WO2018085833A2 - 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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WO2018085833A2
WO2018085833A2 PCT/US2017/060396 US2017060396W WO2018085833A2 WO 2018085833 A2 WO2018085833 A2 WO 2018085833A2 US 2017060396 W US2017060396 W US 2017060396W WO 2018085833 A2 WO2018085833 A2 WO 2018085833A2
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compound
cealk
cealkyl
mmol
methyl
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PCT/US2017/060396
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WO2018085833A3 (fr
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Juan Luengo
Raul A. LEAL
Hong Lin
Rupa SHETTY
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Prelude Therapeutics, Incorporated
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/14—Pyrrolo-pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22

Definitions

  • the disclosure is directed to PRMT5 inhibitors and methods of their use.
  • Protein arginine methylation is a common post-translational modification that regulates numerous cellular processes, including gene transcription, mRNA splicing, DNA repair, protein cellular localization, cell fate determination, and signaling.
  • methylated arginines is catalyzed by the protein arginine methyl transferases (PRMTs) family of methyltransferases.
  • PRMTs protein arginine methyl transferases
  • PRMT ' l , -2,-3,-4,-6,-8 Type I enzymes that are capable of mono- and asymmetric dimethyiation of arginine, with S-adenosylmethionine (SAM) as the methyl donor.
  • SAM S-adenosylmethionine
  • PRMT-5, -7 and -9 are considered to be Type II enzymes that catalyze symmetric dimethyiation of arginines.
  • Each PRMT species harbors the characteristic motifs of seven beta strand methyltransferases (Katz et al., 2003), as well as additional "double E” and "THW” sequence motifs particular to the PRMT subfamily.
  • PRMTS is as a general transcriptional repressor that functions with numerous transcription factors and repressor complexes, including BRG1 and hBRM, Blimp 1, and Snail. Tins enzyme, once recruited to a promoter, symmetrically dimethylates H3R8 and H4R3.
  • H4R3 site is a major target for PRMTl methylation (ADMA) and is generally regarded as a transcriptional activating mark.
  • ADMA PRMTl methylation
  • both H4R3me2s (repressive; me2s indicates SDMA modification) and H4R3me2a (active; me2a indicates ADMA modification) marks are produced in vivo.
  • the specificity of PRMTS for H3R8 and H4R3 can be altered by its interaction with COPR5 and this could perhaps play an important role in determining PRMTS corepressor status. Role of PRMTs in Cancer
  • PRMTs Aberrant expression of PRMTs has been identified in human cancers, and PRMTs are considered to be therapeutic targets.
  • Global analysis of histone modifications in prostate cancer has shown that the dimethylation of histone H4R3 is positively correlated with increasing grade, and these changes are predictive of clinical outcome,
  • PRMTS levels have been shown to be elevated in a panel of lymphoid cancer cell lines as well as mantle cell lymphoma clinical samples.
  • PRMTS interacts with a number of substrates that are involved in a variety of cellular processes, including RNA processing, signal transduction, and transcriptional regulation.
  • PRMTS can directly modify histone 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.
  • the transcription factor MYC also safeguards proper pre- messenger-RNA splicing as an essential step in lymphomagenesis. Koh et al. Nature 2015, 523 7558; Hsu et al. Nature 2015 525, 384.
  • PRMT5 induces the repressive histone mark, H4R3me2s, which serves as a template for direct binding of DNMT3A, and subsequent DNA methyiation. Loss of PRMT5 binding or its enzymatic activity leads to dernethyiation of the CpG dinucleotides and gene activation.
  • H4R3me2s mark and DNA metliylation 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
  • n 0 or 1
  • R 2 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-C6alk-C3-C6cycloalkyl, -Co-Cealk-OH, -Cc-Cealk-O-Ci-Cealkyl, -Co-Cealk-NH , -Co-Cealk-NH-Ci-Cealkyl, -Cc-Cealk-NiCi-Cealky -Ci-Cealkyi, -Co-Cealk-NH-Cs-Cecycloalkyl, -Co-C6alk-N(Ci-C6alkyl)-C:i-C6CycloaIkyl, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN;
  • R 3 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-CealkyL -Co-Cealk- H 2 , -Co-Cealk-NH-Ci-Cealkyl, -Co-Cealk- N(Ci-C6alkyl)-Ci-C 6 aIkyl, -Co-Cealk-NH-Cs-Cecycloalkyl, -Co-Cealk-N(Ci- Cealkyl)-C3-CecycloalkyI, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN: R 4 is H, halo, -Ci-Cealkyl, -Ci-C
  • R 3 and R 4 together with the atom to which they are attached, form a Cj-Cecycloalkyl ring or a heterocycloalkyl ring;
  • R 5 is H, Ci-Cealkyl, or Ci)-C&alk-C3 ⁇ Cecyeloalkyl;
  • R 6 and R 7 are each independently H, Me, NH2, or CH2F;
  • R 8a and R 8b are each independently H, Ci-Cealkyl, or -Co-Cealk-OCi-Cealkyl, or R 8a and R 8b , together with the atom to which they are attached, form a CB-Cecycloalkyi ring;
  • R 8 and R 8' are each independently H, Ci-Cealkyl, or -Co-Cealk-OCi-Cealkyl;
  • R 9 is -Ci-C alkenyl, -Ci-CAaioaikenyl, C2-C4cyanoalkenyl, -C2-C4alkynyl, -Ci-
  • R 10 is -Ci-Cealkyl, or Co-Coalk-CB-Cecycloalkyl
  • R 10a is H, -Ci-Cealkyl, or Co-Ceaik-Cs-Cecycloalkyi.
  • compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect.
  • alkyl when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C1-C12”), preferably 1 to 6 carbons atoms (“Ci-Ce”), in the group.
  • alkyl groups include methyl (Me, Cialkyl), ethyl (Et, Chalky!), n-propyl (Cialkyl), isopropyl (Csalkyi), butyl (C'-ialky]), isobutyl (C alkyl), sec-butyl (Cialkyl), tert-butyl (C-mlkyl), pentyl (Csalkyl), isopentyl (Csalkyl), tert-pentyl (Csalkyl), hexyl (Cealkyl), isohexyl (Ceaikyl), and the like.
  • halo when used alone or as part of a substituent group refers to chloro, fluoro, bromo, or iodo.
  • haloalkyl when used alone or as part of a substituent group refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms.
  • Halogen atoms include chlorine, fluorine, bromine, and iodine.
  • Examples of haloalkyl groups of the disclosure include, for example, trifluoromethyl (-CF3), chloromethyl (- CH 2 Cl), and the like.
  • cycloalkyi 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 (“Cs-Ce”)-
  • Examples of cycloalkyi groups include, for example, cyclopropyl (Ci), cyciobutyl (C 4 ), cyclopentyl (C5), cyclohexyi (Ce), 1- methylcyclopropyi (C 4 ), 2-methylcyclopentyl (C 4 ), adamantanyl (Cio), and the like.
  • halocycloalkyl when used alone or as part of a substituent group refers to a cycloalkyi group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms.
  • Halogen atoms include chlorine, fluorine, bromine, and iodine.
  • Examples of halocycloalkyl groups include, for example, chlorocyclopropyl (C3),
  • heterocycloalkyl when used alone or as part of a substituent group refers to any three to ten membered monocyclic or bicyclic, saturated ring stractuxe containing at least one heteroatom selected from the group consisting of O, N and S.
  • the heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
  • heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyi, piperidinyl, dioxanyl, moipholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahyofuranyl, tetrahydropyranyl, piperazinyi, and the like.
  • oxo-substituted-heterocycloalkyl when used alone or as part of a substituent group refers to a heterocycloalkyl group wherein at least one of the carbon atoms in the ring is substituted with an oxo group.
  • oxo-substiiuted heterocycloalkyl groups include, but are not limited to, 2-aziridinonyl, 2-azetidinonyi, pyrrolidinonyl, dioxolanonyl, imidazolidinonyl, pyrazolidinonyl, piperazinonyl, piperidinonyl, dioxanonyl, dithianonyl, thiomorpholinonyl, oxazepanonyl, oxiranonyl, oxetanonyl, quinuclidinonyl, tetrahyofuranonyl, tetrahydropyranonyl, piperazinonyl, and the like.
  • alkenyl when used alone or as part of a substituent group refers to a straight- or branched-chain group having from 2 to 12 carbon atoms (“C2-C12”), preferably 2 to 4 carbons atoms ("C2-C4"), in the group, wherein the group includes at least one carbon-carbon double bond.
  • haloalkenyl when used alone or as part of a substituent group refers to an alkenyl group wherein at least one carbon atom in the group is substituted by one or more halogen atoms.
  • Halogen atoms include chlorine, fluorine, bromine, and iodine.
  • cyanoalkenyl when used alone or as part of a substituent group refers to an alkenyl group wherein at least one carbon atom in the group is substituted by one or more cyano groups.
  • cycloalkenyl when used alone or as part of a substituent group refers to cyclic, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms (“C3-C10”), preferably from 3 to 6 carbon atoms ("Ci-Ce”) and containing at least one carbon-carbon double bond.
  • cycloalkenyl groups include, but are not limited to cyclopropenyl, cyclobutenyl, and the like.
  • alkynyl when used alone or as part of a substituent group refers to a straight- or branched-chain group having from 1 to 12 carbon atoms ("Ci-Ci j")- preferably 1 to 4 carbons atoms ("C2-C4 " '), in the group, and wherein the group includes at least one carbon- carbon triple bond.
  • alkynyl groups include ethynyl (-O H; C2alkynyl); propargyi ⁇ ;- ⁇ ⁇ .-( ⁇ ( ⁇ ⁇ : Csalkynyl), propynyl ( ⁇ ( " C * i i h; Csalkynyl); butynyl (-G CH2CH3; C/ialkynyl), pentynyl (-OCCH2CH2CH3; Csalkynyl), and the like.
  • aryl when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more of the carbon atoms in the ring is optionally substituted with a halogen atom or with a -C1-C3 alkyl group.
  • Halogen atoms include chlorine, fluorine, bromine, and iodine.
  • aryl groups include phenyl, naphtyl, fluorophenyl, difluorophenyl, chlorophenyl, 4-chlorophenyl, 3,4-difluoropheny], 3-fluoro-4- chlorophenyl, 3-methyl-4-chlorophenyl, 3,4-dichlorophenyl, bromophenyl, iodophenyl, fluoronaphthyl, difluoronaphthyl, chloronaphthyi, bromonaphthyl, iodonaphthyl, methylphenyl, ethylphenyl, and the like.
  • heteroaryF when used alone or as pari 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 ("C5-C10").
  • the heteroaryl moiety can be unsubstituted or one or more of the carbon atoms in the ring can be substituted with a halogen atom or with a -G-C.3 alkyl group.
  • Halogen atoms include chlorine, fluorine, bromine, and iodine.
  • heteroaryl groups include but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, iriazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isomdolinyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolvl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinoliny], isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl
  • Ci-Ce When a range of carbon atoms is used herein, for example, Ci-Ce, all ranges, as well as individual numbers of carbon atoms are encompassed.
  • C1-C3 includes Ci- C3 , C 1-C2, C2-C3, Ci, C2, and C3.
  • 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(CH3) ⁇ , -CH(CH3)-CH2-, and -CiCTT i-.
  • -Coalk- refers to a bond.
  • ''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, hvdrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluen
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • 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 nontoxic, 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.
  • 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.
  • 'treating or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom),
  • treating 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 ( 2 H or D), carbon- 13 ( 13 C), nitrogen- 15 ( 15 N), or the like.
  • the compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (i?)-or ( ⁇ -stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. Where a chiral center exists in a structure, but no specific stereochemistry is shown for that center, both enantiomers, individually or as a mixture of enantiomers, are encompassed by that structure. The methods for the determination of stereochemistr - and the separation of stereoisomers are well-known in the art.
  • the disclosure is directed to compounds of Formula I, Formula II, and Formula III. In some aspects, the disclosure is directed to compounds of Formula I:
  • a in Formula I, Fonnula II and/or Fonnula III is N or CH.
  • a i s N and the compounds of Formula I are of Formula IA :
  • A is N and the compounds of Formula II are of Formula
  • A is CH and the compounds of Formula I are of Formula IB:
  • A is CH and the compounds of Formula II are of Formula ⁇ : s
  • A is CH and the compounds Formula III are of Formula
  • n is 0 (zero) or 1 .
  • the compounds of Formula are of Formula IIC:
  • R i0a is H.
  • R 10a is Ci-C&alkyi, for example, methyl, ethyl, propyl, isopropyi, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.
  • R !(3 ⁇ 4 is Co-C6alk-C3-C6cycloalkyl, for example, Co- alk-Cj-CbCycloalkyl, Ci-Cbalk-Cn-Cecycloalkyl, Ci-Csalk-Cs-Cecycioalkyl, Ci-Gtalk-Cj- Cecycloalkyl, Ci-C3aik-C3-C6cycloalkyi, Ci-C alk-Cs-C&cycloalkyl, Cialk-Cs-Cbcycioalkyl, Coalk ⁇ C3cyeloalkyL Coalk-C cycloalkyl, Coalk-Cscycloalkyl, Coalk-Cecycloalkyi, Ci-Cealk- C'3cycloalkyl, Ci-Cealk-C-cycloalkyl, Ci-Cealk-Cscycloalkyl, or Ci
  • R 1 in Formula I, Formula II and/or Formula III is - Ci-Cealkyl, -CH(OH)Ci-C6alkyl, -Ci-Cchaloalkyl, ⁇ CH(OH)Ci-C6haloalkyl, -Co-Cealk-CV Cecycloalkyl, -Cc-Cealk-C ⁇ -Cehalocycloalky]; -Ci-Cealkeny], -Ci-Cehaloalkenyl, -Ci-Cealkyny], -CFfcS-Ci-Cealkyl, -CHiS-Ci-Cehaloalkyl, -CHjS-Cs-Cecycloalkyl; -CHjS-Cs-Cehaiocycloalkyl; •CI !
  • R ! is -Ci-Cehaloalkyl, -Co-Cealk-C ⁇ -CecycJoalkyl, -CFfcS-Ci- Cealkyl, -CH(OH)-aryl, - ⁇ ! SC! ⁇ :- v 1. or ⁇ Ci K (O)NH-aiyl .
  • R ! is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyi, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.
  • R ] is -CH( ⁇ )H)Ci-C 6 alkyl, for example, -CH(OH)-methyl, - CH(OH)-ethyi, -CH(OH)-propyl, -CH(GH)-isopropyl, -CH(OH)-pentyl, -CH(OH)-butyl, and the like.
  • R 1 is -CH(OH)Ci-C4alkyl.
  • R ! is Ci-Cehaloalkyl, for example, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoropentyl, chloromeihyl, chloroeihyl, chloropropyl, chlorobutvl, chloropentyl, bromomethvl, bromoethvl, bromopropyl, bromobutyl, bromopeniyl, lodomeiiiyl, iodoethy], iodopropyl, iodobutyl, iodopenty] and the like.
  • R 1 is chloromeihyl (i.e. , -CH2-CI.)
  • R 1 is -CH(OH)Ci-C6haloalkyl, for example, -CH(OH)- fluoromethyl, -CH(OH)-fluoroethyl, -CH(OH)-fluoropropyl, -CH(OH)-fluoroisopropyl, - CH(OFT) -fluoropentyl, -CH(OFf)-fluorobutyl, and the like.
  • R 1 is - CH(OH)Ci-C4haloalkyl.
  • R 1 is -Co-Cealk-Cj-Cecycioaikyl, for example, -Coalk-C.3- C&cyeloalkyl, -Ci-Cealk-Cs-Cecyc oalkyi, -Ci -Csalk-Cs-Cecycloalkyl, -Ci-C4alk-C3- Cecycloalkyl, -Ci-C3alk-C3-C6cycloalkyl, -Ci-Cialk-Cs-Cecycloalkyl, -Cialk-Cn-Cecycloalkyl, - Coalk-Cncycloalkyl, -Coalk-Ctcycloalkyk -Coalk-Cscycloalkyl, -Coalk-Cecycloalkyl, -Ci-Cealk- Cicycloalkyl
  • R 1 is -Co-Cealk-Cs-Cehalocycloalkyl, for example, Coalk-Cs- Cehalocycloalkyl, -Ci-Cealk-Ca-Cehalocycloalkyl, -Ci-Cjalk-C-s-Cehalocycloalkyl, -Ci-C4alk-C-3- Cehalocycloalkyl, -Ci-Csalk-Cs-Cehalocycloalkyi, -Ci-Cialk-Cs-Cehalocycloalkyl, -Cialk-CV Cehalocycloalkyl, -CoaSk-Cshalocyeloaikyl, -Coalk-CAalocycloalkyl, -Coalk-Cshalocycloalkyl, - Coalk-Cehalocycloalkyl, -Ci
  • R is -( ' .'-( ' Valkenvi. for example, vinyl, allyl, and the like.
  • R 1 is -Ci-Cealkynyl, for example, ethynyl, propargyl, and the like.
  • R ! is -CftS-Ci-Cealkyl, for example -CH2S-Cialkyl, -CH2S- C2alkyl, -CH 2 S-C3alkyl, -CifcS-C alkyl, -CTfcS-CsalkyL and -CI-LS-Cealkyl.
  • R 1 is -CH-S-Cialkyl.
  • R 1 is -CH2-S-CH3.
  • R is -CftS-Ci-Cehaloalkyl, for example -CH2S-Ciha3oa3kyi, - CftS-Cihaloalkyl, -CHjS-Cshaloalkyl, -CH 2 S-C4haloalkyl, -Cl-fcS-Cshaloalkyl, and -CH2S- Cehaloalkyi.
  • R 1 is -CH2S-C3-C6cycloalkyl, for example -CH2S- C'3Cycloalkyl, -CH2S-C4cycloalkyl, -CTbS-Cscycloalkyl, -CthS-Cecycloalkyl, and the like.
  • R 1 is -Cl ⁇ S-Cn-Cehalocycloalkyl, for example -CH2S- Cshalocycloalkyi, -CH2S-C4halocycloalkyl, -CHaS-Cshalocycloalkyl, -CHaS-Cehalocycloalkyl, and the like.
  • R 1 is for example, -CFhOCialky], - ( 1 !. ⁇ ()( • •aiky! . -CHbOCsalkyl, ⁇ ( ' ! ! ⁇ ()( ' ialk> I. -Ci )Oaik> I. -CHzOCealkyl, and the like.
  • R 1 is -CH20-C3-C6cycloalkyl, for example, -CH2O- Cecycloalkyl, -CFfcO-Cscycloalkyl, -CH20-C4cycloalkyl, -CftO-Cscycloalkyl, and the like.
  • R ! is -CH(OH)-aryl, for example, -CH(OH)-phenyl, -CH(OH)- naphthyl, -CH(QH)-fluorophenyl, -CH(OH)-difluorophenyl, -CH(OH)-3,4-difluorophenyl, - CH(OH ⁇ -fluoronaphthyl, -CH(OH)-cli3oroplienyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro- 4-chlorophenyl, -CH(OH)-dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)- bromophenyl, -CH(OH)-iodopheny 1, -CH(OH)-methylpheny 1 , -CH(OH)-3 -methyl-4- chloropheny
  • R 1 is -CH(OH)-difluorophenyl.
  • R 1 is ⁇ CH(QH) ⁇ 3,4 ⁇ difluorophenyl.
  • R 1 is -CH(OH)-4 ⁇ chlorophenyl.
  • R 1 is -CH(OH)-3-fluoro-4-chlorophenyl.
  • R 1 is -CH(OH)- dichlorophenyl.
  • R 1 is -CH(OH)-3,4-dichlorophenyl.
  • R 1 is - CH(OH) -3 -methy 1-4-chloropheny 1.
  • R ! is -CH(F)-aiyl, for example, -CH(F)-phenyl, -CH(F)- naphthyl, -CH(F)-fluoropheny], -CH(F)-difluorophenyl, -CH(F)-fluoronaphthyl, -CH(F)- chlorophenyl, -CH(F)-bromophenyl, -CH(F)-iodophenyl, -CH(F)-methylphenyl, and the like.
  • R ! is -CH(NFb)-aryl, for example, -CH(NH2)-phenyl, - CH(NH2)-naphthyl, -CH(NH 2 ) -phenyl, -CH(NH 2 )-naphthyl, ⁇ CH(M3 ⁇ 4) ⁇ f]uorophenyl, - CH(NH2)-difluorophenyl, -CH(NH2)-fluoronaphihyl, -CH(NH 2 )-chlorophenyl, -( ⁇ ( ⁇ 2 )- bromophenyl, -CH(NH2)-iodophenyl, -CH( H2)-methyIphenyl, and the like.
  • R ! is ⁇ C(Me)(OH) ⁇ aryl, for example, -C(Me)(OH)-phenyl, - C(Me)(OH)-naphthyl, -C(Me)(OH)-fiuorophenyl, -C(Me)(OH)-difiuorophenyl, -C(Me)(OH) ⁇ fluoronaphthyl, -C(Me)(OH)-chlorophenyl, -C(Me)(OH)-bromophenyl, -C(Me)(OH)- iodophenyl, -C(Me)(OH)-methylphenyl, -C(Me)(OH)-3 ,4-difluorophenyl, -C(Me)(OH)-4- chlorophenyl, -C(Me)(OH)-3-fluoro-4
  • R 1 is - C(Me)(OH)-difluorophenyl.
  • R 1 is -C(Me)(OH)-3,4-difluorophenyl.
  • R 1 is -C(Me)(OH)-4-chloropheny3.
  • R 1 is -C(Me)(OH)-3-fluoro-4- chlorophenyl.
  • R ! is -C(Me)(OH)-dichlorophenyl.
  • R ! is - C(Me)(OH)-3,4-dichlorophenyl.
  • R 1 is -C(Me)(OH)-3 -methyl -4-chlorophenyl.
  • R is ⁇ . ⁇ I 'Si I l ' -ar 1. for example --U i.'SO I -phcn> i. ⁇ CH SCtfc-naphthyi, -CH2SCH2-fiuorophenyl, -CH2 SCFfc-difluorophenyl, -CH2SCH2- fluoronaphthyl, -CHjSCHj-chlorophenyl, -CH2SCH2-bromophenyl, -CH2SCH2-iodophenyl, - CH2SCH2-methylphenyl, and the like.
  • r I ius in some aspects R 1 is -CH SCHj-phenyl.
  • R ! is -CH2C(0)NH-aryl, for example -CH2C(0)NH-phenyl, - CH2C(0) H-naphthyl, -CH 2 C(0)NH-fluoropbenyl, -CH 2 C(0)NH-difiuorophenyl, -CH 2 C(0)NH -fluoronaphthyl, -CH 2 C(0)NH-chIorophenyl, -CH 2 C(0)NH-bromophenyl 5 -CH 2 C(0)NH- iodophenyl, -CH 2 C(0)NH-methylphenvl, and the like.
  • R 1 is - CH2C(0)NH-phenyL 100711 n embodiments of the disclosure wherein the compounds are of Formula I, Formula ⁇ , and/or Formula 111, R 5 is H, -Ci-Cealkyl, or Co-Cealk-Ci-Cecycloalkyl.
  • R 3 is H or -Ci-C&alkyl.
  • R 5 is H.
  • 5 is -Ci-Cealkyl, for example, methyl, ethyl, propyl,
  • R 5 is methyl
  • R 5 is Co-Cealk-Cn-Cecycloalkyl, for example, Co-alk-Ci- Cocycloalkyl, Ci-Cealk-CB-Cecycloalkyl, Ci -Csalk-C -Cecycloalkyl, Ci-C 4 alk-C3-C6cycloalkyl, Ci-C3alk-C3-C6cycloalkyl, Ci-Cialk-Cs-Cecycloalkyl, Cialk-C3-C6cycloalkyl, Coalk- Cscycloalkyl, Coalk-C4cycloalkyl, Coalk-Cscycloalky], Coalk-Cecycloalkyl, Ci-Cealk- Cicycloalkyl, Ci-C6alk-C4cycloalkyl, Ci-Cealk-Cscycloalkyl, or Ci -Coalk-Cecycloalkyl, for example
  • R 6 and R " are each independently H, Me, Nth, or CthF.
  • R 6 is H, Me, or NH2.
  • R 6 is H.
  • R 6 is Me.
  • R b is NH2.
  • R 7 is H, Me, or NH2.
  • R 7 is H.
  • R 6 and R 7 are each H. In some aspects, R 6 is Nth, methyl or CthF, and R 7 is H. In other aspects, R 6 is H and R 7 is NH2, methyl, or CH2F.
  • R 2 is H, halo, -Ci-C&alkyl, -Ci-Cehaloalkyl, -Cc-Cealk-Cs-Cecycloalkyi, -Co-C&alk-OH, -Co-Cealk- O-d-Cealkyl, -Co-C 6 alk-NH 2 , -Co-Cealk-NH-Ci-Cealkyl, -Co-Cealk-NiCi-CealkyO-d-Cealkyl, - Co-Cealk-NH-CB-Cecycloalkyl, -Co-C6alk-N(Ci-C6alkyi)-C3-C6Cycloalkyi, -Co-Cealk- heterocycloalkyl, 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.
  • R 2 is -Ci-Cehaloalkyl, for example, -CF3 or -CHF2.
  • R 2 is -Co-C6alk-C3-C6cycloalkyl, for example, -Coalk-C3- C&cycloalky3, -Ci-Cealk-Cs-Cecycloalkyi, -Ci -Csalk-Cs-Cecycloalkyl, -Ci-C4alk-C3- Cecycloalkyl, -Ci-C3alk-C3-C6cycloalkyl, -Ci-Caalk-Cs-Cecycloalkyl, -Cialk-Cn-Cecycloalkyl, - Coalk-Cncycloalkyl, -Coalk-Ctcycloalkyl, -Coalk-Cscycloalkyl, -Coalk-Cecycloalkyl -Ci-Cealk- Cicycloalkyl, -Ci -C6alk-
  • R 2 is -Co-Cbalk-Cs-Ceeycloalkyl
  • the cycloalkyl is un substituted.
  • the eycioalky] 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 2 is -Co-Cealk-OH, for example, -Coalk-OH, -Ci-Cealk-OH, - Ci-Csalk-OH, -Ci-C4alk-OH 5 -Ci-Csalk-OH, -Ci-Cialk-OH, or -Cialk-OH.
  • R 2 is -Co-Cealk-O-Ci-Cealkyl, for example, -Coalk-O-Ci- Cealkyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-Csalk-O-Ci-Cealkyl, -Ci-Calk-O-Ci-Cealky], -Ci-Csalk- O-Ci-Cealkyl, -d-Cialk-O-Ci-Cealkyl, -Cialk-O-Ci-Cealkyl, -Coalk-O-Ci-Csalkyl, -Coalk-O-Ci-Csalkyl, -Coalk-O-Ci- Ctalkyl, -Coalk-O-Ci-Csalkyl.-Coalk-O-Ci-Caalkyl, -Coalk-O-Ci
  • R 2 is Ci-Qalk-NFfc, for example, -Coalk-NHz, -Ci-Cealk-NH?., - Ci-Csalk-NFfc, -Ci-Cwlk-NHi, -Ci-Csalk-NlHb, ⁇ ( : ⁇ ( ⁇ ⁇ ⁇ 1 1 . or -Cialk-NFfc.
  • R 2 is -Co-Cealk-NH-Ci-Cealkyl, for example, -Coalk-NH-Ci- Ceaikyl, -G-Cealk-NH-Ci-Cealkyl, -Ci- alk-NH-Ci-Cealkyl, -Ci- Csalk-NH-Ci-Cealkyl, -C•( •• •aik-NI i-( ' :-( ' ..a!k s 1.
  • R 2 is -CVC6alk-N(Ci-C&alkyl)-Ci-C6alkyl, for example, -Coalk- N(Ci-C6a3kyl)-Ci-C 6 alkyl, -Ci-C6alk-N(Ci-C 6 aIkyl) ⁇ Ci-C6a3kyl, -Ci-Csalk-N(Ci-C6alkyl)-Ci- Cealkyl, -Ci-aalk-NiCi-CealkylJ-Ci-Cealkyl, -Ci-Cialk-NiCi-CealkylJ-Ci-Cealkyl, -Ci-Cialk- N(Ci-C6alkyl)-Ci-C6alkyl, -Cialk-N(C!-C6aikyl)-Ci-C6alkyl
  • R 2 is -Co-Cealk- H-Cs-Cecycloalkyl, for example, -Coalk-NH- C3-C6cycloalkyl, -Ci-Ceaik- H-Cs-Cecycloalkyl, -Ci-Csalk-NH-Cs-Cecycloalkyl, -Ci-C.alk-NH- C3-C6CV cloalkyl, -Ci-Csalk-NH-Cs-Cecycioalkyl, -Ci-Cialk-NH-Cs-Cecycloalkyl, -Cialk- H-Cs- Cecycloalkyl, -Coalk-NH-C cycloalkyl, -Coalk-NH-C cycloalkyl, -Coalk-NH-C4cycloalkyl, -Coalk-NH-Cscycioaikyl,
  • R 2 is -Co-Cealk-NH- Ci-Cecy cloalkyl
  • the cycloalkyl is unsubstituted.
  • the cycloalkyl is substituted with one, two, or three R substituents
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi- Cealkyl e.g., -Omethyl, -Oethyi, -Opropyl, -Oisopropyl, -Obutyl
  • halo e.g., F or CI
  • R 2 is -Co-C3 ⁇ 4alk-N(C!-C6alkyI)-C3-C6cycloalkyl, for example, - Coalk ⁇ N(Ci-C6alkyl)-C3-C6cycloalkyl, -Ci-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Ci-Csalk- Nid-Cealky -Cs-Cecycloalkyl, -Ci-C4alk-N(Ci-C6alky3)-C3-C6Cycloalkyl, -Ci-C 3 alk-N(Ci- C6alkyl)-C3-C6cycloalkyl, -Ci-C2alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Cialk-N(C;-C6alky
  • R 2 is -Co-C6aik-N(Ci-C6alkyl)-C3-C6cycloalkyl
  • the cycloalkyl is unsubstituted.
  • R 2 is -Co-Cealk-NiCi-Cealkylj-Ci-Cecycloalkyl
  • the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyi, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyi, -Opropyl, -Oisopropyl, - Obutyl), and halo (e.g., F or CI).
  • Ci-Cealkyi e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-Cealkyl e.g., -Omethyl, -Oethyi, -Opropyl, -Oisopropyl, - Obutyl
  • R 2 is -Co-Cealk -lieterocycloalkyl, for example, -Coalk- heterocycloalkyl, -Ci-Ceaik-heterocycioaikyl, -Ci-Csaik-heterocycloalkyl, -Ci-Gialk- heterocycloalkyl, -Ci-Csalk-heteroeycloalkyl, -Ci-C2alk ⁇ heteroeycloalkyl, or -Cialk- heterocy cloalkyl.
  • Preferred lieterocyloalkyi moieties include, for example piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrroiidinyl, tetrahydrofuranyl, tetrahydropyranyl, and oxetanyl.
  • R 2 is -Co-Cealk-heterocycloalkyi
  • the heterocycloalkyl is unsubstituted.
  • R 2 is -Co-Ceaik-heterocyeloalkyl
  • 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, -Obutyi), and halo (e.g., F or Ci).
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-Cealkyl e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyi
  • halo e.g.,
  • R 2 is heteroaryl, for example furanyl, imidazolyl, and pyrazolyl. In some aspects wherein R 2 is heteroaryl, the heteroaryl is unsubstituted. In other aspects wherein R 2 is heteroaryl, the heteroaryl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyi), and halo (e.g., F or CI).
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-Cealkyl e.g., -Omethyl, -Oethyl
  • R 2 is -CN.
  • R 3 is H, halo, -Ci-Oalkyl, -Ci-Cehaloalkyl, -Co-Cealk-C ⁇ -Cecycioaikyl, -Co-Cealk-OH, -Co-Cealk- O-C i-Cealkyl, -Co-Cealk-NFfc, -Co-Cealk-NH-Ci-Cealkyl, -Co-Cealk-NiCi-CealkylJ-Ci-Cealkyl.
  • R 3 is I I .
  • 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 J is -Ci-Cehaloalkyl, for example, -CF3 or --CHF2.
  • R 3 is -Co-Cealk-Cs-Ceeycioaikyl, for example, -Coalk-C3- Cecycloalkyl, -Ci-Cealk-Ci-Cecycloalkyl, -Ci-Csalk-Cj-Cecycloalkyl, -Ci-C-ialk-Cs- Cecycloalkyl, -Ci-Cjalk-Ci-Cecycioaikyl, -Ci-Czaik-CB-Cecycloalkyi, -Cialk-C3-C6cycloalkyl, - Coalk-Cicycloalkyi, -Coalk-C cycloalkyl, -Coalk-Cscycloalkyl, -Coalk-Cecycloalkyl -Ci-Cealk- C'3Cycloalkyl
  • R 3 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 J is -Co-Cealk-OH, for example, -Coalk-OH, -Ci-Cealk-OH, - Ci-Csalk-OH, -Ci-Cialk-OH, -Ci-Csalk-OH, -Ci-Cialk-OH, or -Cialk-OH.
  • R 3 is -Co-Cealk-O-Ci -Cealkyl, for example, -Coalk-O-Ci- Ceaikyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-Csalk-O-Ci-Cealkyl, -Ci-C4alk-0-Ci-C6alkyl, -Ci-Csalk- O-Ci-Cealkyl, ⁇ Ci-C2a3k-0-Ci-C6alkyl, -Cialk-O-Ci-Cealkyl, -Coalk-O-C i-Csalkyl, -Coalk-O-Ci-Csalkyl, -Coalk-O-Ci- C4aikyl, -Coalk-O-Ci-Csalkyl.-Coalk-O-Ci-Czalkyl, -
  • R 3 is Ci-Cealk-Nth, for example, -Coalk-NT-fc, -Ci-Cealk-NHb, - G -Csalk-NHz, -( ' :- ⁇ ' m!k A S S.:. ⁇ ( - ulk-N I I ⁇ . -G-C ⁇ alk-NI-b, or -Cialk- H_.
  • R 3 is -Co-Cealk-NH-Ci-Ceaikyl, for example, -Coalk-NH-Ci - Cealkyl, -Ci-Cealk-NH-Ci-Cealkyl, -Ci-Cs k-NH-Ci-Cealkyl, -( ' ' : -( ' ml k i i-( ' : -( ' a!ky 1.
  • R 3 is -Co-C6alk-N(Ci-C6aikyl)-Ci-C6alkyl, for example, -Coalk- N(Ci-C6alkyl)-Ci-C6alkyl, -d -Cealk-NCCi-CeaikyD-Ci-Cealkyl, -Ci-C 5 alk-N(Ci-C6alkyl)-Ci- Cealkyl, -Ci-C4aIkA Ci-C6alky3)-Ci-C6alk l, -Ci-Csalk-NiCi-CealkylJ-Ci-Cealkyl, -Ci-C2alk- N(Ci-C 6 alkyl)-Ci-C6a]kyl, -Cialk-NCCi-Cealky -Ci-Cealkyl, -Coalk
  • R 3 is -Co-Cealk-NH-Ci-Cecycioaikyl, for example, -Coalk-NH- Cs-Ceeycloalkyl, -Ci-Cealk-NH-Cs-Cecycloalkyl, -C i-Csalk-NH-Cs-Cecycloalkyi , -Ci-C4alk-NH- Ci-Cecycloalkyl, -Ci-Csalk-NH-Cs-Cecycloalkyl, - ⁇ -( ⁇ - ⁇ -( ⁇ ( ⁇ ycioaikyl .
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi- Cealkyl e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl
  • halo e.g., F or CI
  • R 3 is -Co-Cealk-NiCi-Cealkylj-Ci-Cecycloalkyl, for example, - Coalk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Ci-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Ci-Csaik- N(Ci-C6alkyl)-C 3 -C6cycloalkyl, -Ci-C4alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Ci-C 3 aik-N(Ci- Cealkylj-Cs-Cecycloalkyl, -Ci-Ciaik- rCi-CealkylJ-C ⁇ -CecycJoalkyl, -Cialk ⁇ N
  • R 3 is -Co-C6alk-N(Ci-C6alkyl)-C3-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), -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, -Opropy
  • R 3 is -Co-Cealk-heteroeycloalkyl, for example, -Coalk- heterocycioaikyl, -Ci-Cealk-heterocycloalkyl, -Ci-Csalk-heterocycloalkyl, -Ci-C4alk- heterocycloalkyl, -Ci-C alk-heterocycloalkyl, -Ci-Ciaik-heterocycloalkyl, or -Cialk- heterocycloalkyl.
  • Preferred heterocyloalkyl moieties include, for example piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and oxetanyl.
  • 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-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyi, -Obutyl), and halo (e.g., F or CI).
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-Cealkyl e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyi, -Obutyl
  • halo e.g., F or
  • R J is heteroaryl, for example furanyl, imidazolyl, and pyrazolyl.
  • R 3 is heteroaryl
  • the heteroaryl is unsubstituted.
  • the heteroaryl 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, -Oisopropyi, -Obutyl), and halo (e.g., F or CI).
  • Ci-Ceaikyi e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-Cealkyl e.g., -Omethyl, -Oethyl, -Opropyl, -
  • R 3 is -CN.
  • R 4 is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH, -Co-Cealk- O-Ci-Cealkyl, -Co-Cealk-Ntt, -Co-Cealk-NH-C i-Cealkyl, -Co-Cealk-NiCi-Ceaiky ⁇ -Ci-Cealkyl, - Co-Cealk-NH-Ci-Cecycloalkyl, -Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Co-Cealk- heterocycloalkyl, heteroaryl, 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-Cehaloalkyl, for example, -CF3 or -CHF2.
  • R 4 is ⁇ Co-C6alk-C3-C6cycloalkyl, for example, -Coalk-Cs- Cecycloalkyl, -Ci-Cealk-Cs-Cecycloalkyl, -Ci-C5alk-C3-C6cycloalkyl, -Ci-C4alk-C3- CbCycloalkyl, -Ci-C3alk-C3-C6CycloaIkyi, -Ci-Cialk-Cn-Cecycloalkyl, -Ciaik-Cs-Cecycloalkyi, - Coaik-C3cycioaikyl, -Coalk-C4cycloalkyl, -Coalk-Cscycloalkyl, -Coalk-Cecycloalkyl -Ci-Cealk- Cscycloalkyl,
  • R 4 is -Co-Cealk-CB-CbCycloalkyl
  • the cycloalkyl is unsubstituted.
  • R 4 is -Co-C6alk-C3-C6cycloalkyl
  • the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Ceaikyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyi, -Obutyl), and halo (e.g., F or CI).
  • Ci-Ceaikyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-Cealkyl e.g., -O
  • R 4 is -Co-Cealk-OH, for example, -Coalk-OH, -Ci-Cealk-OH, -Ci-Csalk-OH, -( " : -C ialk-OH. -Ci-C 3 aIk-OH, -Ci-Cialk-OH, or ⁇ CiaIk-OH.
  • R 4 is -Co-Cealk-O-Ci-Cealkyl, for example, -Coalk-O-Ci- Cealkyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-Csalk-O-Ci-Cealkyl, -d-C alk-Q-CVCealkyl, -Ci-Csalk- O-Ci-Cealkyl, -Ci-Cialk-O-Ci-Cealkyl, -Galk-G-Ci-Cealkyl, -Coalk-O-Ci-Csalkyl, -Coalk-O-Ci- Ctalkyl, -Coalk-O-Ci-Csalkyi .-Coalk-O-Ci-Cialkyl, -Coalk-O-Cialkyl, -Ci-C
  • R 4 is CVCealk-Nfb, for example, -Coalk-NHa, -Ci-Cealk-NHj., - Ci-Csalk- Hi, -Ci-C4alk- H2, -Ci-C 3 alk-NH2, -Ci-Cialk- Hi, or -Cialk-NHi.
  • R 4 is -Co-Cealk-NH-Ci-Cealkyl, for example, -Coalk-NH-Ci- Cealkyl, -Ci-Cealk-NH-Ci-Ceaikyl, -Ci-Csalk-NH-Ci-Ceaikyl, -Ci-Qalk-NH-Ci-Cealkyl, -Ci- Caalk-NH-Ci-Cealkyl, -Ci-Ciaik-NH-Ci-Cealkyl, -Cialk-NH-Ci-Cealkyl, -Coalk-NH-Ci-Csalkyl, -Coalk-NH-Ci-Csalkyl, -Coalk-NH-Ci-C4alkyl, -Coalk-NH-Ci-Csalkyl, -Coalk-NH-Ci-Cialkyl, or -
  • R 4 is -Co-Cealk-NiCi-CealkyiJ-Ci-Cealkyl, for example, -Coalk- Nid-Cealky -Ci-Cealkyl, -d-Cealk-NiCi-Cealky ⁇ -d-Cealkyl, -Ci-Csalk-NCCi-CealkylVCi- Cealkyl, -Ci-C4aIk-N(Ci-C6alkyl)-Ci-C6alkyl, -Ci-Csalk-NiCi-CealkylJ-Ci-Cealkyl, -Ci-Cialk- N(Ci-C6alkyl)-Ci-C6alkyl, -Cialk-N(Ci-C6alkyl)-Ci-C6alkyl, -Coaik-N(C
  • R 4 is -Co-Cealk-NH-Ci-Cecycloalkyl, for example, -Coalk-NH- Cs-Cbcycloalkyl, -Ci-Cealk-NH-Cs-Cecydoalkyl, -Ci-Csalk-NH-Cs-Cecycloalkjd, -Ci-C4alk-NH- C -Cecycloalkyl, -Ci-Csalk-NH-Cs-Cecycloalkyl, -Ci-dalk-NH-Cs-Cecycloalkyl, -Cialk-NH-Cs- Cecycloalkyl, -Coalk-NH-CjCycloalkyl, -Coalk-NH-C4cycloalkyl, -Coalk-NH-Cscycloalkyl, - Coalk-NH-Cecycloalkyl, - Coalk-
  • R 4 is -Co-Cealk-NH- Cs-Ceeycloalkyl
  • the cycloalkyl is uiisubstituted.
  • the cycloalkyl is substituted with one, two, or three R suhstituents 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, -
  • R 4 is -Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, for example, - -Ci-Csalk- N(Ci-C6alkyl)-C3-C6cycloalkyl, -C i-C4alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Ci-C3aIk-N(C i- CealkyD-Cj-CbCycloalkyl, -Ci -C2alk-N(Ci -C6alkyl)-C3-C6cycloalkyl, -Cialk-NiCi-CealkyD-Cs- Ceeycloalkyl, -Coalk-N(Ci-C6alkyl)-C3cycloalkyl, -Coalk-N(Ci-C6alkyl)-C3cycloal
  • R 4 is -Co-C6alk-N(Ci-C6alkyl)-C3-C6Cycloalkyl
  • the cycloalkyl is unsubstituted.
  • the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Ceaikyi, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-CeaSkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, - Obutyl), and halo (e.g., F or Ci).
  • Ci-Ceaikyi e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-CeaSkyl e.g., -Omethyl, -Oethyl,
  • R 4 is -Co-Cealk-heterocycloalkyi, for example, -Coalk- heterocycloalkyl, -Ci-C&alk-heterocycloalkyl, -Ci-Csalk-heterocycloalkyl, -Ci ⁇ C4alk- heterocycloalky], -Ci-Csalk-heterocycloalkyl, -Ci-Cialk-heterocycloalkyl, or -Cialk- heterocycloalkyl.
  • Preferred heterocyioaikyl moieties include, for example, piperidinyl, piperazmvl, morpholinyi, aziridmyl, dioxanyL pvrrolidinvl, tetrahydrofuranyl, tetrahydropyranyi, or oxetanyl.
  • R 4 is -Co-Cealk-heterocycloalkyl
  • the heterocycloalkyl is unsubstituted.
  • R 4 is -Cc-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-C&alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyl), and halo (e.g., F or CI).
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-C&alkyl e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyl
  • halo e.g., F
  • R 4 is heteroaryl, for example furanyl, imidazolyl, and pyrazolyl. In some aspects wherein R 4 is heteroaryl, the heteroaryl is unsubstituted. In other aspects wherein R 4 is heteroaryl, the heteroaryl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl.
  • Ci-Cealkyl e.g., methyl, ethyl, propyl, isopropyl.
  • -OCi-Cealkyl e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyi, -Obutyl
  • halo e.g., F or CI
  • R 4 is -CN
  • At least one of R 2 , R 3 , and R 4 is H. In some aspects, R 2 , R 3 , and R 4 are each H.
  • R 2 and R 3 are each H and R 4 is halo, -Ci-Cealkyl, -Ci- CehaloalkyL -Cc-Cealk-CB-Cecycloalkyi, -Co-Cealk-OH, -Co-Cealk-Q-Ci-Cealkyi, -Co-Cealk- ⁇ - ⁇ 2, -Co-Cealk-NH-Ci-Cealkyl -Co-Cealk-NiCi-Cealky -Ci-Cealkyl, -Co-Cealk-NH-Cs- Cocycloalkyl, -Co-C6alk-N(C] -C6alkyl)-C3-C6cycloalkyl, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN.
  • R 2 and R 4 are each H and R 3 is halo, -Ci-Cealkyl, -Ci- Cehaloalkyl, -Co-Cealk-Ci-Cecycioaikyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Ceaikyl, -Co-Ceaik- Ntb, -Co-Cealk-NH-Ci-Cealkyl, -Co-Ceaik-NCC] -CealkyD-Ci-Cealkyl, -Co-Cealk-NH-Cs- Ceeycloalkyl, -Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN.
  • R J and R 4 are each H and R 2 is halo, -Ci-Cealkyl, -Ci- C&haloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Cealkyl, -Co-C&alk- NHi, -Co-Cealk-NH-Ci-Cealkyi, -Co-Cealk-NXCi-Cealky -Ci-Cealkyl, -Cc-C6alk-NH-C3- Cecycloalkyl, -Co-C6alk-N(Ci-C6alkyl)-C:i-C6Cycloalkyl, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN.
  • R 2 and R 3 together with the atoms to which they are attached, form a C3-Ci,cycloalkenyl ring, for example, cyclopropenyl, cyclobutenyl, cyclopentenyi, 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 CVCecycIoalkyl ring or a heterocycloalkyi ring.
  • R 3 and R 4 together with the atom to which they are attached, form a C3-Cecycloalkyl ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 3 and R 4 together with the atom to which they are attached, form a heterocycloalkyi ring, for example, piperidinyl, piperazinyl, morpholmyl, aziridinyl, dioxanyi, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or oxetanyi.
  • a heterocycloalkyi ring for example, piperidinyl, piperazinyl, morpholmyl, aziridinyl, dioxanyi, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or oxetanyi.
  • R 8a and R 8b are each independently H, Ci-Ceaikyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like), or -Co-Cealk-QCi-Cealkyl (e.g., Coaik-OCi- Cealkyl, Ci-Cealk-OCi-Cealkyl, Ci-Csalk-OCi-Cealkyl, Ci-Csalk-OCi- Ceaikyl, Ci-Cialk-OCi-Ceaikyl, Cialk-OCi-Cealkyl, Co-Cealk-OCi-Csalkyl, Co-Cealk-OCi- C4aikyl, Co-Cealk-OCi-OCi- C4aikyl, Co-Cealk-OC
  • R 8a is Ci-Cealkyl or -Co-Cealk-GCi-CeaTkyl and R 8b is H, Ci-Cealkyl, or -Co- Qalk-OCi-Cealkyl.
  • R 8a is H or Ci-Cealkyi. In some embodiments, R 8b is H or Ci-C6alkyl.
  • R 8a and R 8b are each H.
  • R 8a and R 8b are each independently C i-Cealkyl. T ms, in some embodiments R 8a is methyl and R 8b is methyl.
  • R a is Ci-Cealkyl and R b is H.
  • R 8a is methyl and R 8b is 1 1.
  • R 8a and R 8b are each independently -Co-Cealk-OCi-Cealkyi.
  • R 8a is -Co-Cealk-OCi-C&alkyl and R 8 is H.
  • R a and R b together with the atom to which they are attached, form a Cj-Cecycloalkyl ring, for example, cyciopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 8a and R 8b together with the carbon atom to which they are attached, form a cyciopropyl ring.
  • R 10 is -Ci-Cealkyl, or -Co-Cealk-Cs-Cocycloalkyi.
  • R 10 is Ci-Ceaikyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.
  • R i0 is methyl .
  • R !u is Cc-Cealk-Ci-Cecycloalkyl, for example, Co-alk-Cs- Cecycloalkyl, Ci-Ceaik-CB-Cecycloalkyi, Ci-Csalk-Ci-Cecycloalkyl, Ci-C aik-CB-Cecycloalkyl, Ci -C3alk-C3-C6cycloalkyl, Ci-Cialk-Cs-Cecycloalkyl, Cialk-C3-C6cycloalkyl, Coalk- C3cycloalkyl, Coalk-C4cycloalkyl, Coalk-Cscycloalkyl, Coalk-Cecycloalkyl, Ci-Cealk- C3cycloalkyl, Ci-Cealk-C cycloalkyl, Ci-Cealk-Cjcycloalkyl, or Ci-C
  • R 8 and R 8 are each independently H, Ci-Cealkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like), or -Co-Coaik-OCi-Cealkyl (e.g., Coalk-OCi- Cealkyl, Ci-Cealk-OCi-Cealkyl, Ci-Csalk-OCi-Cealkyl, Ci-Cialk-OCi-Cealkyl, Ci-Cialk-OCi- Ceaikyl, Cialk-OCi-Cealkyl, Co-Cealk-OCi-Csalkyl, Co-Cealk-OCi- C alkyl, Co-Cealk-OCi-Csalkyi, Co-Cealk-OCi- C alkyl, Co-Ce
  • R 8 is Ci-Cealkyl or -Co-Cealk-OCi-Cealkyl and R 8' is H, Ci-Cealkyl, or -Co-Cealk- OCi-Cealkyl.
  • 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-QCi-Cealkyl.
  • R 8 is -Co-Cealk-QCi-Cealkyl and R 8' is H.
  • R 8 and R 8' together with the atom to which they are attached, form a Cj-Cecycloalkyi ring, for example, cyciopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 9 is -Ci-C-talkenyl, -C?-C4haloalkenyl, C2-C4Cyanoalkenyi, -Ci-C alkynyl, -Ci-C ' 4haloalkyl, -C2- Ceheterocycloalkyl, oxo-substituted-Ci-Ceheterocycioalkyl, -Cj-Cecycloalkyl, -CHO, -C(0)R 10 , - CR 8 R 8' CN, -CH 2 NR 8 R 8' , -Co-Cealk-OH, -NR 8 R 8' , -NH-CN, -N(R 10 )CN, -O-C1-C4 alkyl, - NR 5 C(0) R 8 R 8' , -OC(0)NR R 8' , or -NR
  • R v is -C2-C4alkenyl, for example, vinyl, allyl, and the like.
  • R 9 is vinyl (-CH CH2).
  • R 9 is -C2-C4alkyny], for example, ethynyl, propargyl, and the like.
  • R 9 is ethynyl (-C ⁇ CH).
  • R 9 is -Ci-C4haloalkyl, for example, -CF3 or -CHF2.
  • 9 is -C2-C6heterocycloalkyl, for example
  • R 9 is 2-oxiranyl .
  • R 9 is 1 - azetidinyl.
  • R 9 is oxo-substituted-Cz-Ceheterocydoalkyl, for example, oxo-substituted-C2heterocycloalkyl, oxo-substituted-Ciheterocycloalkyl, oxo- substituted-CAeterocycloalkyl, oxo-substituted-Csheterocycloalkyl, oxo-substituted- Coheterocycloalkyl, including aziridinonyi, azetidinonyl, pyrrolidinonyl, dioxolanonyi, imidazolidinonyl, pyrazolidinonyl, piperazinonyl, piperidinonyl, dioxanonyl, dithianonyl, thiomorpholinonyl, oxazepanonyl, oxiranonyl
  • R 9 is -C -Cecycloalkyl, for example -Cscycloalkyl, - C4cycloalkyl, -Cscycloalkyl, -Cecycloalkyl, and the like.
  • R 9 is - Cicycloalkyl.
  • R 9 is cyclopropyl.
  • R 9 is -CHO.
  • R 9 is -C(O)R i0 .
  • R 9 is -C(0)Ci-Cea]kyl.
  • R !0 is methyl
  • R v is acetyl (i.e., -C(0)CH3).
  • R i0 is Co-Cealk-Cs-Cecycloalkyl
  • R 9 is - C(0)Co-C6alk-C3-C6cycloalkyl.
  • R 9 is -CR 8 R 8' CN.
  • R 9 is cyanomethyl (i.e., -CH2CN).
  • R 8 is - Ci-Ceaikyi and R 8' is H
  • R 9 is -CH(-Ci-C6alkyl)CN.
  • R 9 is -C(Ci-C6alkyl)(Ci-C6alkyl)CN.
  • R 9 is -CH(-Co-C6alk-OCi-C6alkyl)CN. In some embodiments wherein R 8 and R 8' are both -Co-Cealk-OCi-Cealkyi, R 9 is -Ci-Co-Cealk-OCi- Cealkyl -Co-Cealk-OCi-Cealky CN,
  • R 9 is CH2NR 8 R 8' .
  • R 9 is aminomethyl (i.e., -CH2NH2).
  • R 8 is - Ci-Cealkyl and R 8' is H
  • R 9 is -CHiNHiCi-Ceaikyl.
  • R 9 is -CH2N (Ci-C6alkyl)(Ci-C6alkyl).
  • R 9 is -CHi HC-Cc-Cealk-OCi-Cealkyl). In some embodiments wherein R s and R 8 are both -Co-Cealk-OCi-Cealkyl, R 9 is -CH2N (-Co-Cealk-OC 1- CeaikylX-Co-Cealk-QCi-Cealkyl).
  • R 9 is -Co-Cealk-QH, for example, -Coalk ⁇ OH, -Cialk- OH, -Cialk-OH, -Cjalk-OH, -Cialk-OH, -Csalk-OH, -Cealk-OH, and the like.
  • R 9 is -C ialk-OH.
  • R 9 is hydroxymethyl (i.e., -CH2OH).
  • R 9 is -NR 8 R 8' .
  • R 9 is amino (i.e., - H2).
  • R v is -NH(Ci-C6alkyl).
  • R 9 is methylamino (i.e., -NHCTI3).
  • R 9 is -N(-Ci-C&alkyl)( -Ci-Cealkyl).
  • R 9 is -NHi-Co-Cealk-OCi-Cealkyl) . In some embodiments wherein R 8 and R 8' are both -Co-Cealk-OCi-Cealkyl, R 9 is -Nt-Co-Cealk-OCi-CealkylX-Co-Cealk-OCi- Ceaikyl).
  • R 9 is -NH-CN.
  • R 9 is -N(R l0 )CN.
  • R 9 is -N(Ci-C6alkyl)CN.
  • R 10 is methyl
  • R 9 is - N(CH_)CN.
  • R i0 is -Co-Ceaik-Cs-Cecycloalkyi
  • R 9 is -N(-Co- C6alk-C3-C6cycloalkyl)CN.
  • R 9 is -O-C1-C4 alkyl, for example -O-Cialkyl, -O- C aikyl, -O-Csalkyl, -O-Cialkyl.
  • R 9 is -NR 5 C(0)NR 8 R 8' .
  • R v is - HC(0) R 8 R 8' .
  • R 9 is -N(-Ci- Cbalkyl)C(0)NR 8 R 8 .
  • R 9 is - N(Co-C6alk-C3-C6cycloalkyl)C(0)NR 8 R 8' .
  • R 8 is H, R 9 is - NR 5 C(0)NHR 8' .
  • R 8 is H and R 8' is H, R 9 is -NR 5 C(0)NH2.
  • R 9 is urea-l-yl (i.e. , - NHC(0)NH2.
  • R 8 is -Ci-Cealkyl and R 8' is H
  • R 9 is - NR 5 C(Q)NH(C!-C&alkyl).
  • R 9 is -NR 5 C(0)N(Ci-Cealkyl)(Ci-C6alkyl).
  • R 9 is -NR 3 C(0)NH(-Co-C6alk-OCi-C6alkyl). In some embodiments wherein R 8 and R 8' are both -Co-Cealk-OC; -Ceaikyl, R 9 is -NR 5 C(0)N(-Co-C6alk-OC;-Cealkyl)(- Co-Cealk-OCi-Cealkyl). [0171] In some embodiments, R 9 is -OC(0)NR 8 R 8' . In some embodiments wherein R 8 is H, R 9 is -OC(0)NHR 8' .
  • R 9 is -OC(0)NH2. In some embodiments wherein R 8 is -Ci-C&alkyl and R 8' is H, R 9 is -0( ⁇ ()) ⁇ H(C:- Cealkyl). In some embodiments wherein R 8 and R 8' are both -Ci-Cealkyl, R y is -OC(0)N(Ci- CeaikylXCi-Cealkyl). In some embodiments wherein R 8 is (-Co-Cbalk-OCi-Cealkyl and R 8' is H, R 9 is -OC(0)NH(-Co-C6alk-OCi-C6alkyl).
  • R 9 is -OC(0)N(-Co-C6alk-OCi-C6a3kyI)(-Co-C6aIk-OCi-C6alkyl) ,
  • R 9 is -NR 3 C(0)OR 10 .
  • R 9 is -NHC(0)OR 10 .
  • R 3 is -Ci -Cealkyl
  • R v is -N(-Ci- C&aikyl)C(Q)QR 10 .
  • R 3 is Co-C6alk-C3-C6cycloalkyl
  • R 9 is -N Co- CeaIk-C3-C6cycloa]kyl)C(0)OR 10 .
  • R 10 is -Ci-Cealkyl
  • R 9 is - NR 5 C(0)0-Ci-C6alkyl.
  • R 10 is -Co-Cealk-Cj-Cecycloalkyl
  • R v is - NR 5 C(0)0-Co-C6alk-C3-C6cycloalkyl.
  • R 9 is - HC(0)0-Ci-C6alkyl.
  • R 9 is -NHC(0)OCH 3 ,
  • the present disclosure is directed to compounds of the formula
  • R ! is -CH(OH)-aryl, -or -C(Me)(OH)-aryl
  • R 7 is H or NH 2
  • R 9 -C2- C4aikenyl, -C 2 -C4alkynyl, -C(0)R 10 , or -Co-Cealk-OH
  • R i0 is -Ci-Cealkyl
  • R is -CH(OH) ⁇ aryl.
  • R ! is ⁇ CH(OH)-3,4 ⁇ dif!uorophenyl, ⁇ CH(OH) ⁇ 4-chlorophenyl, -CH(OH)-3-fluoro ⁇ 4 ⁇ chlorophenyi, -CH(OH)- dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.
  • R 1 is -C(Me)(OH)- aryl.
  • R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyi, -C(Me)(OH)-3,4-dichlorophenyl, -C(Me)(OH)-3-methyl-4- chlorophenyl.
  • R 7 is H. In other embodiments of the compound of formula IIIA-1, R 7 is NHz.
  • R 9 is -C2-C4alkenyl.
  • R 9 is -Ci-Cialkynyl. r riius, in some embodiments, R 9 is is ethyny l (-C ⁇ CH). In otlier embodiments, R 9 is prop-l-yn-
  • R 9 is -C(O)R !0 where R 10 is methyl. That is, in some embodiments, R 9 is acetyl (i.e. , -C(O)CHj).
  • R 9 is -Co-Cealk-OH.
  • R 9 is hydroxymethyl (i.e. , -CH2OH).
  • R 9 is 1 -hydroxyethyl (i.e., -CH(OH)-CH3).
  • R 9 is 2-hydroxyethyl (i.e., -
  • the present disclosure is directed to compounds of the formula
  • R 1 is -CH(OH)-aryl, -or -C(Me)(OH)-aryl; and R 7 is H or NH2.
  • R : is ⁇ CH(QH) ⁇ aryi.
  • R ! is -CH(OH)-3,4- dif!uorophenyl, ⁇ CH(OH) ⁇ 4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.
  • R 1 is -C(Me)(OH)- aryl.
  • R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or -C(Me)(OH)-3-methyl-4- chlorophenyl.
  • R 7 is H. in other embodiments of the compound of formula ⁇ -2, R 7 is NHJ.
  • the present disclosure is directed to compounds of the formula
  • R 1 is -CH(QH)-aryl, -or -C(Me)(GH)-aryl; and R 7 is H or NH 2 .
  • R 1 is -CH(OH)-aryl.
  • R 1 is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.
  • R 1 is -C(Me)(OH)- aryl.
  • R ! is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyi, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyl, -C(Me)(OH)-3,4-diehlorophenyl, or -C(Me)(OH)-3-methyl-4- chlorophenyl.
  • R 7 is H. in other embodiments of the compound of formula IIIA-3, R 7 is Ntb.
  • the present disclosure is directed to compounds of the formula
  • R 9 is -C...-C ialkem l. - ' .!-C saik> n> i. -Cs-Cecycloalkyl, -C(0)R 10 , or -NR 8 R 8' ;
  • R 7 is H or NH 2 ;
  • R 6 is H or Nth,
  • R 8 and R 8' are both H, and
  • R i0 is -Ci-Cealkyl.
  • R 9 is -Cj-C alkynyl.
  • R 9 is is ethynyl (-C ⁇ CH).
  • R 9 is -C(O)R i0 where R 10 is methyl.
  • TTiai is, in some embodiments, R 9 is acetyl (i.e. , -C(0)CH:i).
  • R 9 is -C3- Cecycloalkyl.
  • R 9 is cyclopropyl.
  • R 9 is -NR 8 R 8' and R 8 and R 8 are both H. That is, in some embodiments, R 9 is amino (-Nth).
  • R 6 is H. In other embodiments of the compound of formula IIIA-4, R 6 is Nth.
  • R 7 is H. In other embodiments of the compound of formula IIIA-4, R 7 is Nth.
  • the present disclosure is directed to compounds of the formula
  • R is -CH(OH)-aryl, -or -C(Me)(QH)-aryl; R 7 is H or NH2; and R" -C2-
  • R 1 is -CH(OH)-a!yl.
  • R ! is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.
  • R 1 is -C(Me)(OH)- aryl.
  • R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(QH)-dichlorophenyi, -C(Me)(OH)-3,4-dichlorophenyl, -C(Me)(OH)-3-methyl-4- chlorophenyl.
  • R 7 is H. In other embodiments of the compound of formula IIIB-1, R 7 is Nth.
  • R 9 is -C2-C4alkenyl.
  • R 9 is -C2-C ' 4alkynyl.
  • R 9 is is ethynyl (-C ⁇ CH).
  • R 9 is prop-l-yn- 1 -yl (-( ( -CH :).
  • R 9 is -C(0)R 10 where R 10 is methyl. That is, in some embodiments, R 9 is acetyl (i.e. , -C(O)Cth).
  • R 9 is -Co-Cealk-OH.
  • R is hydroxymethyl (i.e., -CH2OH).
  • R 9 is 1 -hydroxy ethyl (i.e., -CH(OH)-CH3).
  • R 9 is 2-hydroxyethyl (i.e., -
  • the present disclosure is directed to compounds of the formula IHB- l-a
  • R is -CH(OH)-aryl, -or -C(Me)(QH)-aryl;
  • R 7 is H or NH2; and
  • R 10 is -Ci-Cealkyl; and
  • R 6 is 1 1 or Me (i.e., methyl).
  • R l is -CH(OH)- aryl.
  • R 1 is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichlorophenyl, -CH(GH)-3,4-diehlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.
  • R 1 is -C(Me)(OH)- aryl.
  • R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH) ⁇ dichlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, -C(Me)(OH)-3-methyl-4- chlorophenyl.
  • R 7 is H. In other embodiments of the compound of formula IIIB-l -a, R " is NH2.
  • R 9 is -C2- C4alkenyl.
  • R 9 is -C2- CUalkynyl.
  • R 9 is -C(0)R 10 where R i0 is methyl. That is, in some embodiments, R 9 is acetyl (i. e. , -C(0)CH3).
  • R 9 is -Co-Cealk- OH.
  • R 9 is 1 -hydroxy ethyl (i.e. , ⁇ € ⁇ (0 ⁇ ) ⁇ 3 ⁇ 4).
  • R 1 is -CH(OH)-atyl, -or -C(Me)(OH)-atyl; and R 7 is H or NHJ.
  • R ! is -CH(OH)-aryl.
  • R 1 is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichloropheny], -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.
  • R 1 is -C(Me)(OH)- aryl.
  • R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or -C(Me)(OH)-3-methyl-4- chlorophenyl.
  • R ' is H. in other embodiments of the compound of formula IIIB-2, R 7 is NHi.
  • the present disclosure is directed to compounds of the formula
  • R ! is ⁇ CH(OH) ⁇ aryl, -or -C(Me)(OH) ⁇ aryl; and R 7 is H or NH 2 .
  • R 1 is -CH(OH)-aryl.
  • R 1 is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.
  • R 1 is -C(Me)(OH)- aryl. 1 bus. in some embodiments of the compound of formula IIIB-3, R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyi, -C(Me)(OH)-3,4-dichlorophenyl, or -C(Me)(OH)-3-methyl-4- chlorophenyl.
  • R' is H. in other embodiments of the compound of formula ⁇ -3, R' is NPh. [022ij In some aspects, the present disclosure is directed to compounds of the formula ⁇ -3-a
  • R 1 is -CH S-Ci-Cealkyl; and R 7 is H orNHz
  • R 1 is -CH2S-CH3.
  • 223 ⁇ In some embodiments of the compound of formula ⁇ -3-a, R 7 is H. in other embodiments of the compound of formula IIIB-3-a, R 7 is Nth.
  • the present disclosure is directed to compounds of the formula
  • R ! is ⁇ CH(OH) ⁇ aryl, -or -C(Me)(OH)-aiyl; and R 7 is H or NH2.
  • R 1 is -CH(OH)-aryl.
  • R 1 is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.
  • R 1 is -C(Me)(OH)- aryl.
  • R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyi, -C(Me)(OH)-3,4-dichlorophenyl, or -C(Me)(OH)-3-mefliyl-4- chlorophenyl.
  • R' is H.
  • R 7 is NH2.
  • the present disclosure is directed to compounds of the formula
  • R 1 is -CH(OH)-aryl, -or -C(Me)(GH)-aryl; and R 7 is H or NH 2 .
  • R 1 is -CH(OH)-a!yl.
  • R ! is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.
  • R 1 is ⁇ C(Me)(OH) ⁇ aryl.
  • R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or -C(Me)(OH)-3-methyl-4- chlorophenyl.
  • R 7 is H. in other embodiments of the compound of formula IIIB-5, R 7 is Nth.
  • R 1 is -CH(OH)-aryl, -or -C(Me)(OH)-ar ⁇ 'l; and R " is H or NH2.
  • R ! is -CH(OH)-aryl.
  • R 1 is -CH(OH)-3,4- difluorophenyl, -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)- dichloropheny], -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3-methyl-4-chlorophenyl.
  • R 1 is -C(Me)(OH)- aryl.
  • R 1 is -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-dichlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or -C(Me)(OH)-3-methyl-4- chlorophenyl.
  • R ' is H. in other embodiments of the compound of formula IIIB-6, R 7 is NHi.
  • the present disclosure is directed to compounds of the formula
  • R 7 is H or NH ; and R 9 -Ci-Cialkenyl, -Ci-C alkynyl, -C(0)R 10 , or -Co-Cealk- ( ) ! !. and R 10 is -Ci-Cealkyl.
  • aryl is -3,4- difluorophenyl, -4-chlorophenyl, -3-fluoro-4-chlorophenyl, -dichlorophenyl, -3,4- dichlorophenyl, or - 3-methyl -4-chlorophenyl.
  • R 7 is H. In other embodiments of the compound of formula IIIB-7, R is NH2.
  • R 9 is -C2-C4alkenyl.
  • R 9 is -C2-C4alkynyl.
  • R 9 is is ethynyl (-C ⁇ CH).
  • R 9 is prop-l-yn- 1 -yl ( ⁇ ( ⁇ ( ⁇ ( ' ! ! .).
  • R 9 is -C(0)R 10 where R 10 is methyl. That is, in some embodiments, R 9 is acetyl (i.e. , -C(0)CH3).
  • R 9 is -Co-Cealk-OH.
  • R 9 is hydroxymethy] (i.e., -CH2OH).
  • R 9 is 1 -hydroxyethyl (i.e., -CH(OH)-CH3).
  • R 9 is 2-hydroxyethyl (i.e., -
  • the present disclosure is directed to compounds of the formula
  • R 7 is H or Nth; and R 9 ⁇ C2-C4a3kenyl, ⁇ C2-C4a3kyny3, -C(O)R ! 0 , or -Co-Cealk- OH; and R 10 is -Ci-Cealkyl.
  • aryl is -3,4- difluorophenyl, -4-chlorophenyl, -3-fluoro-4-chlorophenyl, -dichlorophenyl, -3,4- dichlorophenyl, or - 3-methyl-4-chlorophenyl.
  • R 7 is H. In other embodiments of the compound of formula IIIB-8, R 7 is Nth.
  • R 9 is -C2-C4alkenyi.
  • R 9 is -C2-C4alkynyl.
  • R 9 is is ethynyl (-C ⁇ CH).
  • R? is prop-l-yn-
  • R 9 is -C(0)R l ° where R 10 is methyl. That is, in some embodiments, R 9 is acetyl (i.e. , -C(O)Cth).
  • R 9 is -Co-Cealk-OH.
  • R 9 is hydroxymethy] (i.e., -CH2OH).
  • R 9 is 1 -hydroxyethyl (i.e., -CH(OH)-CH3).
  • R 9 is 2-hydroxyethyl (i.e., - CH2CH2OH).
  • the present disclosure is directed to a compound that is
  • the present disclosure is directed to a compound of formula
  • the present disclosure is directed to a compound of formula
  • references to Formula II herein also refer to subgeneric formulae IIA, IIB, IIC, and IID
  • References to Formula III herein also refer to subgeneric formulae I11A, IIIA-l, IIJA-2, IIIA-3, ⁇ -4, IlIB, ⁇ -1, ⁇ -1-a, ⁇ -2, ⁇ -3, ⁇ -3-a, ⁇ -4, ! U B-5. ⁇ -6, ⁇ -7, and IIIB-8.
  • Stereoisomers of compounds of Formula I, Formula ⁇ , and Formula III are also contemplated by the present disclosure.
  • the disclosure encompasses all stereoisomers and constitutional isomers of any compound disclosed or claimed herein, including all enantiomers and diastereomers.
  • compositions and methods of administration are provided.
  • 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 excspients, earners, 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 numbers above
  • the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, .18,75%, 18.50%, .18,25% 18%, 17.75%, 17,50%, 17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9,50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6,75%, 6.50%, 6.25%, 6%, 5.75%, 5,50%,
  • 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%J to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately l% 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 % io approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v orv/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 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0,02 g, 0.01 g, 0.009
  • the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.0 1 g, 0.0 15 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0,008 g, 0,0085 g, 0,009 g, 0,0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g,
  • the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0,0005-9 g, 0.001-8 g, 0.005-7 g, 0,01-6 g, 0,05-5 g, 0,1-4 g, 0,5-4
  • the compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. An exemplar - dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • a pharmaceutical composition of the invention typically contains an active ingredient (i.e., a compound of the disclosure) of the present invention or a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including but not limited to inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • an active ingredient i.e., a compound of the disclosure
  • a pharmaceutically acceptable salt and/or coordination complex thereof include but not limited to inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • compositions for oral administration 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 pharmaceutical composition suitable for oral consumption.
  • Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion.
  • Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the earner, which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately- admixing the acti ve 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 pharmace tical 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 pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • suitable earners 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 pyrrolidine, methyl cellulose, pre-gelatinized starch, hydroxy-propyl 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 pyrrolidine
  • suitable fillers for use in the pharmaceutical compositions and dosage fonns disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, manmtol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algms, other celluloses, gums or mixtures thereof.
  • Lubricants which can be used to form pharmaceutical compositions and dosage fonns of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, 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 gly ceryl 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 m ixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.
  • a suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10.
  • An empirical parameter used to characterize the relative hydrophiiicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-iipophilic balance (" HLB" value).
  • Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • 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 andivdrogenated lysolecithins; phospholipids and derivatives thereof; iysophosphohpids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl iactylates; 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 include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di- glycerides; citric acid esters of mono- and di-glycerides; and m ixtures thereof.
  • Tonic surfactants may be the ionized forms of lecithin, lysolecithin,
  • phosphatidylcholine phosphatidylethanolamine
  • phosphatidylglycerol phosphatidic acid
  • phosphatidylserine ⁇ phosphatidylcholine
  • lysophosphatidylethanolamine phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, ⁇ phosphatidylcholine, lysophosphatidylethanolamine
  • lysophosphatidylglycerol lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-iaciylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetyiated tartaric acid esters of mono/diglycerides, citric acid esters of mono/digiycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl
  • Hydrophilic non-ionic surfactants may include, but are not limited to,
  • alkylglucosides alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides;
  • poiyoxyalkviene alkyl ethers such as polyethylene glycol alkyl ethers; poiyoxyalkyiene alkylphenols such as polyethylene glycol alkyl phenols; poiyoxyalkyiene alkyl phenol fatty ac d esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters;
  • poiyoxyalkyiene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a poly oi with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a poiyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils.
  • the poiyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
  • hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyce
  • Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives;
  • polyethylene glycol aikyl ethers polyethylene glycol aikyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-giyeerides; hydrophobic transesterification products of a poiyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof.
  • preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a poiyol 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 poiyois, such as ethanoi, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaeiythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG ; amides and other nitrogen -containing compounds such as 2-pyrrolidone,
  • solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose,
  • hydroxypropyl cyclodextrins ethanoi, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.
  • Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • the amount of solubilizer that can be included is not particularly limited.
  • the amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art.
  • the solubilizer can be in a weight ratio of 10%, 25%o, 50%), 100%o, or up to about 200%> by weight, based on the combined weight of the drag, and other excipients.
  • solubilizer may also be used, such as 5%>, 2%>, ! %) or even less.
  • solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25 %> by weight.
  • the composition can further include one or more pharmaceutically acceptable additives and excipients.
  • additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons.
  • pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.
  • bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenyisulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids,
  • Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
  • the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like.
  • Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
  • Suitable acids are pharmaceutically acceptable organic or inorganic acids.
  • suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.
  • suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbsc acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thiogiycolic acid, toluene sulfonic acid, uric acid and the like.
  • 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, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required oilier 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- [0300] the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present in vention 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, dimethyl sulfoxide (DMSO)-based solutions.
  • DMSO dimethyl sulfoxide
  • 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, tlierapeuiic 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., ethanol
  • fatty acids e.g., oleic acid
  • surfactants e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.glycerol monolaurate, sulfoxides, terpenes (e.g., menthol)
  • amines amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present in v ention in controlled amounts, either with or without another agent.
  • Such patches may be constructed for continuous, pulsatile, or on demand deliver ⁇ ' 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.
  • Administration of the compounds or pharmaceutical composition of the present invention can be effected by any method that enables deli very 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 .
  • Such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly.
  • injection e.g., intravenous injection
  • other routes may be used as appropriate.
  • a single dose of a compound of the invention may also be used for treatment of an acute condition.
  • a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • Administration of the compounds of the invention may continue as long as necessary.
  • a compound of the invention is administered for more than I, 2, 3, 4, 5, 6, 7, 14, or 28 days.
  • a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day.
  • a compound of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
  • An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneal ly, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
  • a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty.
  • compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis.
  • a compound of the invention may be administered, for example, by local delivery from the stmts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent.
  • a compound of the invention is admixed with a matrix.
  • Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent.
  • Polymeric matrices suitable for such use include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g.
  • 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 brash -coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores.
  • stents When implanted, the compound diffuses out of the body of the stent to contact the arterial wall.
  • 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 drag 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 intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis.
  • the compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure.
  • the subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • 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 downreguiation 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, cell receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50% IC, or IC50).
  • IC50 refers to the plasma concentration required for obtaining 50%> of a maximum effect in vivo.
  • the subject methods utilize a PRMT5 inhibitor with an IC50 value of about or less than a predetermined value, as ascertained in an in vitro assay.
  • the PRMT5 inhibitor inhibits PRMT5 a with an IC50 value of about 1 nM or less, 2 nM or less, 5 n : or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300
  • the PRMT5 inhibitor selectively inhibits PRMT5 a with an IC50 value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times less (or a number in the range defined by and including any two numbers above)than its IC50 value against one, two, or three other PRMTs.
  • the 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.
  • PRMTS has been implicated, for example, in a variety of human cancers as well as a number of hemoglobinopathies.
  • Non- limiting examples of such conditions include but are not limited to Acanthoma, Acinic cell carcinoma, Acoustic neuroma, Acral lentigmous melanoma,
  • Acrospiroma Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute lymphocytic leukemia, Acute megakaryoblastic leukemia.
  • Adult T-cell leukemia Aggressive N -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
  • Bronchioloalveolar carcinoma Brown tumor, Burkitt's lymphoma, Cancer of Unknown Primary Site, Carcinoid Tumor, Carcinoma, Carcinoma in situ, Carcinoma of the penis, Carcinoma of Unknown Primary Site, Carcinosarcoma, Castleman's Disease, Central Nervous System
  • Cholangiocarcmoma Chondroma, Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus papilloma.
  • Chronic Lymphocytic Leukemia Chronic monocytic leukemia, Chronic myelogenous leukemia, Chronic Myeloproliferative Disorder, Chronic neutrophilic leukemia, Clear-cell tumor, Colon Cancer, Colorectal cancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Degos disease, Dermatofrbrosarcoma protuberans, Dermoid cyst, Desmopiastic small round cell tumor, Diffuse large B cell lymphoma, Dysembryoplastic neuroepithelial tumor, Embryonal carcinoma, Endodermal sinus tumor, Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor, Enteropathy-associated T-cell lymphoma, Ependymoblastoma, Ependymoma, Epider
  • 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.
  • SCD sickle cell disease
  • Hemangiosarcoma Hematological malignancy, Hepatocellular carcinoma, Hepatosplenic T-cell lymphoma, Hereditary breast-ovarian cancer syndrome, Hodgkin Lymphoma, Hodgkin's lymphoma, Hypopharyngeal Cancer, Hypothalamic Glioma, Inflammatory breast cancer, Intraocular Melanoma, Islet cell carcinoma, Islet Cell Tumor, juvenile myelomonocytic leukemia, Kaposi Sarcoma, Kaposi's sarcoma, Kidney Cancer, Klatskin tumor, Krukenberg tumor. Laryngeal Cancer, Laryngeal cancer. Lentigo maligna melanoma, Leukemia, Lip and Oral Cavity Cancer, Liposarcoma, Lung cancer, Luteoma, Lymphangioma,
  • Lymphangiosarcoma Lymphoepithelioma
  • Lymphoid leukemia Lymphoma
  • Macroglobulinemia Malignant Fibrous Histiocytoma, Malignant fibrous histiocytoma, Malignant Fibrous Histiocytoma of Bone, Malignant Glioma, Malignant Mesothelioma, Malignant peripheral nerve sheath tumor, Malignant rhabdoid tumor, Malignant tnton tumor, MALT lymphoma, Mantle cell lymphoma, Mast cell leukemia, Mastocytosis, Mediastinal germ cell tumor, Mediastinal tumor, Meduilaiy thyroid cancer, Medulloblastoma, Medulloblastoma, Meduiloepithelioiria, Melanoma, Melanoma, Meningioma, Merkel Ceil Carcinoma,
  • 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 Cavit 7 Cancer, Nasopharyngeal Cancer, Nasopharyngeal carcinoma, Neoplasm, Neurinoma, Neuroblastoma, Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-Hodgkin Lymphoma, Non-Hodgkin lymphoma, Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, ocular oncology, Oligoastrocytoma, Oligodendroglioma, Oncocytoma, Optic nerve sheath meningioma. Oral Cancer, Oral cancer. Oropharyngeal Cancer, Osteosarcoma,
  • Osteosarcoma Osteosarcoma, Ovarian Cancer, Ovarian cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Paget's disease of the breast, Pancoast tumor.
  • Pancreatic Cancer Pancreatic cancer, Papillary thyroid cancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer, Parathyroid Cancer, Penile Cancer, Perivascular epithelioid cell tumor, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumor of Intermediate
  • Pineoblastoma Pineoblastoma, Pituicytoma, Pituitary adenoma, Pituitary tumor, Plasma Ceil Neoplasm, Pleuropulmonary blastoma, Polyembryoma, Precursor T-lymphoblastic lymphoma, Primary central nervous system lymphoma, Primary effusion lymphoma, Primary Hepatocellular Cancer, Primary Liver Cancer, Primary peritoneal cancer, Primitive neuroectodermal tumor, Prostate cancer, Pseudomyxoma peritonei, Rectal Cancer, Renal cell carcinoma, Respiratory Tract Carcinoma Involving the NUT Gene onChromosome 15, Retinoblastoma, Rhabdomyoma, Rhabdomyosarcoma, Richter's transformation, Sacrococcygeal teratoma.
  • Salivary Gland Cancer Sarcoma, Schwannomatosis, Sebaceous gland carcinoma, Secondary neoplasm, Seminoma, Serous tumor, Sertoli-Leydig cell tumor. Sex cord-stromal tumor, Sezary Syndrome, Signet ring cell carcinoma, Skin Cancer, Small blue round cell tumor, Small cell carcinoma, Small Cell Lung Cancer, Small cell lymphoma, Small intestine cancer, Soft tissue sarcoma,
  • Somatostatinoma Soot wart, Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma, Squamous cell carcinoma. Stomach cancer, Superficial spreading melanoma,
  • Supratentorial Primitive Neuroectodermal Tumor Surface epithelial-stromal tumor, Synovial sarcoma, T-ceil acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-ceii leukemia, T-cell lymphoma, T-cell prolymphocyte leukemia, Teratoma, Terminal lymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, Thymic Carcinoma, Thymoma, Thyroid cancer, Transitional Cell Cancer of Renal Pelvis and Ureter, Transitional cell carcinoma, Urachal cancer, Urethral cancer.
  • Urogenital neoplasm Uterine sarcoma, Uveal melanoma, Vaginal Cancer, Verner Morrison syndrome, Verrucous carcinoma, Visual Pathway Glioma, Vulvar Cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor, or any combination thereof.
  • said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer,
  • a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma
  • diabetes diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangio
  • f 333j Hi stone methylation is performed in the presence of DMSO, and 1 -40 ⁇ . ⁇ inhibitor compounds.
  • the first assay that is carried out explored activity on PRMT5 alone in order to calculate an ICso by using 2 ug of HeLa S3 core histones and 500 ng of recombinant PRMT1, 500 ng of recombinant PRMT4, 5 uL of affinity-purified hSWI/SNF associated PRMT5, or 15 ⁇ of affinity- purified hSWI/SNF associated F1 -PRMT7 in a 25 uL reaction mixture containing 15 niM HEPES (pH 7.9), 100 mM KC1, 5 mM MgC12, 20% glycerol, 1 mM EDTA, 0.25 mM dithiothreitol, 0.5 mM phenylmethylsulfonyl fluoride, and 2.75 Ci of S ⁇
  • [3H]adenosylmethionine (SAM) (Amersham Pharmacia Biotech., Inc.). After 1.5 h incubation at 30°C, reaction mixtures are spotted on Whatman P-81 filter paper, washed five times with 10 mL of 0.1 mM sodium carbonate buffer (pH 9.0) to remove unincorporated [3H]SAM, and methylated peptides are detected by scintillation counting.
  • Compounds of the disclosure include, for example, the compounds identified '
  • Step 6 Synthesis of l-((3aR,4R,6S,6aS)-2,2-dime1hyl-6-((methyltliio)me1hyl)telTaliy(kofuro[3,4- d][l,3]dioxol-4-yl)-3-iodo-lH-pyrazolo[3,4-d]pyrimidine (2f)
  • Step 1 Synthesis of l-((3aR,4R,6S,6aS)-2,2 -dimet yl-6 -
  • Example 25 ⁇ 2R.2RAS, 5,S)-2-(3 -amino- lH-py razoio [3 ,4-a pyrimidin- 1 -y l)-5 - ((methylthio)methyl)tetrahydrofuran ⁇ 3,4-diol (25)
  • Step 1 Synthesis of l -((3aR,4R,6S,6aS) ⁇ 2,2 ⁇ dimethyl -6- ((methylthio)rnethyl)tetrahydrofuro
  • N-emyl-N-isopropyl-propan-2 -amine (1.5 lmL, 8.64 mmol) was added to a suspension of the crude acid, N-methoxymethanan ine;hydrochloride (632.35mg, 6.48 mmol).
  • Propylphosphonic Acid Anhydride (5.5rnL, 8.64 mmol) in Ethyl acetate (20 mL) at 0 °C.
  • the reaction mixture became clear and was stirred at RT. A few minutes later, the precipitate was formed again. TLC showed the completion of the reaction.
  • the reaction mixture was poured on ice, which was extracted by EtOAc 2X. The combined organic layers was washed with water, sat. aq.
  • 6-yl]-(3,4-difluorophenyl)methanol (65f) (370. mg, 0.767 mmol), cuprous iodide ( 15.6 mg, 0.080 mmol), Pd(PPli3)4 (45 mg, 0.040 mmol), and triethylamine (0.7 mL, 5 mmol) under Ar was charged with DMF (3 mL) and sparged with Ar for 2 min. The mixture was charged with ethynyl(trimethyl)silane (0.32 mL, 2.3 rnmol) dropwise over 1 min while still sparging, and then stirred at 80 °C for 5 h.
  • Step 8 Synthesis of (R)-
  • Rf 0.5 (10% MeOH m DCM): H NMR (400 MHz, DMSO-ifc + D20) 6 9.04 (s, IH), 8.89 (s, I I I). 8.20 (s, 1H), 7.43 - 7.31 (m, 2H), 7,2,3 ⁇ .
  • reaction mixture was stirred at 25 °C for 18 h under N 2 .
  • the reaction mixture was diluted with EA (100.0 mL) and washed with H2O (25.0 mL X 2), dried over Na2S04, filtered and concentrated in vacuum to give crude product which was purified by silica gel column chromatography, eluted with PE : EA from 3 : 1 to 1 : 1 to give (3aS,4S,6R,6aR)-6-(4-amino-3 -((tiiisopropylsilyl)etliynyi)-lH-pyrazolo
  • Example 113 and Example 114 (2 ?,3 ?,4>?>,5 ?)-2-(4-amiiio-3-vinyl-lH-pyrazolo[3,4- d]pyrimidm ⁇ i ⁇ yl) ⁇ S ⁇ ((i?) ⁇ (4-chlorophenyiX ⁇ (113) and
  • Step 4a Synthesis of (2i?,3i?,45',5i?)-2-(4-amino-3-vinyl-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-5-
  • Step 4b Synthesis of (2i?,3 ?,45,5 ?)-2-(4-amino-3-viny]-lH-pyrazolo[3,4-£3 ⁇ 4pyrimidin-l-y ⁇ ((5)-(4-chlorophenyl)(hydroxy)methyl)tetrahydrofuran-3,4-diol (114)
  • NaBH4 (lO.mg, 0.2600 mmol) was added to a solution of[(R)- [(3aR,4R,6R,6aR)-4-(5-acetylpyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][l ,3]dioxol-6-yl]-(3,4-difluorophenyl)methyl] benzoate (11.6b) (55.mg, 0.10 mmol) in Methanol (1 rnL) at RT. The resulting solution was stirred at RT for 1 hr.
  • LCMS showed >80% of hydrolysis based on LTV trace.
  • the reaction mixture was diluted with EtOAc, which was washed with sat. aq. NH4CI, brine, dried over Na2S04, filtered and concentrated.
  • difluorophenyl)methanol (66c) ( lOO.mg, 0.20 mmol), 1-Ethoxyvinyltri-n-butyltin (O. lmL, 0.3000 mmol), and dichioromethaiieidichioropalladiimi ⁇ l'-diphenylphosphanyiferi cen-l-yl)- diphenyl-phosphane (8.2mg, 0.010 mmol) in dry 1 ,4-Dioxane (2 mL) was purged with N2, sealed and heated at 95 °C overnight.
  • yljethanone (30 mg, 0,065 mmol) was dissolved in a mixed solvent: TFA (0.25mL, 3 mmol) and Water (0.25 mL) . The resulting mixture was stirred at RT for 2hr, cooled to 0 °C, cone. aq. NH4OH was added and pH was ⁇ 8. The resulting mixture was concentrated and inorganic salt was filter.
  • reaction mixture was quenched with water (100 ⁇ ,), concentrated under reduced pressure, and purified by FCC (40 g SiCh, ()-- ⁇ 30% EtOAc in hexanes, wet-loaded in DCM). Mixed fractions were combined and repurified by FCC (12 g Gold Redisep SiO?., 0 ⁇ 30% EtOAc in hexanes, wet-loaded in DCM). Fractions containing pure desired product from both purifications were combined and concentrated under reduced pressure to yield 1.18c (277 mg, 0.395 mmol, 32% yield) as a white foam.
  • a 5 mL microwave vial containing a mixture of 118c (276 mg, 0. 10 mmol) in 1,4-dioxane (3 mL) was sparged with Ar for 5 min, charged with ammonium hydroxide ( 1.1 mL, 28 mmol), and heated in a microwave reactor at 120 °C for 3 h.
  • the reaction mixture was charged with hydrazine solution, 1.0 M in THF (2 mL, 2 mmol) and heated in a microwave reactor at 120 °C for 8 h.
  • the reaction mixture was diluted with EtOAc (60 mL), washed with sat.
  • the flask was charged with 1 ,4-dioxane (900 uL) and Water (90 uL), purged with for 2 min, then charged with 4,4,5,5-tetramethyl-2-vinyl- l,3,2-dioxaborolane (1 15 uL, 0.680 mmol) and heated at 60 °C for 3 h.
  • the reaction mixture was diluted with EtOAc (80 mL), washed with water (2x 80 mL), brine (40 mL), and dried over Na2S04.

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  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pyrrole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule I, de formule II et de formule III. L'invention concerne également des procédés d'utilisation et de préparation de ces composés.
PCT/US2017/060396 2016-11-07 2017-11-07 Inhibiteurs sélectifs de la protéine arginine méthyltransférase 5 (prmt5) WO2018085833A2 (fr)

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US10570140B2 (en) 2017-08-09 2020-02-25 Prelude Therapeutics Incorporated Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
US10711007B2 (en) 2018-03-14 2020-07-14 Prelude Therapeutics Incorporated Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)
WO2020206308A1 (fr) * 2019-04-05 2020-10-08 Prelude Therapeutics, Incorporated Inhibiteurs sélectifs de la protéine arginine méthyltransférase 5
US11214574B2 (en) 2018-03-14 2022-01-04 Prelude Therapeutics, Incorporated Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)

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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)
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)
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)
WO2020206308A1 (fr) * 2019-04-05 2020-10-08 Prelude Therapeutics, Incorporated Inhibiteurs sélectifs de la protéine arginine méthyltransférase 5

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