl citrate, tri ethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ⁇ -caproiactone and isomers thereof, ⁇ -valerolactone and isomers thereof, ⁇ -butyrolactone and isomers thereof; and other solubiiizers known in the art, such as dimethyl acetamide, dimethyl isosorhide, N-methyl pyrrolidones, monooctanoin, di ethylene glycol monoethyl ether, and water.
  • solubiiizers known in the art, such as dimethyl acetamide, dimethyl isosorhide, N-methyl pyrrolidone
  • solubiiizers may also be used. Examples include, but not limited to, triacetin, tri ethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N- hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcel lulose, hy droxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubiiizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • 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, am - foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • 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, diisopropylethyl amine, ethanol amine, eth yl en edi amine, triethanoiamine, triethyiamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.
  • bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, aiginic acid, alkanesultonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfomc acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p- toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, aiginic acid, alkanesultonic acid,
  • 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, aiginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfomc acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toiuenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid,
  • compositions for injection are provided.
  • 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, chJo obutanol, 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. There are many of these 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., ethanoi
  • fatty acids e.g., oleic acid
  • surfactants e.g., isopropyl my ri state and sodium lauryl sulfate
  • pyrrol idones e.g., isopropyl my ri state and sodium lauryl sulfate
  • pyrrol idones e.g., isopropyl my ri state and sodium lauryl sulfate
  • pyrrol idones e.g., isopropyl my ri state and sodium lauryl sulfate
  • pyrrol idones e.g., isopropyl my ri state and sodium lauryl sulfate
  • pyrrol idones e.glycerol
  • transdermal delivery devices 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 deliver ⁇ ' of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001 ,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • 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.
  • a compound of the invention is administered in a single dose.
  • jl242j Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate.
  • a single dose of a compound of the invention may also be used for treatment of an acute condition.
  • 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.
  • a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
  • An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant,
  • 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 wail which contribute to restenosis.
  • a compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent.
  • a compound of the invention is admixed with a matrix.
  • a matrix may be a polymeric matrix, and may serve to bond the compound to the stent.
  • Polymeric matrices suitable for such use include, for example, laetone-based polyesters or copolyesters such as polyiactide, poiycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO- PLLA); poiydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters.
  • laetone-based polyesters or copolyesters such as polyiactide, poiycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes,
  • 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. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages.
  • Compounds of the invention may additionally be administered intravasculariy from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via adventiai application of formulations of the invention may also be performed to decrease restenosis.
  • 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 subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition may he in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient.
  • it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • 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.
  • 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.
  • IC50 refers to the half maximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, ceil receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50% IC, or IC50).
  • 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.
  • nM or less 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 n : or less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or less, 400 nM or less, 425 nM or less, 450 nM or less, 475 nM or less, 500 ⁇ 4 or less, 550 nM or less, 600 n : or less, 650 nM or less, 700 nM or less, 750 nM or less, 800 nM: or less, 850 nM or less, 900
  • the PRMTS inhibitor selectively inhibits PRMT5 a with an IC50 value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times less (or a number in the range defined by and including any two numbers abovejthan its IC50 value against one, two, or three other PRMTs.
  • the PRMTS inhibitor selectively inhibits PRMT5 a with an IC50 value that is less than about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM:, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900
  • the subject methods are useful for treating a disease condition associated with PRMTS. Any disease condition that results directly or indirectly from an abnormal activity or expression level of PRMT5 can be an intended disease condition.
  • i2S Different disease conditions associated with PRMT5 have been reported. PRMT5 has been implicated, for example, in a variety of human cancers as well as a number of
  • hemogl obi nopathi es hemogl obi nopathi es .
  • Non- limiting examples of such conditions include but are not limited to
  • Acanthoma Acinic cell carcinoma, Acoustic neuroma, Acral lentiginous melanoma, Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute lymphocytic leukemia, Acute megakaryoblastic leukemia, Acute monocytic leukemia, Acute myeloblasts leukemia with maturation, Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acute myelogenous leukemia, Acute promyelocytic leukemia, Adamantinoma, Adenocarcinoma, Adenoid cystic carcinoma.
  • Adenoma Adenomatoid odontogenic tumor, Adrenocortical carcinoma, Adult T-cell leukemia, Aggressive NK-cell leukemia, AIDS-Related Cancers, AIDS-related lymphoma, Alveolar soft part sarcoma, Ameloblastic fibroma, Anal cancer, Anaplastic large cell lymphoma, Anaplastic thyroid cancer, Angioimmunoblastic T-cell lymphoma, Angiomyolipoma, Angiosarcoma, Appendix cancer, Astrocytoma, Atypical teratoid rhabdoid tumor, Basal cell carcinoma, Basal-like carcinoma, B-cell leukemia, B-ceil iymphoma, Bellini duct carcinoma, Biliary tract cancer, Bladder cancer, Blastoma, Bone Cancer, Bone tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer, Brenner tumor, Bronchial Tumor, Bronchioloalveolar carcinoma, Brown tumor,
  • Endodermai sinus tumor Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor, Enteropathy -associated T-cell lymphoma, Ependymoblastoma, Ependymoma, Epidermoid cancer, Epithelioid sarcoma, Erythroleukemia, Esophageal cancer, Esthesioneuroblastoma, Ewing Family of Tumor, Ewing Family Sarcoma, Ewing's sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Extramammary Paget's disease, Fallopian tube cancer, Fetus in fetu, Fibroma, Fibrosarcoma, Follicular lymphoma, Follicular thyroid cancer, Gallbladder Cancer, Gallbladder cancer, Ganglioglioma, Ganglioneuroma, Gastric Cancer, Gastric lymphoma.
  • Gastrointestinal cancer Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor, Gastrointestinal stromal tumor, Germ cell tumor, Germinoma, Gestational choriocarcinoma, Gestational Trophoblastic Tumor, Giant cell tumor of bone, Glioblastoma multiforme, Glioma, Gliomatosis cerebri, Glomus tumor, Glucagonoma, Gonadobiastoma, Granulosa cell tumor, Hairy Cell Leukemia, Head and Neck Cancer, Head and neck cancer, Heart cancer, Hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD), Hemangiobiastoma, Hemangiopericytoma, Hemangiosarcoma, Hematological malignancy, Hepatocellular carcinoma, Hepatosplenic T-cell lymphoma, Hereditary breast-ovarian cancer syndrome, Hodgkin Lymphoma, Hodgkin's lymphom
  • Medulloepithelioma Melanoma, Melanoma, Meningioma, Merkel Cell Carcinoma, Mesothelioma, Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Metastatic urothelial carcinoma, Mixed Mullerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Multiple myeloma, Mycosis Fungoides, Mycosis fungoides, Myelodysplasia Disease, Myelodysplasia Syndromes, Myeloid leukemia.
  • Myeloid sarcoma Myeloproliferative Disease, Myxoma, Nasal Cavity Cancer, Nasopharyngeal Cancer, Nasopharyngeal carcinoma, Neoplasm, Neurinoma, Neuroblastoma, Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-Hodgkin Lymphoma, Non-Hodgkin lymphoma, Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, Ocular oncology, Oiigoastrocytoma, Oligodendroglioma, Oncocytoma, Optic nerve sheath meningioma, Oral Cancer, Oral cancer.
  • Oropharyngeal Cancer Osteosarcoma, Osteosarcoma, Ovarian Cancer, Ovarian cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Paget' s disease of the breast, Pancoast tumor, Pancreatic Cancer, Pancreatic cancer, Papillary thyroid cancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer, Parathyroid Cancer, Penile Cancer, Perivascular epithelioid ceil tumor, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumor of Intermediate Differentiation, Pineoblastoma, Pituicytoma, Pituitary adenoma, Pituitary tumor, Plasma Cell Neoplasm, Pleuropulmonary blastoma, Polyembryoma, Precursor T- lymphoblastic lymphoma, Primary central nervous system lymphoma, Primary effusion lymphoma, Primary Hepatocellular
  • Retinoblastoma Retinoblastoma, Rhabdomyoma, Rhabdomyosarcoma, Richter's transformation, Sacrococcygeal teratoma, Salivary Gland Cancer, Sarcoma, Schwannomatosis, Sebaceous gland carcinoma,
  • Secondary neoplasm Seminoma, Serous tumor, Sertoli-Leydig cell tumor, Sex cord-stromal tumor, Sezary Syndrome, Signet ring cell carcinoma, Skin Cancer, Small blue round cell tumor, Small cell carcinoma, Small Ceil Lung Cancer, Small cell lymphoma, Small intestine cancer, Soft tissue sarcoma, Somatostatinoma, Soot wart, Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma, Squamous cell carcinoma, Stomach cancer, Superficial spreading melanoma,
  • 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
  • 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),
  • 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)
  • CLL chronic lymphocytic leukemia
  • MM multiple myeloma
  • MDS myelodysplastic syndrome
  • SCD sickle cell disease
  • 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 in Table A,
  • reaction mixture was stirred at 30 °C for 1 h. I. CMS showed the reaction was completed.
  • the reaction mixture was concentrated and purified by reversed-phase combi-flash (neutral condition) eiuting with H 2 0:CH 3 CN from 90: 10 to 5:95 to give ] ( ⁇ - ⁇ 4- chlorophenyl)-[(2S,3S,4R,5R)-5-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy
  • reaction mixture (clear solution) was concentrated under reduced pressure and purified by FCC (12 g Si02, 0->6% MeOH in DCM, wet-loaded in eluent) to yiekj (2R,3S,4R,5R) ⁇ 2-[(R) ⁇ (3,4 ⁇ difluoro ⁇
  • reaction mixture was purified directly by reversed phase Chem-flash eluting with CH3CN/H2O (neutral condition) from 5/95 to 95/5 to give the solution of the desired product which was lyphilized to give (2R,3R,4S,5R)-2-[4-(2-cMoroethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-5-[(R)-(4- chloro-3-fluoro-phenyl)-hydroxy-methyl]tetrahydrofuran-3,4-diol (Ex. 101) (1 .38 mg, 0.003 mmol , 4.6% yield) as a white solid.
  • Example 104 4-(7-((2R,3R,4S,5R)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)butan-2-o (104)
  • Example 114 l-(7-((2Et,3R,4S,5R)-5-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylimidazolidin- (1
  • 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 ⁇ .
  • Cells incubated with DMSO was used as a vehicle control.
  • Cells were washed once with PBS, trypsinized in 150 uL 0.25% Trypsin (Coming, Catalog #: 25-053-CI), neutralized with 1 raL complete medium, transferred to micr°Centrifuge tubes and collected.
  • Cell pellet was then resuspended in 15 uL PBS, lysed in 4% SDS, and homogenized by ⁇ passing through homogenizer column (Omega Biotek, Catalog #: HCR003).
  • Total protein concentrations were determined by BCA assay (ThermoFisher Scientific, Catalog #: 23225). Lysates were mixed with 5x Laemmli buffer and boiled for 5 min.
  • compound working stocks were further diluted at 1 :50 with fresh medium in 96 well plate, and 10 uL of diluted drugs were added to a new 96 well plate for proliferation assay.
  • Cells growing at exponential phase were spun down at 1500 rpm for 4 min and resuspend in fresh medium to reach a density of O.SxlO 6 cells/ml. 200 ul of cells were added to 96 well plate containing diluted drugs and incubated for 3 days, DMSO was used a vehicle control.
  • Example 99 In vivo pharmacokinetic properties of Example 99.
  • ICS331 Granta-519 ceils was maintained in DMEM medium supplemented with 10% fetal bovine serum and 2 mM L-Glutamine at 37 °C in an atmosphere of 5% CO2 in air.
  • Cells in exponential growth phase were harvested and Ixl O 7 cells in 0.1 mL of PBS with Matrigel (1 : 1) were injected subcutaneously at the right lower flank region of each mouse for tumor development. The treatments were started when the mean tumor size reaches approximately 300-400mm 3 .
  • Mice were assigned into groups using StudyDirector IM software (Studylog Systems, Inc. CA, USA) and one optimal randomization design (generated by either Matched distribution or Stratified method) that shows minimal group to group variation in tumor volume was selected for group allocation.
  • Example 99 or vehicle (0.5% Na CMC + 0.5% TweenSO, suspension) were administered orally (QD for Example 99, QD for vehicle) at a dose of 10 mg/kg (QD) for 27 days.
  • Body weights and tumor size were measured every 3 to 4 days after randomization. Animals were euthanized 4 hours after last dosing, and blood and tumor samples were collected for analysis.
  • Aspect 1 A compound of Formula I, Formula II, Formula III, or Formula IV:
  • A is CH or N
  • R 1 is -Co-Cealk-Ci-Cealkyl, -Co-Cealk-Ci-Cehaloalkyl, -Co-Cealk-C ⁇ CH, -Co-C 6 alk-C ⁇ C- Ci-Cealkyl, -Co-C6alk-C ⁇ C-C 1 -C6haloalkyl, -Co-C6alk-C ⁇ C-C 3 -C6cycloalkyl, or -Ci- Cealk-aryl,
  • R 2 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cj-Cecycloalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Cealkyl, -Co-Cealk-NIfc, -Co-Cealk-NH-Ci-Cealkyl,
  • R 3 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cj-Cecycloalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Cealkyl, -Co-Cealk- Hi, -Co-Cealk-NH-Ci-Cealkyl, -Co-C 6 alk-N(Ci- Cealkyl)-Ci-C 6 alkyl, -C 0 -Cealk-NH-C 3 -Cecycloalkyl, 0 -Cealk-N(Ci-Cealkyl)-C 3 - Cecycloalkyl, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN;
  • R is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalky , -Co-Cealk-OH,
  • Cecycloaikyi Cecycloaikyi, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN;
  • Ci-Cecycloalkenyl ring Ci-Cecycloalkenyl ring
  • R 5 and R 4 together with the atom to which they are attached, form a C 3 -C6cycloalkyl ring or a heterocycloalkyl ring;
  • R 5 is H, halo, NH 2 , or -Ci-Cealkyl
  • R 6 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, or -Co-Cealk-C 3 -Cecycloalkyl,
  • R 7 is halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Cj-Cecyeloalkyl, -CVCehaloeyeloalkyl, ⁇ Ci- Cealk-O-Ci-Cealkyl, -Ci-C6alk-S(0)-Ci-C6alkyl, -Ci-C6alk-S(0)2-Ci-C6alkyl, - CR 8 R S' CN, NHCR 8 R 8' CN, -NH-CN, -NHCONR 8 R 8' , -NHC(0)OR 9 , -NHC(0)-Ci- Cealkyl, or -NHC(0)-Ci-Cehaloalkyl;
  • R 8 and R 8' are each independently H, -CJ -Cealkyl, or -Co-Cealk-OCi -Cealkyl;
  • R 8 and R 8' together with the atom to which they are attached, form a Cs-Cecycloalkyl ring; and R 9 is -Ci-Cealkyl, or Co-C6aik-C3-C&cycfoalkyl.
  • Aspect 2 The compound of aspect 1 wherein R 1 is -Ci-Cealk-aryl.
  • Aspect 3 The compound of aspect 2 wherein the -Ci-Cealk-aryl is -CEb-aryl, -CH(OH)-aryl, - CH(F)-aryl, -CH(NH2)-aryl, -CH(Me)-ar l, or -C(Me)(OH)-aryl .
  • Aspect 4 The compound of aspect 3 wherein the -Ci-Gsaik-aryl is -CFb-phenyl, - i -4- chlorophenyl, -CH 2 -4-fluorophenyl, -CH_-3,4-dichlorophenyl, -CH 2 -3,4-difluorophenyl, - CH 2 -3-fluoro-4-chlorophenyl, -CH2-3-chloro-4-fluorophenyl, -CH(OH)-4-chlorophenyl, - CH(OI-I)-3 ,4-dichlorophenyl, -CI [(()! !
  • Aspect 6 The compound of aspect 5 wherein the -CH(OH)-C ⁇ C Ci-Cealkyl, -CH(F)-C ⁇ C-C l-Cealky 1, -CH(NH2)-C ⁇ C-Ci-C6alkyl, -CH(Me)-C ⁇ C-C i- Cealkyl, or -C(Me)(OH)-C ⁇ C-Ci-C6alkyl.
  • Aspect 7 The compound of aspect 6 wherein the is -CH(OH)-0 ⁇ C Clh, -CH(F)-C ⁇ C-CH 3 , -CH(NH 2 )-C ⁇ C-CH 3 , -CH(Me)-C ⁇ C-CH 3 , or -C(Me)(OH)-C ⁇ C-
  • Aspect 8 The compound of aspect 1 wherein Rj is -C 0 -C6alk-C ⁇ C-Ci-C6haloalkyl.
  • Aspect 9 The compound of aspect 8 wherein the -Co-C6alk-C ⁇ C-Ci-C6haloalkyl is -CH(OH)- C ⁇ -Ci-C 6 haloalkyl, -CH(F)-C ⁇ C-Ci-C6haloalkyl, -CH(NH2)-C ⁇ C-Ci-C6haloalkyl, - CH(Me)-C ⁇ C-Ci-C6haloalkyl, or -C(Me)(OH)-C ⁇ C-Ci-C&haloaikyi .
  • Aspect 10 The compound of aspect 8 wherein the -Co-C6alk-C ⁇ C-Ci-C6haloalkyl is -CH(OH)- C ⁇ -Ci-C 6 haloalkyl, -CH(F)-C ⁇ C-Ci-C6haloalkyl, -CH(NH2)-C ⁇ C-Ci-C6halo
  • Aspect 1 The compound of aspect 1 wherein Ri is -Co-C6al k-C ⁇ C-C 3 -C6cycloalkyl .
  • Aspect 12 The compound of aspect 1 1 wherein the -Co-C6alk-C ⁇ C-C 3 -C6cycloalkyl is - CH(OH)-C ⁇ C-C 3 -C6cycloalkyl, -CH(F)-C ⁇ C-C 3 -C6cycloalkyl, - ⁇ K M i ⁇ )-C C--CV Cecycloalkyl, -CM( ⁇ !e)-C C- -CYcycioal kyL or -C(Me)(OH)-C ⁇ C-C 3 -C6 ⁇ cloalkyl.
  • Aspect 13 The compound of aspect 12 wherein the -Co-C6alk-C ⁇ C-C 3 -C6cycloalkyl is ⁇
  • Aspect 14 The compound of any one of aspects 1 to 13 wherein R 3 is H.
  • Aspect 15 The compound of any one of aspects 1 to 14 that is a compound of Formula I or Formula II.
  • Aspect 16 The compound of aspect 15 wherein A is CH.
  • Aspect 17 The compound of aspect 15 wherein A is N.
  • Aspect 18 The compound of any one of aspects 15 to 17 wherein R 6 is H.
  • Aspect 19 The compound of any one of aspects 1 to 18 that is a compound of Formula I or Formula III.
  • Aspect 20 The compound of aspect 19 wherein R 2 i s H.
  • Aspect 21 The compound of aspect 19 wherein R 2 i s -Ci-Cealkyl.
  • Aspect 22 The compound of any one of aspects 19 to 21 wherein R 3 is H.
  • Aspect 23 The compound of any one of aspects 19 to 22 wherein R 4 is H.
  • Aspect 24 The compound of any one of aspects 1 to 18 that is a compound of Formula II or Formula IV.
  • Aspect 25 The compound of aspect 24 wherein R' is halo.
  • Aspect 26 The compound of aspect 24 wherein R' is -Ci-C 4 haloalkyl.
  • Aspect 27 The compound of aspect 26 wherein the -d-CAaloalkyl is --CH2CH2CI, -CH2CH2F,
  • Aspect 28 The compound of aspect 24 wherein R'' is -Cs-Cecycloalkyl.
  • Aspect 29 The compound of aspect 28 wherein the -Cs-Cecycloalkyl is cyclopropyl.
  • Aspect 30 The compound of aspect 24 wherein R 7 is -C 1 -Cealk-O-C 1 -Cealky 1.
  • Aspect 31 The compound of aspect 24 wherein R' is -Ci-Ceaik-SfOVCi-Cealkyl.
  • Aspect 32 The compound of aspect 24 wherein R 7 is -Ci-Cealk-SfOVCi-Ceaikyi.
  • Aspect 33 The compound of aspect 24 wherein R' is -NH-CN.
  • Aspect 34 The compound of aspect 24 wherein R 7 is -CR 8 R 8' CN.
  • Aspect 35 The compound of aspect 24 wherein R' is NHCR 8 R 8 CN.
  • Aspect 36 The compound of aspect 24 wherein R' is - HCONR 8 R 8 .
  • Aspect 37 The compound of aspect 24 wherein R' is - HR 8 R 8 .
  • Aspect 38 The compound of any one of aspects 34 to 37 wherein R 8 and R 8' are each,
  • Aspect 39 The compound of aspect 24 wherein R' is NHC(0)-Ci-C6alkyl.
  • Aspect 40 The compound of aspect 24 wherein R' is NHC(0)-Ci-C6haloalkyl.

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Abstract

L'invention concerne des composés de formule I, de formule II, de formule III et de formule IV : (I) (II) (III) (IV). L'invention concerne également des méthodes d'utilisation et de préparation qui s'y rapportent.
PCT/US2018/020483 2017-03-01 2018-03-01 Inhibiteurs sélectifs de la protéine arginine méthyltransférase 5 (prmt5) WO2018160855A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10570140B2 (en) 2017-08-09 2020-02-25 Prelude Therapeutics Incorporated Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
WO2020089892A1 (fr) * 2018-10-28 2020-05-07 Yeda Research And Development Co. Ltd. Prévention de l'hématopoïèse clonale liée à l'âge et de maladies associées à celle-ci
US10711007B2 (en) 2018-03-14 2020-07-14 Prelude Therapeutics Incorporated Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
JP2021505583A (ja) * 2017-12-05 2021-02-18 エンジェクス ファーマシューティカル インコーポレイテッド Ｐｍｒｔ５阻害剤としての複素環式化合物
US11214574B2 (en) 2018-03-14 2022-01-04 Prelude Therapeutics, Incorporated Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
EP3939988A4 (fr) * 2019-03-20 2022-08-24 Korea Research Institute of Chemical Technology Composition pharmaceutique comprenant un nouveau composé hétérocyclique azolopyrimidine en tant que principe actif
CN116478172A (zh) * 2023-06-20 2023-07-25 英矽智能科技(上海)有限公司 吡咯并[3,2-d]嘧啶类化合物及其应用

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3657744A (en) 1970-05-08 1972-04-25 Univ Minnesota Method for fixing prosthetic implants in a living body
US4739762A (en) 1985-11-07 1988-04-26 Expandable Grafts Partnership Expandable intraluminal graft, and method and apparatus for implanting an expandable intraluminal graft
US4992445A (en) 1987-06-12 1991-02-12 American Cyanamid Co. Transdermal delivery of pharmaceuticals
US5001139A (en) 1987-06-12 1991-03-19 American Cyanamid Company Enchancers for the transdermal flux of nivadipine
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
US5040548A (en) 1989-06-01 1991-08-20 Yock Paul G Angioplasty mehtod
US5061273A (en) 1989-06-01 1991-10-29 Yock Paul G Angioplasty apparatus facilitating rapid exchanges
US5195984A (en) 1988-10-04 1993-03-23 Expandable Grafts Partnership Expandable intraluminal graft
US5292331A (en) 1989-08-24 1994-03-08 Applied Vascular Engineering, Inc. Endovascular support device
US5451233A (en) 1986-04-15 1995-09-19 Yock; Paul G. Angioplasty apparatus facilitating rapid exchanges
US5496346A (en) 1987-01-06 1996-03-05 Advanced Cardiovascular Systems, Inc. Reinforced balloon dilatation catheter with slitted exchange sleeve and method
US5674278A (en) 1989-08-24 1997-10-07 Arterial Vascular Engineering, Inc. Endovascular support device
US6344053B1 (en) 1993-12-22 2002-02-05 Medtronic Ave, Inc. Endovascular support device and method
US20160244475A1 (en) 2015-02-24 2016-08-25 Pfizer Inc. Substituted nucleoside derivatives useful as anticancer agents
WO2016178870A1 (fr) 2015-05-04 2016-11-10 Eli Lilly And Company Analogues nucléosidiques 5'-substitués

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3657744A (en) 1970-05-08 1972-04-25 Univ Minnesota Method for fixing prosthetic implants in a living body
US4739762A (en) 1985-11-07 1988-04-26 Expandable Grafts Partnership Expandable intraluminal graft, and method and apparatus for implanting an expandable intraluminal graft
US4739762B1 (en) 1985-11-07 1998-10-27 Expandable Grafts Partnership Expandable intraluminal graft and method and apparatus for implanting an expandable intraluminal graft
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
US5451233A (en) 1986-04-15 1995-09-19 Yock; Paul G. Angioplasty apparatus facilitating rapid exchanges
US5496346A (en) 1987-01-06 1996-03-05 Advanced Cardiovascular Systems, Inc. Reinforced balloon dilatation catheter with slitted exchange sleeve and method
US4992445A (en) 1987-06-12 1991-02-12 American Cyanamid Co. Transdermal delivery of pharmaceuticals
US5001139A (en) 1987-06-12 1991-03-19 American Cyanamid Company Enchancers for the transdermal flux of nivadipine
US5195984A (en) 1988-10-04 1993-03-23 Expandable Grafts Partnership Expandable intraluminal graft
US5061273A (en) 1989-06-01 1991-10-29 Yock Paul G Angioplasty apparatus facilitating rapid exchanges
US5040548A (en) 1989-06-01 1991-08-20 Yock Paul G Angioplasty mehtod
US5292331A (en) 1989-08-24 1994-03-08 Applied Vascular Engineering, Inc. Endovascular support device
US5674278A (en) 1989-08-24 1997-10-07 Arterial Vascular Engineering, Inc. Endovascular support device
US5879382A (en) 1989-08-24 1999-03-09 Boneau; Michael D. Endovascular support device and method
US6344053B1 (en) 1993-12-22 2002-02-05 Medtronic Ave, Inc. Endovascular support device and method
US20160244475A1 (en) 2015-02-24 2016-08-25 Pfizer Inc. Substituted nucleoside derivatives useful as anticancer agents
WO2016178870A1 (fr) 2015-05-04 2016-11-10 Eli Lilly And Company Analogues nucléosidiques 5'-substitués

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
"Basic and Clinical Pharmacology", MCGRAW HILL
"Handbook of Clinical Drug Data", 2002, MCGRAW-HILL
"Principles of Drug Action", 1990, CHURCHILL LIVINGSTON
"Remingtons Pharmaceutical Sciences", 2000, LIPPINCOTT WILLIAMS & WILKINS
"The Pharmacological Basis of Therapeutics", 2001, MCGRAW HILL
CHUNG ET AL., J BIOL CHEM, 2013, pages 5534
HSU ET AL., NATURE, vol. 525, 2015, pages 384
KOH ET AL., NATURE, vol. 523, 2015, pages 7558
MARTINDALE: "The Extra Pharmacopoeia", 1999, THE PHARMACEUTICAL PRESS
PAL ET AL., MOL. CELL. BIOL., 2003, pages 7475
PAL ET AL., MOL. CELL. BIOL., 2004, pages 9630
WANG ET AL., MOL. CELL. BIOL., 2008, pages 6262
ZHAO ET AL., NAT STRUCT MOL BIOL., vol. 16, 2009, pages 304

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10570140B2 (en) 2017-08-09 2020-02-25 Prelude Therapeutics Incorporated Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
US11078205B2 (en) 2017-08-09 2021-08-03 Prelude Therapeutics, Incorporated Selective inhibitors of protein arginine methlytransferase 5 (PRMT5)
US11208416B2 (en) 2017-08-09 2021-12-28 Prelude Therapeutics Incorporated Selective inhibitors of protein arginine methytransterase 5 (PRMT5)
JP2021505583A (ja) * 2017-12-05 2021-02-18 エンジェクス ファーマシューティカル インコーポレイテッド Ｐｍｒｔ５阻害剤としての複素環式化合物
AU2018381004B2 (en) * 2017-12-05 2021-04-29 Angex Pharmaceutical, Inc. Heterocyclic compounds as PRMT5 inhibitors
US10711007B2 (en) 2018-03-14 2020-07-14 Prelude Therapeutics Incorporated Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
US11214574B2 (en) 2018-03-14 2022-01-04 Prelude Therapeutics, Incorporated Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
US11254683B2 (en) 2018-03-14 2022-02-22 Prelude Therapeutics Incorporated Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
WO2020089892A1 (fr) * 2018-10-28 2020-05-07 Yeda Research And Development Co. Ltd. Prévention de l'hématopoïèse clonale liée à l'âge et de maladies associées à celle-ci
EP3939988A4 (fr) * 2019-03-20 2022-08-24 Korea Research Institute of Chemical Technology Composition pharmaceutique comprenant un nouveau composé hétérocyclique azolopyrimidine en tant que principe actif
CN116478172A (zh) * 2023-06-20 2023-07-25 英矽智能科技(上海)有限公司 吡咯并[3,2-d]嘧啶类化合物及其应用
CN116478172B (zh) * 2023-06-20 2023-09-05 英矽智能科技(上海)有限公司 吡咯并[3,2-d]嘧啶类化合物及其应用

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