WO2010028193A1 - Composés comprenant des dérivés d'acide pimélique en tant qu'inhibiteurs de hdac - Google Patents

Composés comprenant des dérivés d'acide pimélique en tant qu'inhibiteurs de hdac Download PDF

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WO2010028193A1
WO2010028193A1 PCT/US2009/055954 US2009055954W WO2010028193A1 WO 2010028193 A1 WO2010028193 A1 WO 2010028193A1 US 2009055954 W US2009055954 W US 2009055954W WO 2010028193 A1 WO2010028193 A1 WO 2010028193A1
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alkyl
independently selected
phenyl
amino
alkoxy
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PCT/US2009/055954
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English (en)
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James R. Rusche
Norton P. Peet
Allen T. Hopper
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Repligen Corporation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to methods of identifying compounds useful for treatment of neurological conditions and new compounds for the treatment of neurological conditions.
  • FRDA Friedreich's ataxia
  • Frataxin insufficiency leads to progressive spinocerebellar neurodegeneration resulting in gait and hand in-coordination, slurred speech, muscle weakness and sensory loss with extraneural scoliosis, cardiomyopathy, and diabetes.
  • an affected individual is confined to a wheelchair and in later stages, become completely incapacitated.
  • Most affected individuals die in early adulthood of heart disease.
  • antioxidant- and iron-chelator-based strategies have been used to treat FRDA, these strategies treat only the symptoms of the disease and not the cause, i.e., frataxin deficiency. Therefore, there is a need to develop molecules that could restore frataxin protein expression for the treatment of a neurological condition such as FRDA.
  • Triplet repeat expansion in genomic DNA is associated with many other neurological conditions (e.g., neurodegenerative and neuromuscular diseases) including myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntingdon's disease, spinocerebellar ataxias, amyotrophic lateral sclerosis, Kennedy's disease, spinal and bulbar muscular atrophy, and Alzheimer's disease. Triplet repeat expansion may cause disease by altering gene expression.
  • neurological conditions e.g., neurodegenerative and neuromuscular diseases
  • myotonic dystrophy e.g., spinal muscular atrophy, fragile X syndrome, Huntingdon's disease, spinocerebellar ataxias, amyotrophic lateral sclerosis, Kennedy's disease, spinal and bulbar muscular atrophy, and Alzheimer's disease.
  • Triplet repeat expansion may cause disease by altering gene expression.
  • HDAC3 inhibitors can be used for the treatment or prevention of certain neurological disorders.
  • the invention features pentane bisamide compounds of Formula (I):
  • R 1 is selected from H, C 1 . 4 alkyl, CM haloalkyl, Ci -4 alkoxycarbonyl, carbamyl, di-Ci_ 4 -alkyl-carbamyl, and CM alkylcarbamyl;
  • Ar 1 is selected from phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by n independently selected R y groups; wherein said phenyl, 6- membered heteroaryl, and 5-membered heteroaryl are each further optionally fused to a phenyl ring, which is optionally substituted by 1 or 2 groups independently selected from halogen, hydroxyl, cyano, nitro, Ci -4 alkyl, C 1 . 4 haloalkyl, Ci -4 alkoxy, CM haloalkoxy, amino, CM alkylamino, and di-Ci. 4 -alkylamino;
  • Ar 2 is selected from phenyl and 6-membered heteroaryl; wherein said phenyl and 6- membered heteroaryl are each substituted at one ortho position by one J group and are each substituted by m independently selected R z groups;
  • J is selected from hydroxyl and amino;
  • L 1 is selected from a bond or CM alkylene, when Ar 1 is an optionally substituted 6- membered heteroaryl or 5-membered heteroaryl; or L 1 is a bond, when Ar 1 is optionally substituted phenyl;
  • L 2 is straight chain C 5 - CO alkylene, wherein (i) the straight chain C 5 - Ce alkylene is optionally substituted by 1, 2, 3, or 4 independently selected R* groups or (ii) one of the carbon atoms of the straight chain C 5 - Ce alkylene is replaced with -O-, provided that the carbon atom replaced with-O- is not the carbon atom that is directedly attached to C(O)NHAr 2 or the carbon atom that is directedly attached to C(O)NR 1 -L l -Ar l ; or
  • L 2 is C 4 -C 6 alkenylene, which is optionally substituted by 1 , 2, 3, or 4 independently selected R x groups; each R" is independently selected from halogen, hydroxyl, oxo, cyano, nitro, CM alkyl, C) -4 alkoxy, Ci -4 haloalkyl, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, and di-Ci -4 - alkylamino; each R y is independently selected from halogen, cyano, nitro, C 1 .
  • Ci -S haloalkoxy C
  • Ci -6 alkylcarbonyl carbamyl, C 1 . 6 alkylcarbamyl, di-Ci. 6 alkylcarbamyl
  • Ci-6 alkylcarbonylamino Ci -6 alkylcarbonyl-(Ci- 4 -alkyl)amino
  • Ci- 6 alkoxycarbonylamino and di- C ⁇ - 6 alkylamino
  • said C 3-7 cycloalkyl, C 2 - 6 heterocycloalkyl, phenyl, C
  • 6 heteroaryl, C3.7 cycloaIkyl-Ci- 4 -alkyl, C 2 - 6 heterocydoalkyl-Ci ⁇ -alkyl, phenyl-Ci -4 -alkyl, and Ci. 6 heteroaryl- Ci. 4 -alkyl are each optionally substituted by 1 , 2, or 3 independently selected R y groups; provided that only one of R y is selected from optionally substituted C 3 - 7 cycloalkyl,
  • each R z is independently selected from halogen, cyano, nitro, hydroxyl, Ci-6 alkyl, C2- 6 alkenyl, C 2 - 6 alkynyl, Ci_ 6 haloalkyl, C 1 . 6 alkoxy, C 1 . 6 haloalkoxy, Ci.
  • Ci- 6 alkoxycarbonylamino Ci- 6 alkoxycarbonylamino, C ⁇ . ⁇ alkylamino, and di-Ci.6 alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R z groups; and wherein said C 3 .
  • R 7 cycloalkyl,C 2 -6 heterocycloalkyl, phenyl, and Ci_6 heteroaryl are each optionally substituted by 1 , 2, or 3 independently selected R z groups; provided that only one of R z is selected from optionally substituted C 3 - 7 cycloalkyl, optionally substituted C 2 - 6 heterocycloalkyl, optionally substituted phenyl, and optionally substituted Ci_ 6 heteroaryl; each R y and R z is independently selected from hydroxyl, cyano, nitro, C 1 - 4 alkoxy, C 1 . 4 haloalkoxy, amino, C 1 . 4 alkylamino, and di-C
  • each R y and R z is independently selected from halogen, hydroxyl, cyano, nitro, C 1 .4 alkyl, C 1 .4 haloalkyl, CM alkoxy, C ⁇ haloalkoxy, amino, Ci -4 alkylamino, and di-Ci-4- alkylamino; n is an integer selected from 0, 1, 2, 3, and 4; and m is an integer selected from 0, 1 , 2, and 3.
  • R z is optionally substituted phenyl or optionally substituted C ⁇ _ 6 heteroaryl; and provided that the compound is not N'-(2-aminophenyl)-N 7 -phenyl-l ,7-heptanedioic acid diamide, N'-(2-aminophenyl)-N 7 -p-tolyl-l ,7-heptanedioic acid diamide, N'-(2- aminopheny I)-N 7 -o-toly 1-1 ,7-heptanedioic acid diamide, N'-(2-aminophenyl)-N 7 -(2- methoxyphenyl)-l,7-heptanedioic acid diamide, N'-(2-aminophenyl)-N 7 -(pyridin-2-yl)-l
  • the compound is other than Nl -(4- aminobiphenyl-3-y])-N7-phenylheptanediamide.
  • the invention features pentane bisamide compounds of Formula (I):
  • R 1 is selected from H, C M alkyl, C M haloalkyl, C M alkoxycarbonyl, carbamyl, di-C
  • Ar 1 is selected from phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by n independently selected R y groups; and wherein said phenyl, 6-membered heteroaryl, and 5-membered heteroaryl may each be optionally fused to a phenyl ring, which is optionally substituted by 1 or 2 groups independently selected from halogen, hydroxyl, cyano, nitro, C M alkyl, C M haloalkyl, Ci -4 alkoxy, C M haloalkoxy, amino, C1.4 alkylamino, and di-Ci-4-alkylamino;
  • Ar is selected from phenyl and 6-membered heteroaryl; wherein said phenyl and 6- membered heteroaryl are each substituted at one ortho position by one J group and are each substituted by m independently selected R z groups; J is selected from hydroxyl and amino;
  • L 1 is selected from a bond or Ci -4 alkylene, when Ar 1 is an optionally substituted 6- membered heteroaryl or 5-membered heteroaryl; or L 1 is a bond, when Ar 1 is optionally substituted phenyl;
  • L 2 is a straight chain C5 alkylene, which is optionally substituted by 1 , 2, 3, or 4 independently selected R" groups; each R x is independently selected from halogen, hydroxyl, cyano, nitro, Ci -4 alkyl, Ci. 4 alkoxy, C M haloalkyl, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, and di-Ci. 4 -alkylamino; each R y is independently selected from halogen, cyano, nitro, Ci-6 alkyl, C 2 -6 alkenyl,
  • Ci_6 alkoxycarbonyl Ci_6 alkoxycarbonyl, C 1 .6 alkylcarbonyl, carbamyl, Q.6 alkylcarbamyl, di-Cj.6 alkylcarbamyl, C1.6 alkylcarbonylamino, Ci_6 alkylcarbonyl-(Ci. 4 -alkyl)amino, Ci_6 alkoxycarbonylamino, and di- C 1 .6 alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R y groups; and wherein said C 3 / 7 cycloalkyl, C 2 -6 heterocycloalkyl, phenyl, C
  • cycloalkyl-C M -alkyl, C 2 - 6 heterocycloalkyl-C M -alkyl, phenyl-Ci. 4 -alkyl, and Ci. 6 heteroaryl- Ci. 4 -alkyl are each optionally substituted by 1 , 2, or 3 independently selected R y groups; provided that only one of R y is selected from optionally substituted C3.7 cycloalkyl, C 2 - 6 heterocycloalkyl, phenyl, C 1 . 6 heteroaryl, C3-7 cycloalkyl-CM-alkyl, C 2-6 heterocycloalkyl-Ci ⁇ -alkyl, phenyl-C
  • each R z is independently selected from halogen, cyano, nitro, hydroxyl, C ⁇ _6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, Ci -6 haloalkyl, C
  • Ci -6 alkoxycarbonylamino amino, C
  • each R y and R z is independently selected from halogen, hydroxyl, cyano, nitro, Ci -4 alkyl, C M haloalkyl, C M alkoxy, C M haloalkoxy, amino, Ci -4 alkylamino, and di-Ci -4 - alkylamino;
  • n is an integer selected from 0, 1, 2, 3, and 4; and
  • m is an integer selected from 0, 1, 2, and 3.
  • the invention features phenylethylene bisamide compounds of Formula (II):
  • Ar 1 is selected from C ⁇ -io aryl and C 1 -9 heteroaryl; each of which is substituted with n independently selected R y groups;
  • R 1 is selected from H, C M alkyl, C M haloalkyl, C M alkoxycarbonyl, carbamyl, di-Ci. 4 -alkyl-carbamyl, and Ci -4 alkylcarbamyl;
  • L 1 is selected from a bond and C M alkylene
  • Ar 2 is selected from phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; wherein said phenyl, 5-membered heteroaryl, and 6-membered heteroaryl are each substituted at one ortho position by one J group and by m independently selected R z groups; and wherein, in addition, said phenyl, 5-membered heteroaryl, and 6-membered heteroaryl may be further optionally fused to a phenyl or C ⁇ _ 6 heteroaryl ring, each of which is optionally substituted by 1 or 2 groups independently selected from halogen, hydroxy!, cyano, nitro, C M alkyl, Ci -4 haloalkyl, Ci -4 alkoxy, C M haloalkoxy, amino, Ci -4 alkylamino, and di-Ci_ 4 - alkylamino; each R a is independently selected from H, Ci-6 alkyl and Ci-6 haloalkyl;
  • R b is selected from Ci_6 alkyl and Ci.6 haloalkyl
  • J is selected from amino and hydroxyl; each R x is independently selected from halogen, hydroxyl, cyano, nitro, Ci -4 alkyl, C
  • R y groups 2, or 3 independently selected R y groups; provided that only one of R y is selected from optionally substituted C3.7 cycloalkyl, C 2 -6 heterocycloalkyl, phenyl, C 1 .6 heteroaryl, C3-7 cycloalkyl-Ci -4 -alkyl, C2-6 heterocycloalkyl-C M -alkyl, phenyl-CM-alkyl, and C ⁇ .(, heteroaryl-CM-alkyl; each R z is independently selected from halogen, cyano, nitro, hydroxyl, Cj.6 alkyl, C 2 .
  • 6 heteroaryl-Ci- 4 -alkyl are each optionally substituted by 1 , 2, or 3 independently selected R z groups; provided that only one of R z is selected from optionally substituted C 3 .7 cycloalkyl and C2-6 heterocycloalkyl; each R y and R z is independently selected from hydroxyl, cyano, nitro, C M alkoxy, C ⁇ - 4 haloalkoxy, amino, Ci -4 alkylamino, and di-Cj.
  • each R y and R z is independently selected from halogen, hydroxyl, cyano, nitro, C M alkyl, C M haloalkyl, C M alkoxy, C M haloalkoxy, amino, C M alkylamino, and di-C ⁇ - 4 - alkylamino; n is an integer selected from 0, 1, 2, 3, and 4; and m is an integer selected from 0, 1, 2, and 3.
  • the invention features bisamide or hydroxamide compounds of Formula (III): and pharmaceutically acceptable salts, hydrates, and solvates thereof; wherein: R 1 is selected from H, C M alkyl, C M haloalkyl, C M alkoxycarbonyl, carbamyl, di-C
  • R a is selected from C ⁇ . ⁇ alkyl, C ⁇ . ⁇ haloalkyl, C 2 - 6 alkenyl, and C2-6 alkynyl; each R b is independently selected from H, Ci_6 alkyl, Ci_6 haloalkyl, C 2 -6 alkenyl, and C 2 -6 alkynyl;
  • Ar 1 is phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by a R y group and by n additional independently selected R y groups;
  • L 2 is straight chain C 5 alkylene, which is optionally substituted by 1, 2, 3, or 4 independently selected R x groups; each R x is independently selected from halogen, hydroxy!, cyano, nitro, Ci -4 alkyl, Ci.
  • each R y is independently selected from halogen, cyano, nitro, Ci- ⁇ alkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyl, C 1 .
  • each R y is independently selected from hydroxyl, cyano, nitro, Ci -4 alkoxy, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, and di-Ci -4 -alkylamino; and n is an integer selected from 0, 1, 2, and 3.
  • compositions e.g., a pharmaceutical composition
  • a pharmaceutical composition which includes a compound of formula (I) (or II or III) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein and a pharmaceutically acceptable carrier.
  • the composition can include an effective amount of the compound or salt.
  • the composition can further include an additional therapeutic agent.
  • the invention relates generally to inhibiting HDAC (e.g., HDACl, HDAC2, and/or HDAC3) with a compound of formula (I) (or II or III) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein.
  • the methods can include, e.g., contacting an HDAC (e.g., HDACl, HDAC2, or HDAC3) in a sample (e.g., a cell or tissue) with a compound of formula (I) (or II) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein.
  • the methods can include administering a compound of formula (I) (or II) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein to a subject (e.g., a mammal, such as a human).
  • a subject e.g., a mammal, such as a human.
  • this invention includes methods of screening for compounds that inhibit (e.g., selectively inhibit) one or more HDACs.
  • methods of selectively inhibiting HDAC3 which includes contacting an HDAC3 in a sample (e.g., a cell or tissue) with a compound of formula (I) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein; or administering a compound of formula (I) (or II or HI) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein to a subject (e.g., a mammal, such as a human).
  • a subject e.g., a mammal, such as a human.
  • methods of selectively inhibiting HDACl or HDAC2 are featured, which include contacting HDACl or HDAC2 (e.g., HDACl) in a sample (e.g., a cell or tissue) with a compound of formula (I) (or II or III)or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein; or administering a compound of formula (I) (or II or HI) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein to a subject (e.g., a mammal, such as a human).
  • a subject e.g., a mammal, such as a human.
  • this application features methods of treating a neurological condition (e.g., Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease) that include administering an HDAC inhibitor described herein to a patient having a neurological condition.
  • a neurological condition e.g., Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease
  • this application features the use of an HDAC inhibitor described herein in the preparation of, or for use as, a medicament for the treatment or prevention of a neurological condition (e.g., Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease).
  • a neurological condition e.g., Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease.
  • this application features methods of treating a cancer (e.g., cutaneous T cell lymphoma, B cell lymphomas, and colorectal cancer), an inflammatory disorder (e.g., psoriasis, rheumatoid arthritis, and osteoarthritis), a neurological condition (e.g., Friedreich's ataxia, myotonic dystrophy, Parkinson's disease, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease), or a Plasmodium falciparum infection (e.g., malaria) that includes administering an HDAC inhibitor described herein to a patient, e.g., a patient having a neurological condition
  • a cancer e.g., cutaneous T cell lymphoma, B cell lymphomas, and colorectal cancer
  • an inflammatory disorder e.g.,
  • this application features the use of an HDAC inhibitor described herein as a medicament, e.g., for the treatment or prevention of a cancer, an inflammatory disorder, a Plasmodium falciparum infection, or a neurological condition (e.g., as listed herein).
  • formula (I) compounds described herein have enhanced (e.g., increased, e.g., increased by a factor of about 2 or more) stabilities in acid.
  • the formula (I) compounds have enhanced resistances to degradation, e.g., less than about 25% degradation (e.g., less than about 20% degradation, less than about 15% degradation, or less than about 10% degradation) when exposed to acidic pH, e.g., acidic conditions intended to mimic those in the stomach, e.g., incubation (e.g., as al O ⁇ M solution) at 50 0 C and at a pH of about 2.0 for about four hours.
  • the resistance of compounds to degradation or metabolism at acidic pH can be a useful feature for a pharmaceutical agent (e.g., a drug).
  • Increased stability at low pH can allow, for example, process preparation steps, such as salt formation, to occur without significant degradation of the desired salt.
  • process preparation steps such as salt formation
  • orally administered pharmaceuticals are stable to the acidic pH of the stomach.
  • Embodiments can include one or more of the following features.
  • Ar 1 is not substituted at the ortho position.
  • Ar 1 is substituted at the para position by C h alky], then Ar 2 is substituted by at least one R z group.
  • L 2 is straight chain Cs alkylene, which is optionally substituted by 1 , 2, 3, or 4 independently selected R" groups (e.g., -CH 2 CH 2 CH 2 CH 2 CH 2 -). m is 0.
  • Each R z is independently selected from halogen, cyano, nitro, Ci ⁇ alkyl, Ci-6 haloalkyl, C
  • Ci ⁇ haloalkoxy are each optionally substituted by 1 or 2 independently selected R z groups; and wherein said C 3 - 7 cycloalkyl, C 2 .6 heterocycloalkyl, phenyl, and Cue heteroaryl are each optionally substituted by 1, 2, or 3 independently selected R z groups.
  • Each R z is independently selected from halogen, cyano, nitro, Ci- ⁇ alkyl, C
  • Each R z is independently selected from halogen, cyano, nitro, Ci ⁇ alkyl, C
  • Each R z is independently selected from halogen, cyano, nitro, Ci- ⁇ alkyl, Ci-6 haloalkyl, Ci_ 6 alkoxy, Ci- ⁇ haloalkoxy.
  • m is 1.
  • R z can be selected from halogen, C
  • R z is halogen (e.g., fluoro).
  • R z can be selected from phenyl and C ⁇ -6 heteroaryl, each of which is optionally substituted by 1 , 2, or 3 independently selected R z groups.
  • R 1 is hydrogen.
  • the compound is a compound of Formula (Ic):
  • Ar 1 is 5-membered heteroaryl; which is substituted by n independently selected R y groups; and Ar 2 is phenyl; which is substituted by m independently selected R z groups; or Ar 1 is 6-membered heteroaryl; which is substituted with n independently selected R y groups; and Ar 2 is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R z groups.
  • Embodiments can include or further include any one or more of the features set forth in detailed description.
  • alkyl, alkoxy, alkenyl, and the like denote both straight and branched groups.
  • alkyl employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched. In some embodiments, the alkyl group contains 1 to 12, 1 to 8, or 1 to 6 carbon atoms.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl- 1 -butyl, n-pentyl, 3-pentyl, n-hexyl, 1 ,2,2-trimethylpropyl, n-heptyl, n-octyl, and the like.
  • the alkyl moiety is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, or 2,4,4-trimethylpentyl.
  • C n - m alkylene refers to a divalent alkyl linking group having n to m carbon atoms.
  • alkylene groups include, but are not limited to, ethan-l,2-diyl, propan-l,3-diyl, propan-1,2- diyl, butan-l ,4-diyl, butan-l ,3-diyl, butan-l,2-diyl, 2-methyl-propan-l ,3-diyl, and the like.
  • straight chain C n - m alkylene employed alone or in combination with other terms, refers to a non-branched alkylene group of n to m carbon atoms.
  • alkoxy refers to a group of formula -O(alkyl).
  • Alkoxy can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec- butoxy, pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy.
  • aryl employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused or covalently linked rings) aromatic hydrocarbon moiety, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl groups have from 6 to 20 carbon atoms, about 6 to 10 carbon atoms, or about 6 to 8 carbons atoms.
  • heteroaryl refers to a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one (typically one to about three) nitrogen, oxygen, or sulfur atoms in an aromatic ring. Heteroaryl groups can possess optional substituents as described herein.
  • heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H- indolyl, 4H-quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl, ⁇ -carbolinyl, carbazolyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,
  • heteroaryl can include a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1 , 2, 3, or 4 heteroatoms independently selected from non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O, alkyl, phenyl or benzyl.
  • the term heteroaryl can also include an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
  • optionally substituted group refers to the substitution of a group in which one or more hydrogen atoms are each independently replaced with a non- hydrogen substituent.
  • Groups that are optionally substituted are typically substituted with one to five substituents. In other embodiments, optionally substituted groups are substituted with one to three substituents.
  • the phrase "optionally substituted” means unsubstituted (e.g., substituted with a H) or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a substitutent. It is understood that substitution at a given atom is limited by valency.
  • a first ring when a first ring is "optionally fused" to a second ring, the first ring may be unfused, or may be fused to the second ring.
  • a phenyl ring optionally fused to a phenyl ring refers to either an unfused phenyl ring or a naphthalene ring.
  • a ring "substituted at one ortho position” refers to a ring substituted at the position of the ring directly adjacent to the point of attachment of the ring to the core moiety (e.g. the core moiety of Formula (I)).
  • substituents of compounds described herein are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • the term "Ci- 6 alkyl” is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • n-membered where n is an integer typically describes the number of ring- forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • 1 ,2,3,4-tetrahydro- naphthalene is an example of a 10-membered cycloalkyl group.
  • each variable can be a different moiety independently selected from the group defining the variable.
  • the two R groups can represent different moieties independently selected from the group defined for R.
  • an optionally multiple substituent is designated in the form:
  • substituent R can occur/? number of times on the ring, and R can be a different moiety at each occurrence. It is understood that each R group may replace any hydrogen atom attached to a ring atom, including one or both of the (CH 2 )P hydrogen atoms. Further, in the above example, should the variable Q be defined to include hydrogens, such as when Q is said to be CH 2 , NH, etc., any floating substituent such as R in the above example, can replace a hydrogen of the Q variable as well as a hydrogen in any other non- variable component of the ring.
  • C n . m (e.g., Ci -4 , C ⁇ . ⁇ , and the like) is used, wherein n and m are integers and indicate the number of carbons, wherein n-m indicates a range which includes the endpoints.
  • C ⁇ _6 heteroaryl-Ci. 4 alkyl refers to a moiety of heteroaryl-alkylene-, wherein the heteroaryl group has 1 to 6 carbon atoms, the alkylene linker has 1 to 4 carbons, and the substituent is attached through the alkylene linker.
  • C n . m alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds with n to m carbon atoms.
  • Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn- 2-yl, and the like.
  • the alkynyl moiety contains 2 to 10 or 2 to 6 carbon atoms.
  • C n - m alkynylene refers to a divalent alkynyl group having n to m carbon atoms.
  • the alkynylene moiety contains 2 to 12 carbon atoms. In some embodiments, the alkynylene moiety contains 2 to 6 carbon atoms.
  • Example alkynylene groups include, but are not limited to, ethyn-l ,2-diyl, propyn-l ,3,-diyl, l-butyn-l ,4-diyl, l-butyn-l ,3-diyl, 2- butyn-l ,4-diyl, and the like.
  • C n . m alkenyl employed alone or in combination with other terms, refers to an alkyl group having one or more double carbon-carbon bonds, with n to m carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 10 or 2 to 6 carbon atoms.
  • Example alkenyl groups include, but are not limited to, ethenyl, «-propenyl, isopropenyl, n- butenyl, jec-butenyl, and the like.
  • alkenylene employed alone or in combination with other terms, refers to a divalent alkenyl group.
  • the alkenylene moiety contains 2 to 12 carbon atoms. In some embodiments, the alkenylene moiety contains 2 to 6 carbon atoms.
  • Example alkenylene groups include, but are not limited to, ethen-l ,2-diyl, propen-l ,3-diyl, propen-l ,2-diyl, buten-l,4-diyl, buten-l ,3-diyl, buten-l ,2-diyl, 2-methyl- propen-l ,3-diyl, and the like.
  • amino employed alone or in combination with other terms, refers to a group of formula -NH 2 .
  • C n - m alkylamino employed alone or in combination with other terms, refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms.
  • di-C n - m -alkylamino employed alone or in combination with other terms, refers to a group of formula -N(alkyl)2, wherein the alkylene group and two alkyl groups each has, independently, n to m carbon atoms.
  • carbamyl employed alone or in combination with other terms, refers to a group of formula -C(O)NHi.
  • C- m alkylcarbamyl employed alone or in combination with other terms, refers to a group of formula -C(O)-NH(alkyl), wherein the alkyl group has n to m carbon atoms.
  • di-C n - m -alkylcarbamyl refers to a group of formula -C(O)N(alkyl) 2 , wherein the alkyl group has n to m carbon atoms.
  • C n - m alkoxycarbonyl employed alone or in combination with other terms, refers to a group of formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms.
  • C n - m alkylcarbonyl employed alone or in combination with other terms, refers to a group of formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms.
  • C n - m alkylcarbonylamino employed alone or in combination with other terms, refers to a group of formula -NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms.
  • C n - m alkylcarbonyl-(C n - m alkyl)amino employed alone or in combination with other terms, refers to a group of formula -N(alkyl)C(O)-alkyl, wherein each alkyl group, independently, has n to m carbon atoms.
  • C n - m alkoxycarbonylamino employed alone or in combination with other terms, refers to a group of formula -NHC(O)O-alkyl, wherein the alkyl group has n to m carbon atoms.
  • carbonyl employed alone or in combination with other terms, refers to a -C(O)- group, which is a divalent one-carbon moiety further bonded to an oxygen atom with a double bond.
  • carboxy employed alone or in combination with other terms, refers to a group of formula -C(O)OH.
  • cycloalkyl employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon moiety, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused or covalently linked rings) ring systems.
  • moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example,
  • cycloalkyl also includes bridgehead cycloalkyl groups and spirocycloalkyl groups.
  • bridgehead cycloalkyl groups refers to non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as adamantazn-1-yl.
  • spirocycloalkyl groups refers to non-aromatic hydrocarbon moieties containing at least two rings fused at a single carbon atom, such as spiro[2.5]octane and the like.
  • the cycloalkyl group has 3 to 14 ring members, 3 to 10 ring members, or 3 to 8 ring members.
  • One or more ring- forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcarnyl, adamantyl, and the like.
  • the cycloalkyl group is admanatan-1 -yl.
  • cyano employed alone or in combination with other terms, refers to a group of formula -CN, wherein the carbon and nitrogen atoms are bound together by a triple bond.
  • haloalkyl employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2n+l halogen atoms which may be the same or different, where "n” is the number of carbon atoms in the alkyl group.
  • the halogen atoms are fluoro atoms.
  • haloalkoxy employed alone or in combination with other terms, refers to a group of formula -O-haloalkyl.
  • An example haloalkoxy group is OCF 3 .
  • the halogen atoms are fluoro atoms.
  • C o - p heteroaryl-C- m -alkyl employed alone or in combination with other terms, refers to a group of formula -alky lene-heteroaryl, the alkylene linker has n to m carbon atoms and the heteroaryl group has 0 to p carbon atoms. In some embodiments, the alkylene portion has 1 to 4 carbon atoms.
  • C o -pCycloalkyl-Cn-m-alkyl refers to a group of formula -alkylene-cycloalkyl, the alkylene linker has n to m carbon atoms and the cycloalkyl group has 0 to p carbon atoms. In some embodiments, the alkylene portion has 1 to 4 carbon atoms.
  • C o -paryl-C-m-alkyl refers to a group of formula -alky lene-aryl, the alkylene linker has n to m carbon atoms and the aryl group has o to p carbon atoms. In some embodiments, the alkylene portion has 1 to 4 carbon atoms.
  • phenyl-C n - m -alkyl employed alone or in combination with other terms, refers to a group of formula -alkylene-phenyl, the alkylene linker has n to m carbon atoms. In some embodiments, the alkylene portion has 1 to 4 carbon atoms.
  • C o-p heterocycloalkyl-C n - m -alkyl refers to a group of formula -alkylene-heterocycloalkyl, the alkylene linker has n to m carbon atoms and the heterocycloalkyl group has o to p carbon atoms. In some embodiments, the alkylene portion has 1 to 4 carbon atoms.
  • heterocycloalkyl refers to a group of formula -alkylene-heterocycloalkyl
  • the alkylene linker has n to m carbon atoms
  • the heterocycloalkyl group has o to p carbon atoms.
  • the alkylene portion has 1 to 4 carbon atoms.
  • heterocycloalkyl “heterocycloalkyl ring,” or
  • heterocycloalkyl group employed alone or in combination with other terms, refers to a non-aromatic ring system, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure, and which has at least one heteroatom ring member selected from nitrogen, sulfur, and oxygen.
  • heteroatom ring member selected from nitrogen, sulfur, and oxygen.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused or covalently bonded rings) ring systems. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic ring, for example, 1 ,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups and spiroheterocycloalkyl groups.
  • bridgehead heterocycloalkyl group refers to a heterocycloalkyl moiety containing at least one bridgehead atom, such as azaadamantan- 1 - yl and the like.
  • spiroheterocycloalkyl group refers to a heterocycloalkyl moiety containing at least two rings fused at a single atom, such as [1 ,4-dioxa-8-aza- spiro[4.5]decan-N-yl] and the like.
  • the heterocycloalkyl group has 3 to 20 ring-forming atoms, 3 to 10 ring-forming atoms, or about 3 to 8 ring forming atoms.
  • the carbon atoms or hetereoatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized.
  • a pyrazole ring the term is intended to refer to a pyrazole ring attached at any atom of the ring, as permitted by valency rules, and is intended to include various tautomeric forms of the ring.
  • the point of attachment is indicated by the name, e.g., pyrazol-1-yl refers to a pyrazole ring attached at the 1 -position of the ring.
  • pyrazol-1-yl refers to a pyrazole ring attached at the 1 -position of the ring.
  • hydroxyl employed alone or in combination with other terms, refers to a group of formula -OH.
  • any of the above groups that contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns that are sterically impractical and/or synthetically un- feasible.
  • the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds.
  • a base refers to any molecule, ion, or other entity that acts as a proton acceptor.
  • a base can be an organic compound or ion with an unshared electron pair. Typical bases include mono-, di-, and tri-alkyl substituted amines.
  • a base can also be an inorganic compound or ion, such as a metal oxide or metal hydroxide. Bases used in organic synthesis are well known to those of skill in the art. Many bases are disclosed in, for example, the Aldrich Handbook of Fine Chemicals, 2003-2004 (Milwaukee, WI).
  • solvent refers to a substance, usually a liquid, capable of dissolving another substance, e.g., a solid substance, semi-solid substance, or a liquid. Typical solvents include water and organic solvents. It is appreciated by those of skill in the art that the solvent should not chemically react with any of the starting materials or reagents present in the reaction mixture, to any significant degree, under the reaction conditions employed.
  • solvent system refers to a medium that includes one or more solvents.
  • a solvent system can be homogeneous (miscible solvents) or heterogeneous (e.g., an organic/aqueous system).
  • purifying refers to the process of ridding a substrate (e.g., crystals, an amorphous solid, a liquid, or an oil) of impurities. Suitable methods of purifying include, for example, filtering, washing, recrystallizing and drying, distilling, and chromatography.
  • isolated and purified refer to substances that are at least about 90% of other agents, for example, at least about 95%, , at least about 98%, or at least about 99% pure by weight.
  • anhydrous refers to a substance that contains less than 10 wt.% water, less than about 1 wt.% water, less than about 0.5 wt.% water, less than about 0.1 wt.% water, e.g., or less than about 0.01 wt.% water.
  • Anhydrous conditions refer to reaction conditions that have less than 2 wt.% water, e.g. less than about 1 wt.% water, less than about 0.5 wt.% water, less than about 0.1 wt.% water, or less than about 0.01 wt.% water present.
  • contacting refers to the act of touching, making contact, or of bringing into immediate proximity.
  • Compounds are typically contacted by forming a solution in a suitable solvent system.
  • the numerical ranges given herein are those amounts that provide functional results in the composition.
  • ranges are generally introduced with the term “about” to indicate a certain flexibility in the range.
  • the term “about” can refer to +/- one integer from a given number or the upper or lower limit of range.
  • the term “about” can refer to +/- two integers from a given number or the upper or lower limit of range.
  • the term “about” can also refer to +/- 20% of a given number or numerical range.
  • the term “about” can refer to +/- 10%, or +/- 5% of a given number or numerical range.
  • the term “about” refers to +/- 1%.
  • the term “about” refers to exactly the given number or numerical range.
  • FIG 1 is a bar graph depicting fold-upregulation of frataxin mRNA expression in human cells after administration of the indicated concentrations of the HDAC3-specific histone deacetylase inhibitor RGFA8.
  • This application provides new HDAC inhibitor compounds, including compounds that specifically inhibit HDAC3 or HDCAl and/or HDAC2. Described herein are compounds of Formulas (I)-(III), methods of making the compounds, and methods of using the compounds to treat certain disorders, e.g., neurological disorders, cancers, inflammatory disorders, and malaria.
  • the invention features pentane bisamide compounds of Formula (I):
  • R 1 is selected from H, C 1 . 4 alkyl, CM haloalkyl, C 1 . 4 alkoxycarbonyl, carbamyl, di-C
  • Ar 1 is selected from phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by n independently selected R y groups; wherein said phenyl, 6- membered heteroaryl, and 5-membered heteroaryl are each further optionally fused to a phenyl ring, which is optionally substituted by 1 or 2 groups independently selected from halogen, hydroxyl, cyano, nitro, C 1 . 4 alkyl, CM haloalkyl, CM alkoxy, CM haloalkoxy, amino, Ci -4 alkylamino, and di-C
  • Ar 2 is selected from phenyl and 6-membered heteroaryl; wherein said phenyl and 6- membered heteroaryl are each substituted at one ortho position by one J group and are each substituted by m independently selected R z groups; J is selected from hydroxyl and amino;
  • L 1 is selected from a bond or CM alkylene, when Ar 1 is an optionally substituted 6- membered heteroaryl or 5-membered heteroaryl; or
  • L 1 is a bond, when Ar 1 is optionally substituted phenyl
  • L 2 is straight chain C 5 - Ce alkylene, wherein (i) the straight chain C 5 - Ce alkylene is optionally substituted by 1 , 2, 3, or 4 independently selected R x groups or (ii) one of the carbon atoms of the straight chain C 5 - Ce alkylene is replaced with -O-, provided that the carbon atom replaced with-O- is not the carbon atom that is directedly attached to C(O)NHAr 2 or the carbon atom that is directedly attached to C(O)NR'-L'-Ar'; or
  • L 2 is C4-C 6 alkenylene, which is optionally substituted by 1, 2, 3, or 4 independently selected R x groups; each R x is independently selected from halogen, hydroxyl, oxo, cyano, nitro, C1.4 alkyl, C 1 .
  • each R y is independently selected from halogen, cyano, nitro, C ⁇ . ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C ⁇ . ⁇ haloalkyl, C ⁇ . ⁇ alkoxy, Cj.6 haloalkoxy, C1.6 alkoxycarbonyl, C1.6 alkylcarbonyl, carbamyl, C
  • . 6 alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R y groups; and wherein said C 3 . 7 cycloalkyl, C 2 - 6 heterocycloalkyl, phenyl, C ⁇ _ 6 heteroaryl, C 3 .7 cycloalkyl-Ci ⁇ -alkyl, C 2 - 6 heterocycloalkyl-Ci ⁇ -alkyl, phenyl-C
  • R 4 -alkyl, and C ⁇ -6 heteroaryl- C ⁇ - 4 -alkyl are each optionally substituted by 1 , 2, or 3 independently selected R y groups; provided that only one of R y is selected from optionally substituted C 3 .7 cycloalkyl, C 2 - 6 heterocycloalkyl, phenyl, C
  • Ci_ 6 alkyl C2- 6 alkenyl, C 2-6 alkynyl, C ⁇ . ⁇ haloalkyl, Ci-6 alkoxy, Ci- ⁇ haloalkoxy, C
  • Ci -6 alkoxycarbonylamino, C ⁇ _6 alkylamino, and di-Ci- 6 alkylamino are each optionally substituted by 1, 2, or 3 independently selected R z groups; and wherein said C 3 .7 cycloalkyl,C 2 - 6 heterocycloalkyl, phenyl, and Ci- ⁇ heteroaryl are each optionally substituted by 1 , 2, or 3 independently selected R z groups; provided that only one of R z is selected from optionally substituted C 3 .7 cycloalkyl, optionally substituted C 2 - 6 heterocycloalkyl, optionally substituted phenyl, and optionally substituted C 1.
  • each R y and R z is independently selected from hydroxyl, cyano, nitro, C M alkoxy, C M haloalkoxy, amino, C 1 . 4 alkylamino, and di-C
  • n is an integer selected from 0, 1 , 2, 3, and 4; and m is an integer selected from 0, 1 , 2, and 3; provided that when L 2 is straight chain C O alkylene, then m 1 , 2, and 3, and one occurrence of R z is optionally substituted phenyl or optionally substituted Ci -6 heteroaryl; and provided that the compound is not N'-(2-aminophenyl)-N 7 -phenyl-l ,7-heptanedioic acid diamide, N'-(2-aminophenyl)-N 7 -p-tolyl-l ,7-heptanedioic acid diamide, N'-(2- aminophenyl)-N 7 -o-tolyl-l ,7-heptanedioic acid diamide, N'-(2-aminophenyl)-N 7 -(2- methoxyphenyl)-l ,7-heptanedio
  • the compound is other than Nl -(4- aminobiphenyl-3-yl)-N7-phenylheptanediamide.
  • the invention features pentane bisamide compounds of Formula (I):
  • R 1 is selected from H, C 1 . 4 alkyl, CM haloalkyl, CM alkoxycarbonyl, carbamyl, di-C
  • Ar 1 is selected from phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by n independently selected R y groups; and wherein said phenyl, 6-membered heteroaryl, and 5-membered heteroaryl may each be optionally fused to a phenyl ring, which is optionally substituted by 1 or 2 groups independently selected from halogen, hydroxyl, cyano, nitro, CM alkyl, CM haloalkyl, CM alkoxy, Ci -4 haloalkoxy, amino, CM alkylamino, and di-C ⁇ - 4 -alkylamino;
  • Ar 2 is selected from phenyl and 6-membered heteroaryl; wherein said phenyl and 6- membered heteroaryl are each substituted at one ortho position by one J group and are each substituted by m independently selected R z groups;
  • J is selected from hydroxyl and amino;
  • L 1 is selected from a bond or CM alkylene, when Ar 1 is an optionally substituted 6- membered heteroaryl or 5-membered heteroaryl; or
  • L 1 is a bond, when Ar 1 is optionally substituted phenyl
  • L 2 is a straight chain Cs alkylene, which is optionally substituted by 1 , 2, 3, or 4 independently selected R x groups; each R x is independently selected from halogen, hydroxyl, cyano, nitro, CM alkyl, C
  • each R y is independently selected from halogen, cyano, nitro, Ci- 6 alkyl, C 2 _6 alkenyl, C 2 - 6 alkynyl, Ci- 6 haloalkyl, C ⁇ _ 6 alkoxy, Ci- 6 haloalkoxy, C1.6 alkoxy carbony I, C
  • Ci- 6 alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R y groups; and wherein said C 3 . 7 cycloalkyl, C 2 - 6 heterocycloalkyl, phenyl, C
  • .6 heteroaryl- C ⁇ - 4 -alkyl are each optionally substituted by 1 , 2, or 3 independently selected R y groups; provided that only one of R y is selected from optionally substituted Cj,. ⁇ cycloalkyl,
  • each R z is independently selected from halogen, cyano, nitro, hydroxyl, Ci_6 alkyl, C2. 6 alkenyl, C 2 - 6 alkynyl, Ci. 6 haloalkyl, Ci-6 alkoxy, C
  • Ar' is not substituted at the ortho position.
  • Ar 1 when Ar 1 is substituted at the para position by C 1 . 6 alkyl, then Ar 2 is substituted by at least one R z group.
  • Ar 1 when Ar 1 is substituted at the para position by Ci ⁇ alkyl, then Ar 2 is substituted by at least one R z group selected from halogen.
  • the following provisos apply: (a) Ar 1 is not substituted at one ortho position, and (b) when Ar 1 is substituted at the para position by C 1 .6 alkyl, then Ar is substituted by at least one R z group.
  • each R y is independently selected from halogen, cyano, nitro, Ci-6 alkyl, C 2 -6alkenyl, C 2 -6alkynyl, C ⁇ _6 haloalkyl, C
  • Ci- ⁇ heteroaryl-Ci ⁇ -alkyl are each optionally substituted by 1, 2, or 3 independently selected R y groups; with the proviso that only one of R y is selected from optionally substituted C 3 .7 cycloalkyl, C 2 -6 heterocycloalkyl, phenyl, C
  • each R y is independently selected from halogen, cyano, nitro, Ci- ⁇ alkyl, Ci.6 haloalkyl, Ci- ⁇ alkoxy, Ci.6 haloalkoxy, phenyl, Ci_ 6 heteroaryl, C 3 . 7 cycloalkyl-C M -alkyl, and C 2 -6 heterocycloalkyl-Ci- 4 -alkyl; wherein said Q- 6 alkyl, C
  • cycloalkyl-Ci- 4 -alkyl, and C 2-6 heterocycloalkyl-Ci- 4 -alkyl are each optionally substituted by 1 or 2 independently selected R y groups; provided that only one of R y is selected from optionally substituted phenyl, C 1 -6 heteroaryl, C3.7 Cycloalkyl-Ci.4-alkyl, and C2- 6 heterocycloalkyl-Ci ⁇ -alkyl.
  • each R y is independently selected from halogen, cyano, C 1 .6 alkyl, C 1 . 6 haloalkyl, Ci ⁇ alkoxy, C 1 . 6 haloalkoxy, Ci_6alkoxycarbonyl, C
  • each R y is independently selected from halogen, cyano, C
  • each R y is independently selected from halogen, C 1 .6 alkyl, C 1 .6 haloalkyl, Ci. 6 alkoxy, C 2 - 6 heterocycloalkyl, phenyl, Ci_6 heteroaryl, and C 2 -6 heterocycloalkyl-Ci- 4 -alkyl; wherein said Ci ⁇ alkyl, Ci- ⁇ haloalkyl, Ci- ⁇ alkoxy, and Ci-6 haloalkoxy are each optionally substituted by a R y group; and wherein said phenyl, C1.6 heteroaryl, C 3 .
  • cycloalkyl-Ci ⁇ -alkyl, and C 2 .6 heterocycloalkyl-C M -alkyl are each optionally substituted by a R y group; with the proviso that only one of R y is selected from optionally substituted phenyl, C 1 . 6 heteroaryl, and C 2 -6 heterocycloalkyl-C
  • each R y is independently selected from halogen, cyano, nitro,
  • each R y is independently selected from halogen, cyano, Ci_6 alkyl, Ci -6 haloalkyl, Ci- 6 alkoxy, and C
  • each R y is independently selected from halogen, Ci -4 alkyl, C] -4 haloalkyl, Ci -4 alkoxy, and Ci -4 haloalkoxy. In some embodiments, each R y is independently selected from halogen, C
  • each R y is independently selected from fluoro, methyl, trifluoromethyl, methoxy, phenyl, pyridin-4-yl, pyridin-3-yl, piperidinylmethyl, and morpholin-4-yl-methyl; wherein said methyl is optionally substituted by a R y group; and wherein said phenyl is optionally substituted by a R y group.
  • each R y is phenyl; wherein said phenyl is optionally substituted by a R y group.
  • each R y is independently selected from Ci_6 alkyl and C].6 alkoxy, wherein said C
  • each R z is independently selected from halogen, cyano, nitro, Ci-6 alkyl, C 2 -6alkenyl, C 2 - 6 alkynyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci .6 haloalkoxy, C3.7 cycloalkyl, and C 2 -6heterocycloalkyl; wherein said C
  • cycloalkyl and C 2 - 6 heterocycloalkyl are each optionally substituted by 1, 2, or 3 independently selected R z groups; with the proviso that only one of R z is selected from optionally substituted C3.7 cycloalkyl and C2-6 heterocycloalkyl.
  • each R z is independently selected from halogen, cyano, C h alky!, Ci- 6 haloalkyl, C
  • Ci- ⁇ alkoxycarbonylamino Ci- ⁇ alkoxycarbonylamino, and di-Ci_6 alkylamino; wherein said C
  • each R z is independently selected from halogen, cyano, nitro,
  • each R z is independently selected from halogen, cyano, nitro,
  • each R z is independently selected from halogen, cyano, nitro,
  • each R z is independently selected from halogen, cyano, nitro, Ci.6 alkyl, Q.6 haloalkyl, Ci-6 alkoxy, C
  • each R z is independently selected from halogen, cyano, Ci- 6 alkyl, Ci-6 haloalkyl, Ci_6 alkoxy, and C1.6 haloalkoxy. In some embodiments, each R z is independently selected from halogen, C 1.6 alkyl, C 1 - 6 haloalkyl, Ci_ 6 alkoxy, and Q -6 haloalkoxy. In some embodiments, each R z is independently selected from halogen and Ci_6 alkoxy. In some embodiments, each R z is independently selected from halogen, C 1 . 4 alkyl, C M haloalkyl, Q. 4 alkoxy, and C 1 . 4 haloalkoxy.
  • each R z is independently selected from halogen, C 1 -4 alkyl and C 1 . 4 alkoxy. In some embodiments, each R z is independently selected from C 1 . 4 alkyl and C M alkoxy. In some embodiments, each R z is halogen. In some embodiments, each R z is independently selected from fluoro, methyl, and methoxy. In some embodiments, each R z is fluoro. In some embodiments, each R z is selected from halogen and Ci_ 6 haloalkyl. In some embodiments, each R z is selected from halogen and trifluoromethyl.
  • each R z is selected from phenyl and Q.6 heteroaryl, each of which is optionally substituted by 1, 2, or 3 independently selected R z groups. In some embodiments, each R z is selected from phenyl and C ⁇ . ⁇ heteroaryl. In certain embodiments, each R z is phenyl or phenyl, which is substituted by 1, 2, or 3 independently selected R z groups. In certain embodiments, each R z is C
  • m is 1.
  • R z is selected from halogen, C
  • R z is halogen (e.g., fluoro).
  • R z is selected from phenyl and Ci_ 6 heteroaryl, each of which is optionally substituted by 1 , 2, or 3 independently selected R z groups. In some embodiments, R z is selected from phenyl and C
  • each R y and R z group is independently selected from hydroxyl, cyano, nitro, Ci -4 alkoxy, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, and di-C M - alkylamino. In some embodiments, each R y and R z group is independently selected from hydroxyl, Ci -4 alkoxy, and Ci -4 haloalkoxy. In some embodiments, each R y and R z group is independently selected from hydroxyl, cyano, nitro, Ci -4 alkoxy, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, and di-C]. 4 -alkylamino.
  • each R y and R z group is independently selected from hydroxyl, Ci. 4 alkoxy, and Ci -4 haloalkoxy. In some embodiments, each R y is hydroxyl; and each R y is selected from fluoro and methoxy.
  • R 1 is selected from H, Ci -4 alkyl, and Ci -4 haloalkyl. In some embodiments, R 1 is selected from H and Ci -4 alkyl. In some embodiments, R 1 is selected from H and C 1 - 3 alkyl. In some embodiments, R 1 is H. In further embodiments, L 1 is selected from a bond and C ⁇ _ 3 alkylene. In some embodiments, L 1 is selected from a bond and C 1 . 2 alkylene. In some embodiments, L 1 is selected from a bond, methan-l ,l -diyl, and ethan-l ,2-diyl.
  • L 2 is straight chain C 5 alkylene, in which (i) the straight chain
  • C 5 alkylene is optionally substituted by 1 , 2, 3, or 4 independently selected R" groups or (ii) one of the carbon atoms of the straight chain C 5 alkylene is replaced with -O-, provided that the carbon atom replaced with-O- is not the carbon atom that is directedly attached to
  • one of the carbon atoms of the straight chain C 5 alkylene is replaced with -O-, provided that the carbon atom replaced with-O- is not the carbon atom that is directedly attached to C(O)NHAr 2 or the carbon atom that is directedly attached to
  • L 2 can be -CH 2 -CH 2 -O-CH 2 -CH 2 .
  • L 2 is straight chain C 5 alkylene; wherein said straight chain C 5 alkylene is optionally substituted by 1 , 2, or 3 independently selected R x groups. In some embodiments, L 2 is straight chain Cs alkylene; wherein said straight chain C 5 alkylene is optionally substituted by 1 or 2 independently selected R" groups. In some embodiments, L 2 is straight chain Cs alkylene; wherein said straight chain Cs alkylene is optionally substituted by a R" group. In some embodiments, L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • L 2 is C 4 -G 6 alkenylene, which is optionally substituted by 1 , 2, 3, or 4 independently selected R" groups.
  • L 2 is straight chain C4.6 alkenylene, which is optionally substituted by 1 , 2, or 3 independently selected R" groups, and which has one double bond.
  • L 2 is unsubstituted straight chain C4-6 alkenylene. In certain embodiments, L 2 is unsubstituted straight chain C4.6 alkenylene having one double bond. For example, L 2 is selected from:
  • L 2 is
  • - (CH 2 )io — CH 2 — CH CH -
  • a non-limiting example of such a compound is:
  • L 2 is C 4 alkenylene.
  • each R x is independently selected from halogen, hydroxyl, C 1 .4 alkyl, Ci. 4 alkoxy, Ci -4 haloalkyl, and Ci. 4 haloalkoxy.
  • each R x is independently selected from hydroxyl, Ci -4 alkyl, and C 1 . 4 alkoxy.
  • each R* is independently selected from hydroxyl and C 1 . 4 alkyl.
  • each R x is independently selected from CM alkyl.
  • each R" is independently selected from halogen, hydroxyl, oxo
  • each R x is independently selected from hydroxyl, Cu 4 alkyl, and Ci -4 alkoxy. In some embodiments, each R x is independently selected from hydroxyl and CM alkyl. In some embodiments, each R x is independently selected from Ci -4 alkyl.
  • R x when one (or more) of R x is oxo, the oxo group is not attached to the carbon atom that is directedly attached to C(O)NHAr 2 or to the carbon atom that is directedly attached to C ⁇ NR'-L'-A ⁇ 1 .
  • J is amino. In some embodiments, J is hydroxyl. In other embodiments, n is an integer selected from 0, 1 , 2, and 3. In some embodiments, n is an integer selected from 0, 1, and 2. In some embodiments, n is an integer selected from 0 and 1. In some embodiments, n is 0. In some embodiments, m is an integer selected from 0, 1 , and 2. In some embodiments, m is an integer selected from 0 and 1. In some embodiments, m is 0. In some embodiments, m is 1.
  • Ar 1 is 6-membered heteroaryl; which is substituted by n independently selected R y groups; and Ar 2 is phenyl; which is substituted by m independently selected R z groups.
  • Ar 1 is phenyl; which is substituted by n independently selected R y groups;
  • Ar 2 is 6- membered heteroaryl; which is substituted by m independently selected R z groups.
  • Ar 1 is phenyl; which is substituted by n independently selected R y groups;
  • Ar 2 is a pyridine ring; which is substituted by m independently selected R z groups; and any two R y groups, together with the atoms to which they are attached, do not form an optionally substituted phenyl ring.
  • Ar 1 is pyridine ring; which is substituted by n independently selected R y groups;
  • Ar 2 is phenyl; which is substituted by m independently selected R z groups; and any two R y groups, together with the atoms to which they are attached, do not form an optionally substituted phenyl ring.
  • Ar 1 is selected from 5-membered heteroaryl; which is substituted with n independently selected R y groups; and Ar 2 is selected from phenyl and 6-membered heteroaryl; wherein said phenyl and 6-membered heteroaryl are each substituted at one ortho position by one J group and by m independently selected R z groups.
  • Ar 1 is 5-membered heteroaryl; which is substituted by n independently selected R y groups; and Ar 2 is phenyl; which is substituted by m independently selected R z groups; or Ar 1 is 6-membered heteroaryl; which is substituted with n independently selected R y groups; and Ar 2 is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R z groups.
  • Ar 1 is 5-membered heteroaryl fused to an optionally substituted phenyl ring; which is substituted by n independently selected R y groups.
  • Ar 1 is indolyl or indazolyl, each of which is substituted with n independently selected R y groups.
  • Ar 1 is indazolyl, which is substituted with n independently selected R y groups.
  • n 0.
  • n is an integer selected from 1 and 2.
  • each occurrence of R y is independently selected from Cue alkyl and C ⁇ . ⁇ alkoxy, wherein said C ⁇ - 6 alkyl and Cj.6 alkoxy are each optionally substituted by 1, 2, or 3 independently selected R y groups.
  • Ar 1 is 5-membered heteroaryl fused to an optionally substituted phenyl ring; which is substituted by n independently selected R y groups; and Ar 2 is phenyl; which is substituted by m independently selected R z groups.
  • Ar 1 is selected from 5-membered heteroaryl; which is substituted with n independently selected R y groups; and Ar 2 is 6-membered heteroaryl; wherein said 6- membered heteroaryl is substituted at one ortho position by one J group and by m independently selected R z groups.
  • Ar 1 is thiazol-2-yl; which is substituted with n independently selected R y groups; and Ar 2 is pyridin-2-yl; which is substituted at one ortho position by one J group and by m independently selected R z groups.
  • Ar 1 is thiazol-2-yl; which is substituted with n independently selected R y groups; and Ar 2 is pyridin-2-yl; which is substituted at one ortho position by one J group and by m independently selected R z groups.
  • Ar 1 is 5-membered heteroaryl; which is substituted with n independently selected R y groups; and Ar 2 is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R z groups.
  • Ar 1 is a thiazole ring; which is substituted with n independently selected R y groups; and Ar 2 is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R z groups.
  • the compound is a compound of Formula (If):
  • the compound has Formula (Ie):
  • the compound is a compound of Formula (Ia): or pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (Ia-I) or (Ia-2):
  • the compound is a compound of Formula (Ia-2), or pharmaceutically acceptable salt thereof, wherein: J is hydroxyl; L 2 is Cs alkylene; R 1 is H; each R z is phenyl; n is 0; and m is 1.
  • the compound is a compound of Formula (Ib):
  • the compound is a compound of Formula (Ic):
  • the compound is a compound of Formula (Ic), or pharmaceutically acceptable salt thereof, wherein:
  • L 2 is straight chain Cs alkylene
  • R 1 is H; each R y is halogen; each R z is independently selected from halogen and phenyl; n is 1 ; and m is an integer selected from 1 and 2.
  • the compound is a compound of Formula (Ic), or pharmaceutically acceptable salt thereof, wherein:
  • J is selected from amino and hydroxy!
  • L 2 is selected from straight chain C 5 alkylene, which is optionally substituted by 1 , 2, 3, or 4 independently selected R x groups;
  • R 1 is selected from H, C 1 . 4 alkyl, and C 1 . 4 haloalkyl; each R y is independently selected from halogen, cyano, nitro, C 1 . 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 alkoxy, Ci- ⁇ haloalkoxy, C 3 . 7 cycloalkyl, C 2 - 6 heterocycloalkyl, phenyl, and Ci. 6 heteroaryl; each R z is independently selected from halogen, cyano, nitro, C 1 .
  • each R" is independently selected from halogen, hydroxy 1, cyano, nitro, Ci -4 alkyl, Ci.4 alkoxy, Ci -4 haloalkyl, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, and di-C
  • the compound is a compound of Formula (Ic), or pharmaceutically acceptable salt thereof, wherein: J is amino and hydroxyl;
  • L 2 is selected from Cs alkylene, which is optionally substituted by 1, 2, or 3 independently selected R* groups;
  • R 1 is selected from H and Ci -4 alkyl; each R y is independently selected from halogen, cyano, Ci. 6 alkyl, Ci_6 haloalkyl, Ci. ⁇ alkoxy, and Ci. 6 haloalkoxy; each R z is independently selected from halogen, cyano, Ci -O alkyl, Ci.6 haloalkyl, Ci_ 6 alkoxy, and Ci_ 6 haloalkoxy; each R x is independently selected from halogen, hydroxyl, Ci -4 alkyl, Ci -4 alkoxy, Ci -4 haloalkyl, and Ci-4 haloalkoxy; n is an integer selected from 0, 1, and 2; and m is an integer selected from 0, 1, and 2.
  • the compound is a compound of Formula (Ic), or pharmaceutically acceptable salt thereof, wherein: J is amino;
  • L 2 is selected from C 5 alkylene, which is optionally substituted by 1 or 2 independently selected R x groups;
  • R 1 is selected from H and C 1 - 3 alkyl;
  • each R y is independently selected from halogen, Ci -4 alkyl, Ci -4 haloalkyl, Ci -4 alkoxy, and Ci -4 haloalkoxy;
  • each R z is independently selected from halogen, Ci -4 alkyl, Ci -4 haloalkyl, CM alkoxy, and Ci -4 haloalkoxy;
  • each R x is independently selected from hydroxyl, Ci -4 alkyl, and Ci -4 alkoxy;
  • n is an integer selected from 0, 1 , and 2; and
  • m is an integer selected from 0, 1 , and 2.
  • the compound is a compound of Formula (Ic), or pharmaceutically acceptable salt thereof, wherein: J is amino;
  • L 2 is selected from C 5 alkylene, which is optionally substituted by 1 or 2 independently selected R* groups;
  • R 1 is selected from H; each R y is independently selected from halogen, Ci ⁇ alkyl, C
  • the compound is a compound of Formula (Ic), or pharmaceutically acceptable salt thereof, wherein:
  • J is amino;
  • L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • R 1 is selected from H; each R y is independently selected from halogen, C ⁇ alkyl, and Ci -4 haloalkoxy; each R z is independently selected from halogen, Q ⁇ alkyl, and CM alkoxy; n is an integer selected from 0, 1 , and 2; and m is an integer selected from 0 and 1.
  • the compound is a compound of Formula (Ic), or pharmaceutically acceptable salt thereof, wherein:
  • J is amino;
  • L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • R 1 is selected from H; each R y is independently selected from fluoro, methyl, and trifluoromethoxy; each R z is independently selected from fluoro, methyl, and methoxy; n is an integer selected from 0, 1 , and 2; and m is an integer selected from 0 and 1.
  • the compound has Formula (Ic), provided that Ar 2 is substituted at the para position by halogen; or Ar 2 is substituted at the meta position by C
  • the compound has Formula (Ic), provided that Ar 2 is substituted at the para position by fluoro; or Ar 2 is substituted at the meta position by methyl or methoxy; or Ar 1 is substituted at the ortho position by trifluoromethoxy.
  • Each R z is independently selected from halogen, cyano, nitro, Ci-6 alkyl, C ⁇ . ⁇ haloalkyl, C ⁇ _ 6 alkoxy, Ci- ⁇ haloalkoxy, C 3 _ 7 cycloalkyl, C 2 - 6 heterocycloalkyl, phenyl, and Ci.
  • Ci- ⁇ alkyl, Ci.6 haloalkyl, C).6 alkoxy, and Ci- ⁇ haloalkoxy are each optionally substituted by 1 or 2 independently selected R z groups; and in which said C3-7 cycloalkyl, C 2 - 6 heterocycloalkyl, phenyl, and C
  • Each R z is independently selected from halogen, cyano, nitro, C h alky!, C
  • Each R z is selected from phenyl and C
  • Each R z is selected from phenyl and Ci-6 heteroaryl.
  • Each R z is phenyl or phenyl, which is substituted by 1, 2, or 3 independently selected R z groups.
  • Each R z is Ci_6 heteroaryl or Cj.6 heteroaryl, which is optionally substituted by 1 , 2, or 3 independently selected R z groups.
  • Ar 2 is selected from phenyl; which is substituted at one ortho position by one J group and by m independently selected R z groups;
  • L 2 is:
  • R z or one R z is selected from phenyl and C
  • Ar 2 is selected from phenyl; which is substituted at one ortho position by one J group and by m independently selected R z groups;
  • L 2 is straight chain C5 alkylene
  • R z or one R z is selected from phenyl and C ⁇ - ⁇ heteroaryl, each of which is optionally substituted by 1 , 2, or 3 independently selected R z groups, and attached to the meta position (i.e., para to J); and m is 1 and 2.
  • R z or one R z is selected from phenyl optionally substituted by 1 , 2, or 3 independently selected R z groups, and attached to the meta position (i.e., para to J).
  • R z or one R z is Q. 6 heteroaryl, each of which is optionally substituted by 1, 2, or 3 independently selected R z groups, and attached to the meta position (i.e., para to J).
  • the compound of formula (I) can be:
  • Ar 2 is selected from phenyl; which is substituted at one ortho position by one J group and by m independently selected R z groups;
  • L 2 is optionally substituted straight chain C 4 . 6 alkenylene (e.g., L is unsubstituted straight chain C 4 . 6 alkenylene having one double bond; e.g., L 2 is
  • - (CH 2 )Io — CH 2 — CH CH
  • ); J is amino;
  • R z or one R z is selected from phenyl and C ⁇ _ 6 heteroaryl, each of which is optionally substituted by 1 , 2, or 3 independently selected R z groups, and attached to the meta position (i.e., para to J); and m is 1 and 2.
  • R z or one R z is selected from phenyl optionally substituted by 1 , 2, or 3 independently selected R z groups, and attached to the meta position (i.e., para to J).
  • R z or one R z is Ci. 6 heteroaryl, each of which is optionally substituted by 1 , 2, or 3 independently selected R z groups, and attached to the meta position (i.e., para to J).
  • the compound of formula (I) can be:
  • the compound is a compound of Formula (Id):
  • R 2p is selected from H, halogen, and Cue alkyl; each R 2 ° is independently selected from H, halogen, and C
  • L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • the compound is a compound of Formula (Id), or pharmaceutically acceptable salt thereof, wherein:
  • R 2p is selected from H, fluoro, and methyl; each R 2 ° is independently selected from H and trifluoromethoxy;
  • R lm is selected from H, methyl and methoxy
  • R lp is selected from H and fluoro
  • L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • the compound is a compound of Formula (Id), or pharmaceutically acceptable salt thereof, wherein: R 2p is fluoro; each R 20 is H;
  • R lm is H or R z as defined above in conjunction with formula (Ic); R lp is selected from H, phenyl, fluoro; and L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • the compound is a compound of Formula (Ia-I), (Ia-2), or (Ib), or pharmaceutically acceptable salt thereof, wherein: J is selected from amino and hydroxyl;
  • L 2 is selected from C 5 alkylene, which is optionally substituted by 1 or 2 independently selected R x groups;
  • R 1 is selected from H and C 1 -4 alkyl; each R z is independently selected from halogen, cyano, Ci_ 6 alkyl, C ⁇ _6 haloalkyl, C
  • each R x is independently selected from halogen, hydroxyl, Ci -4 alkyl, Ci -4 alkoxy, Ci -4 haloalkyl, and Ci -4 haloalkoxy; n is an integer selected from 0, 1, 2, and 3; and m is an integer selected from 0, 1, and 2.
  • the compound is a compound of Formula (Ia-I), (Ia-2), or
  • J is selected from amino;
  • L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -;
  • R 1 is selected from H;
  • each R z is independently selected from halogen, C 1 . 6 alkyl, C
  • each R y is independently selected from halogen, C 1 . 6 alkyl, Ci -6 haloalkyl, Ci_ 6 alkoxy, and Ci -6 haloalkoxy;
  • n is an integer selected from 0, 1 , and 2;
  • m is an integer selected from 0 and 1.
  • the compound is a compound of Formula (Ia-I), (Ia-2), or (Ib), or or pharmaceutically acceptable salt thereof, wherein: J is selected from amino;
  • L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -;
  • R 1 is selected from H;
  • each R z is independently selected from halogen;
  • each R y is independently selected Ci-6 alkoxy;
  • n is an integer selected from 0, 1, and 2; and
  • m is an integer selected from 0 and 1.
  • the compound has Formula (Ia-I), (Ia-2), or (Ib), provided that Ar 2 is substituted at the para position by halogen; or Ar 1 is substituted at one ortho position by Ci_ 6 alkoxy; or Ar 1 is substituted at one para position by C ⁇ _6 alkoxy.
  • the compound has Formula (Ia-I), (Ia-2), or (Ib), provided that Ar 2 is substituted at the para position by halogen.
  • R z can also be as defined in conjunction with formula (Ic). In some embodiments:
  • Ar 1 is 5-membered heteroaryl; which is substituted with n independently selected R y groups; wherein said or 5-membered heteroaryl may be optionally fused to a phenyl ring; which is optionally substituted by 1 or 2 groups selected from halogen, hydroxyl, cyano, nitro, C h alky], Ci -4 haloalkyl, Ci -4 alkoxy, C
  • Ar 2 is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R z groups;
  • J is selected from amino and hydroxyl
  • R 1 is selected from H, Ci -4 alkyl, and Ci -4 haloalkyl
  • L 1 is selected from a bond and Ci -4 alkylene
  • L 2 is straight chain C5 alkylene; wherein said straight chain C5 alkylene is optionally substituted by 1, 2, 3, or 4 independently selected R x groups; each R x is independently selected from halogen, hydroxyl, cyano, nitro, Ci -4 alkyl, Ci -4 alkoxy, Ci -4 haloalkyl, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, and di-Ci. 4 - alkylamino; each R y is independently selected from halogen, cyano, nitro, C1.6 alkyl, C2-6 alkenyl, C 2 - 6 alkynyl, Ci .
  • .6 alkoxy, and Cu ⁇ haloalkoxy are each optionally substituted by 1 , 2, or 3 independently selected R y groups; and wherein said C3.7 cycloalkyl, C 2 -6 heterocycloalkyl, phenyl, Ci- 6 heteroaryl, C 3 - 7 cycloalkyl-C M -alkyl, C 2 - 6 heterocycloalkyl-Ci. 4 -alkyl, phenyl-C
  • each R z is independently selected from halogen, cyano, nitro, Ci ⁇ alkyl, C2-6 alkenyl, C 2 - 6 alkynyl, C
  • Ar 1 is 5-membered heteroaryl; which is substituted with n independently selected R y groups; wherein said or 5-membered heteroaryl may be optionally fused to a phenyl ring;
  • Ar 2 is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R z groups;
  • J is selected from amino and hydroxyl
  • R 1 is selected from H, CM alkyl, and CM haloalkyl
  • L 1 is selected from a bond and C 1 . 3 alkylene
  • L 2 is straight chain C 5 alkylene; wherein said straight chain C 5 alkylene is optionally substituted by 1 , 2, or 3 independently selected R x groups; each R x is independently selected from halogen, hydroxyl, cyano, CM alkyl,
  • each R y is independently selected from halogen, cyano, nitro, C
  • each R z is independently selected from halogen, cyano, nitro, C
  • each R y and R z group is independently selected from hydroxyl, Ci -4 alkoxy, and Ci -4 haloalkoxy; each R y and R z group is independently selected from halogen, hydroxyl, C1.4 alkyl, Ci -4 haloalkyl, Ci -4 alkoxy, and Ci -4 haloalkoxy; n is an integer selected from 0, 1, 2, and 3; and m is an integer selected from 0, 1 , and 2.
  • Ar 1 is 5-membered heteroaryl; which is substituted with n independently selected R y groups; wherein said or 5-membered heteroaryl may be optionally fused to a phenyl ring;
  • Ar 2 is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R z groups; J is selected from amino;
  • R 1 is H
  • L 1 is selected from a bond and Ci -2 alkylene
  • L 2 is straight chain C 5 alkylene; wherein said straight chain C 5 alkylene is optionally substituted by 1 or 2 independently selected R x groups; each R x is independently selected from Ci -4 alkyl and Ci -4 alkoxy; each R y is independently selected from halogen, C
  • Ci_6 alkyl, Ci- 6 haloalkyl, C ⁇ _6 alkoxy, and C i_ 6 haloalkoxy are each optionally substituted by a R y group; and wherein said phenyl, Ci- ⁇ heteroaryl, C 3 . 7 cycloalkyl-C 1 .4- alkyl, and C2-6 heterocycloalkyl-Ci- 4 -alkyl are each optionally substituted by a R y group; provided that only one of R y is selected from optionally substituted phenyl, C
  • R y is hydroxyl
  • R y is selected from halogen and CM alkoxy; n is an integer selected from 0, 1, and 2; and m is an integer selected from 0, 1 , and 2.
  • L 1 is a bond.
  • L 1 is Ci. 2 alkylene.
  • Ar 1 is a thiazole ring; which is optionally substituted with 1 or 2 independently selected R y groups; and
  • L 1 is a bond.
  • Ar 1 is selected from a thiazole ring, an imidazole ring, an oxazole ring, and a thiophene ring; each of which is substituted with n independently selected R y groups; wherein said thiazole ring, imidazole ring, oxazole ring, and thiophene ring are each optionally fused to a phenyl ring.
  • Ar 2 is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R z groups; J is selected from amino; R 1 is H;
  • L 1 is selected from a bond, methan-l,l-diyl, and ethan-l ,2-diyl;
  • L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -;
  • each R y is independently selected from halogen, Ci ⁇ alkyl, C
  • . 4 -alkyl are each optionally substituted by a R y group; with the proviso that only one of R y is selected from optionally substituted phenyl, C
  • R y is hydroxyl; R y is selected from halogen and d ⁇ alkoxy; n is an integer selected from 0, 1, and 2; and m is an integer selected from 0, 1 , and 2.
  • Ar 1 is selected from thiazol-2-yl, imidazol-2-yl, imidazol-4-yl, oxazol-2-yl, and thiophen-2-yl; each of which is substituted with n independently selected R y groups; and wherein said -2-yl, imidazol-2-yl, imidazol-4-yl, oxazol-2-yl, and thiophen-2-yl may each be optionally fused to a phenyl ring;
  • Ar 2 is phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R z groups; J is selected from amino; R 1 is selected from H;
  • L 1 is selected from a bond, methan-l ,l-diyl, and ethan-l,2-diyl;
  • L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -; each R y is independently selected from fluoro, methyl, trifluoromethyl, methoxy, phenyl, pyridin-4-yl, pyridin-3-yl, piperidinylmethyl, and morpholin-4-yl-methyl; wherein said methyl is optionally substituted by a R y group; and wherein said phenyl is optionally substituted by a R y group; with the proviso that only one of R y is selected from optionally substituted phenyl, pyridin-4-yl, pyridin-3-yl, piperidinylmethyl, and morpholin-4-yl-methyl;
  • R z is selected from halogen and trifluoromethyl;
  • R y is hydroxy I;
  • R y is selected from fluoro and methoxy; n is an integer selected from 0, 1 , and 2; and m is an integer selected from 0, 1, and 2.
  • Ar 1 is selected from 5-membered heteroaryl; which is substituted with n independently selected R y groups;
  • Ar 2 is 6-membered heteroaryl; wherein said 6-membered heteroaryl is substituted at one ortho position by one J group and by m independently selected R z groups; J is selected from amino and hydroxyl; R 1 is selected from H, C 1 . 4 alkyl, and CM haloalkyl; L 1 is selected from a bond; L 2 is straight chain Cs alkylene; wherein said straight chain Cs alkylene is optionally substituted by 1 , 2, or 3 independently selected R x groups; each R x is independently selected from halogen, hydroxyl, cyano, CM alky 1, C
  • each R y is independently selected from halogen, cyano, nitro, Q. 6 alkyl, Ci_6 haloalkyl, Ci- 6 alkoxy, C ⁇ - 6 haloalkoxy, phenyl, Ci. 6 heteroaryl, C 3 . 7 cycloalkyl-C
  • Ci-6 haloalkoxy are each optionally substituted by 1 or 2 independently selected R y groups; and wherein said phenyl, Ci. 6 heteroaryl, C 3 . 7 cycloalkyl-Ci. 4 -alkyl, and C 2 - 6 heterocycloalkyl-Ci_ 4 -alkyl are each optionally substituted by 1 or 2 independently selected R y groups; with the proviso that only one of R y is selected from optionally substituted phenyl, Ci_ 6 heteroaryl, C 3 . 7 cycloalkyl-Ci_ 4 -alkyl, and C 2 - 6 heterocycloalkyl-Ci.
  • each R z is independently selected from halogen, cyano, nitro, Ci. 6 alkyl, Ci_6 haloalkyl, C
  • each R y and R z group is independently selected from halogen, hydroxyl, C1.4 alkyl, CM haloalkyl, CM alkoxy, and CM haloalkoxy; n is an integer selected from 0, 1, and 2; and m is an integer selected from 0, 1, and 2.
  • Ar 1 is selected from 5-membered heteroaryl; which is substituted with n independently selected R y groups;
  • Ar 2 is 6-membered heteroaryl; wherein said 6-membered heteroaryl is substituted at one ortho position by one J group and by m independently selected R z groups; J is selected from amino; R 1 is H; L 1 is a bond;
  • L 2 is straight chain C 5 alkylene; wherein said straight chain C 5 alkylene is optionally substituted by 1 or 2 independently selected R x groups; each R x is independently selected from CM alkyl and Ci -4 alkoxy; each R y is independently selected from halogen, C
  • Ci- ⁇ haloalkoxy are each optionally substituted by a R y group; and wherein said phenyl, Ci_ 6 heteroaryl, C 3 .7 cycloalkyl-Ci.4- alkyl, and C 2 - 6 heterocycloalkyl-C M -alkyl are each optionally substituted by a R y group; with the proviso that only one of R y is selected from optionally substituted phenyl, C 1 .
  • R z is selected from halogen and Ci_ 6 haloalkyl
  • R y is hydroxyl
  • R y is selected from halogen and Ci- 4 alkoxy
  • n is an integer selected from 0, 1, and 2
  • m is an integer selected from 0, 1 , and 2.
  • Ar 1 is selected from a thiazol-2-yl ring; which is substituted with n independently selected R y group;
  • Ar 2 is pyridin-2-yl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R z groups; J is selected from amino; R 1 is H; L 1 is a bond;
  • L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -; each R y is phenyl; wherein said phenyl is optionally substituted by a R y group;
  • R y is selected from CM alkoxy; n is an integer selected from 0 and 1 ; and m is an integer selected from 0, 1 , and 2.
  • the compound is:
  • the invention features phenylethylene bisamide compounds of
  • R 1 is selected from H, Ci -4 alkyl, CM haloalkyl, Ci -4 alkoxycarbonyl, carbamyl, di-Cj. 4 -alkyl-carbamyl, and C
  • L 1 is selected from a bond and Ci -4 alkylene;
  • Ar 2 is selected from phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; wherein said phenyl, 5-membered heteroaryl, and 6-membered heteroaryl are each substituted at one ortho position by one J group and by m independently selected R z groups; and wherein, in addition, said phenyl, 5-membered heteroaryl, and 6-membered heteroaryl may be further optionally fused to a phenyl or Ci_ 6 heteroaryl ring, each of which is optionally substituted by 1 or 2 groups independently selected from halogen, hydroxyl, cyano, nitro, Ci -4 alkyl, Ci -4 haloalkyl, Ci -4 alkoxy, CM haloalkoxy, amino, Ci -4 alkylamino, and di-C
  • each R a is independently selected from H, C 1 . 6 alkyl and Ci- 6 haloalkyl;
  • R b is selected from C ⁇ _ 6 alkyl and C 1 . 6 haloalkyl;
  • J is selected from hydroxyl and amino; each R x is independently selected from halogen, hydroxyl, cyano, nitro, Ci -4 alkyl, Ci- 4 alkoxy, Ci -4 haloalkyl, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, and di-C]. 4 -alkylamino; p is an integer selected from 0, 1 , 2, and 3; each R y is independently selected from halogen, cyano, nitro, hydroxyl, C 1 . 6 alkyl, C 2 .
  • . 4 -alkyl are each optionally substituted by 1 , 2, or 3 independently selected R y groups; provided that only one of R y is selected from optionally substituted C 3 . 7 cycloalkyl, C 2 - 6 heterocycloalkyl, phenyl, C ⁇ . ⁇ heteroaryl, C 3 .
  • each R z is independently selected from halogen, cyano, nitro, hydroxyl, Cue alkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyl, Ci_ 6 haloalkyl, C 1 . 6 alkoxy, Ci. 6 haloalkoxy, C
  • each R y and R z is independently selected from halogen, hydroxyl, cyano, nitro, C 1 .4 alkyl, CM haloalkyl, Ci -4 alkoxy, CM haloalkoxy, amino, CM alkylamino, and di-C ⁇ .4- alkylamino; n is an integer selected from 0, 1 , 2, 3, and 4; and m is an integer selected from 0, 1 , 2, and 3.
  • each R y is independently selected from halogen, cyano, nitro, Ci-6 alkyl, C 2-O alkenyl, C 2 - 6 alkynyl, C ⁇ . ⁇ haloalkyl, C 1 . 6 alkoxy, C1.6 haloalkoxy, C3.7 cycloalkyl, C 2 - 6 heterocycloalkyl, phenyl, C ⁇ . ⁇ heteroaryl, C 3 . 7 cycloalkyl-Ci-4-alkyl, C 2 .
  • each R y is independently selected from halogen, cyano, nitro,
  • C 2 -6 heterocycloalkyl-Ci ⁇ -alkyl are each optionally substituted by 1 or 2 independently selected R y groups; provided that only one of R y is selected from optionally substituted phenyl, C ⁇ _6 heteroaryl, C3.7 cycIoalkyl-Ci_ 4 -alkyl, and C 2 -6 heterocycloalkyl-Ci. 4 -alkyl.
  • each R y is independently selected from halogen, cyano, C ⁇ alkyl, C
  • Ci- 6 alkylcarbonyl, carbamyl, Ci- 6 alkylcarbamyl, di-Ci- ⁇ alkylcarbamyl, Ci-galkylcarbonylamino, Ci- ⁇ alkylcarbonyKCi ⁇ - alkyl)amino, Ci_6 alkoxycarbonylamino, and di-Ci- 6 alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R y groups.
  • each R y is independently selected from halogen, cyano, Cj.6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, Ci_ 6 haloalkyl, C 1 . 6 alkoxy, Cj. 6 haloalkoxy, and di-Cj. 6 alkylamino; wherein said Cj.6 alkyl, C 2 -6alkenyl, C 2 - ⁇ alkynyl, Cue haloalkyl, Cj.6 alkoxy, Q.6 haloalkoxy, and di-Q- 6 alkylamino are each optionally substituted by 1 , 2, or 3 independently selected R y groups.
  • each R y is independently selected from halogen, Ci-6 alkyl, Ci_6 haloalkyl, Ci_ 6 alkoxy, C 2 -6 heterocycloalkyl, phenyl, Ci.6 heteroaryl, and C 2 -6 heterocycloalkyl-Ci ⁇ -alkyl; wherein said Ci_6 alkyl, C ⁇ . ⁇ haloalkyl, C1.6 alkoxy, and C
  • each R y is independently C h alky). In some embodiments, each R y is methyl. In some embodiments, each R z is independently selected from halogen, cyano, nitro, Ci-6 alkyl, C 2 -6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci_6 alkoxy, C1.6 haloalkoxy, C3.7 cycloalkyl, and C 2 - 6 heterocycloalkyl; wherein said Ci_6 alkyl, C 2 -6 alkenyl, C2.6 alkynyl, C ⁇ _6 haloalkyl, C 1 .
  • each R z is independently selected from halogen, cyano, C 1 .6 alkyl, Ci_6 haloalkyl, Ci-6 alkoxy, C 1-6 haloalkoxy, Ci.6 alkoxycarbonyl, Ci.6 alkylcarbonyl, carbamyl, Ci_6alkylcarbamyl, di-Ci- ⁇ alkylcarbamyl, Ci_6 alkylcarbonylamino, Ci.6alkylcarbonyl-(Ci.
  • each R z is independently selected from halogen, cyano, nitro, C
  • each R z is independently halogen.
  • each R z is fluoro.
  • each R y and R z group is independently selected from hydroxyl, cyano, nitro, C 1 .4 alkoxy, C1-4 haloalkoxy, amino, C1.4 alkylamino, and di-CM- alkylamino. In some embodiments, each R y and R z group is independently selected from hydroxyl, C M alkoxy, and C M haloalkoxy. In some embodiments, each R y and R z group is independently selected from hydroxyl, cyano, nitro, C M alkoxy, C M haloalkoxy, amino, C M alkylamino, and di-Ci- 4 -alkylamino. In some embodiments, each R y and R z group is independently selected from hydroxyl, C M alkoxy, and C M haloalkoxy.
  • R 1 is selected from H, C M alkyl, and C M haloalkyl. In some embodiments, R 1 is selected from H and C M alkyl. In some embodiments, R 1 is H. In other embodiments, L 1 is selected from a bond and Ci ⁇ alkylene. In some embodiments, L 1 is selected from a bond and Ci.2 alkylene. In some embodiments, each R* is independently selected from halogen, hydroxyl, Ci -4 alkyl, Ci ⁇ alkoxy, Ci. 4 haloalkyl, and C M haloalkoxy. In some embodiments, each R x is independently selected from hydroxyl, C) -4 alkyl, and Ci -4 alkoxy. In some embodiments, each R x is independently selected from Ci -4 alkyl. In further embodiments, J is selected from amino and hydroxyl. In some embodiments, J is amino.
  • p is an integer selected from 0, 1 , and 2. In some embodiments, p is an integer selected from 0 and 1. In some embodiments, p is 0. In some embodiments, n is an integer selected from 0, 1 , 2, and 3. In some embodiments, n is an integer selected from 0, 1 , and 2. In some embodiments, n is an integer selected from 0 and 1. In some embodiments, n is 0. In some embodiments, m is an integer selected from 0, 1 , and 2. In some embodiments, m is an integer selected from 0 and 1. In some embodiments, m is 0.
  • each R a is independently selected from H and C
  • Ar 1 is phenyl; which is substituted with n independently selected R y groups;
  • Ar 2 is phenyl; which is substituted at one ortho position by one J group and by m independently selected R z groups.
  • Ar 1 is phenyl; which is substituted with n independently selected R y groups;
  • Ar 2 is 5-membered heteroaryl; which is substituted at one ortho position by one J group and by m independently selected R z groups.
  • Ar 1 is phenyl; which is substituted with n independently selected R y groups;
  • Ar 2 is 6-membered heteroaryl; which is substituted at one ortho position by one J group and by m independently selected R z groups.
  • Ar 1 is Ci- 6 heteroaryl; which is substituted with n independently selected R y groups;
  • Ar 2 is phenyl; which is substituted at one ortho position by one J group and by m independently selected R z groups. In some embodiments:
  • Ar 1 is Ci_ 6 heteroaryl; which is substituted with n independently selected R y groups;
  • Ar 2 is 5-membered heteroaryl; which is substituted at one ortho position by one J group and by m independently selected R z groups.
  • Ar 2 is 5-membered heteroaryl; which is substituted at one ortho position by one J group and by m independently selected R z groups.
  • Ar 1 is Ci. 6 heteroaryl; which is substituted with n independently selected R y groups;
  • Ar 2 is 6-membered heteroaryl; which is substituted at one ortho position by one J group and by m independently selected R z groups.
  • Ar 2 is 6-membered heteroaryl; which is substituted at one ortho position by one J group and by m independently selected R z groups.
  • Ar 1 is selected from phenyl and C ⁇ _ 6 heteroaryl; each of which is substituted with n independently selected R y groups;
  • R 1 is selected from H, C 1 . 4 alkyl, and Ci -4 haloalkyl;
  • L 1 is selected from a bond and Ci -4 alkylene;
  • Ar 2 is selected from phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; wherein said phenyl, 5-membered heteroaryl, and 6-membered heteroaryl are each substituted at one ortho position by one J group and by m independently selected R z groups; each R a is independently selected from H, Ci. 6 alkyl and Ci. 6 haloalkyl; R b is selected from Ci_ 6 alkyl and Ci- 6 haloalkyl;
  • . 4 -alkyl are each optionally substituted by 1 or 2 independently selected R y groups; with the proviso that only one of R y is selected from optionally substituted C3.7 cycloalkyl, C 2 - 6 heterocycloalkyl, phenyl, C ⁇ _ 6 heteroaryl, C 3 -7cycloalkyl-Ci_4-alkyl, C2-6 heterocycloalkyl-Ci- 4 -alkyl, phenyl-Ci. 4 -alkyl, and Ci- 6 heteroaryl-Ci.
  • each R z is independently selected from halogen, cyano, nitro, Ci-6 alkyl, C1.6 haloalkyl, Ci. 6 alkoxy, and Ci_ 6 haloalkoxy; wherein said C 1 . 6 alkyl, Ci. 6 haloalkyl, C1.6 alkoxy, and C i_ 6 haloalkoxy are each optionally substituted by 1 , 2, or 3 independently selected R z groups; or any two R z groups, together with the atoms to which they are attached, form a phenyl or C 1 .
  • each of which is optionally substituted by 1 or 2 groups selected from halogen, hydroxy!, cyano, nitro, Ci- 4 alkyl, C 1 . 4 haloalkyl, C 1 . 4 alkoxy, and C1-4 haloalkoxy; each R y and R z is independently selected from hydroxyl, cyano, nitro, CM alkoxy, and Ci -4 haloalkoxy; each R y is independently selected from halogen, hydroxyl, cyano, nitro, Ci -4 alkyl, C 1 . 4 haloalkyl, C 1 . 4 alkoxy, and CM haloalkoxy; n is an integer selected from 0, 1, 2, and 3; and m is an integer selected from 0, 1 , and 2.
  • Ar 1 is selected from phenyl and C i_ 6 heteroaryl; each of which is substituted with n independently selected R y groups;
  • X is -NHAr 2 ; R 1 is selected from H and C]. 4 alkyl;
  • L 1 is selected from a bond and C
  • Ar 2 is selected from phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; wherein said phenyl, 5-membered heteroaryl, and 6-membered heteroaryl are each substituted at one ortho position by one J group and by m independently selected R z groups; J is selected from amino and hydroxyl; each R x is independently selected from halogen, hydroxyl, cyano, nitro, CM alkyl, CM alkoxy, CM haloalkyl, and CM haloalkoxy; p is an integer selected from 0 or 1 ; each R y is independently selected from halogen, cyano, Ci ⁇ alkyl, Ci-6 haloalkyl, Ci- 6 alkoxy, and Ci- ⁇ haloalkoxy; wherein said Ci- ⁇ alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, and Ci ⁇ haloalkoxy are each optionally substituted by 1 , 2, or 3 independently selected R y groups;
  • ⁇ haloalkoxy are each optionally substituted by 1 or 2 independently selected R z groups; each R y and R z group is independently selected from hydroxyl, Ci -4 alkoxy, and Ci. 4 haloalkoxy; n is an integer selected from 0, 1, and 2; and m is an integer selected from 0, 1 , and 2.
  • Ar 1 is selected from phenyl and 5-membered heteroaryl; each of which is substituted with n independently selected R y groups; X is -NHAr 2 ; R 1 is H;
  • L 1 is selected from a bond, methan-l ,l-diyl, and ethan-l ,2-diyl;
  • Ar 2 is selected from phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R z groups; J is amino; p is O;
  • R y is C
  • Ar 1 is selected from phenyl, thiophen-2-yl, and pyrazol-2-yl; each of which is substituted with n independently selected R y group;
  • X is -NHAr 2 ;
  • R 1 is H;
  • L 1 is selected from a bond, methan-l ,l -diyl, and ethan-l ,2-diyl;
  • Ar 2 is selected from phenyl; wherein said phenyl is substituted at one ortho position by one J group and by m independently selected R z group; J is amino; p is O; R y is methyl; and
  • R z is fluoro
  • the compound is selected from:
  • the invention features bisamide or hydroxamide compounds of Formula (III): and pharmaceutically acceptable salts, hydrates, and solvates thereof; wherein: R 1 is selected from H, Ci -4 alkyl, Ci -4 haloalkyl, Ci -4 alkoxycarbonyl, carbamyl, di-Ci. 4 -alkyl-carbamyl, and Ci -4 alkylcarbamyl; R 3 is selected from -R a and -N(R b ) 2 ;
  • R a is selected from Ci.6 alkyl, C ⁇ _ 6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; each R b is independently selected from H, Ci- 6 alkyl, Ci_ 6 haloalkyl, C 2 - 6 alkenyl, and C 2 -6 alkynyl;
  • Ar 1 is phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by a R y group and by n additional independently selected R y groups;
  • L 2 is straight chain C 5 alkylene, which is optionally substituted by 1 , 2, 3, or 4 independently selected R x groups; each R x is independently selected from halogen, hydroxyl, cyano, nitro, Ci -4 alkyl, Ci- 4 alkoxy, CM haloalkyl, Ci -4 haloalkoxy, amino, Ci -4 alkylamino, and di-C
  • Ci_ 6 alkoxycarbonyl C 1 .6 alkylcarbonyl, C 1 .6 alkylcarbamyl, di-Ci.6 alkylcarbamyl, C ⁇ _6 alkylcarbonylamino, C 1 .6 alkylcarbonyl-(Ci.4-alkyl)amino, C 1 .6 alkoxycarbonylamino, amino, C 1 .
  • each R y is independently selected from hydroxyl, cyano, nitro, C1-4 alkoxy, C1.4 haloalkoxy, amino, C 1 . 4 alkylamino, and di-C
  • Ci.6 alkoxycarbonyl C ⁇ -6 alkylcarbonyl, carbamyl
  • Ci_ 6 alkylcarbamyl di-Ci.6 alkylcarbamyl
  • Ci_6 alkylcarbonylamino Ci ⁇ alkylcarbonyl-(Ci- 4 -alkyl)amino, C 1 .
  • each R y is independently selected from halogen, C 1 .6 alkyl, C 1 .6 haloalkyl, C ⁇ _6 alkoxy, and C ⁇ _6 haloalkoxy; wherein said Q.6 alkyl, Ci_6 haloalkyl, Q.6 alkoxy, and C1.6 haloalkoxy are each optionally substituted by 1 or 2 independently selected R y groups.
  • each R y is independently selected from halogen, Ci_6 alkyl, C ⁇ _6 haloalkyl, C 1 . 6 alkoxy, and C 1 .6 haloalkoxy; wherein said C 1 .6 alkyl, C 1 .6 haloalkyl, C
  • R 1 is selected from H, C 1 . 4 alkyl, and C M haloalkyl. In some embodiments, R 1 is selected from H and C M alkyl. In some embodiments, R 1 is H.
  • L 2 is straight chain C5 alkylene; wherein said straight chain C5 alkylene is optionally substituted by 1 , 2, or 3 independently selected R x groups. In some embodiments, L 2 is straight chain C 5 alkylene; wherein said straight chain C 5 alkylene is optionally substituted by 1 or 2 independently selected R x groups. In some embodiments, L 2 is straight chain C 5 alkylene; wherein said straight chain C 5 alkylene is optionally substituted by a R x group. In some embodiments, L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • each R x is independently selected from halogen, cyano, nitro, C M alkyl, C M haloalkyl; In some embodiments, each R x is independently selected from halogen, C M alkyl and Ci- 4 haloalkyl. In some embodiments, each R x is independently selected from Ci -4 alkyl and C]. 4 haloalkyl. In some embodiments, each R x is independently selected from C
  • R a is selected from C
  • each R b is independently selected from H and C
  • n is an integer selected from O, 1 , and 2. In some embodiments, n is an integer selected from 0 and 1. In some embodiments, n is 0.
  • Ar 1 is phenyl; which is substituted by a R y group and by n additional independently selected R y groups.
  • Ar 1 is 5-membered heteroaryl; which is substituted by a R y group and by n additional independently selected R y groups.
  • Ar 1 is 6-membered heteroaryl; which is substituted by a R y group and by n additional independently selected R y groups.
  • the compound is a compound of Formula (IHa): or pharmaceutically acceptable salt thereof.
  • the compound is a compound of Formula (HIb):
  • the compound is a compound of Formula (IHa) or (HIb), or pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from H, C 1 . 4 alkyl, and Ci -4 haloalkyl;
  • R a is selected from C
  • each R b is independently selected from H and Ci. 6 alkyl;
  • Ar 1 is phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by a R y group and by n additional independently selected R y groups;
  • L 2 is straight chain C 5 alkylene, which is optionally substituted by 1 , 2, or 3 independently selected R x groups; each R x is independently selected from halogen, hydroxyl, Ci -4 alkyl, Ci -4 alkoxy, Ci -4 haloalkyl, and C 1 . 4 haloalkoxy; each R y is independently selected from halogen, cyano, Ci_ 6 alkyl, C 1 . 6 haloalkyl, C ⁇ _ 6 alkoxy, C
  • .4- alkyl)amino, Ci- ⁇ alkoxycarbonylamino, and di-Ci- ⁇ alkylamino are each optionally substituted by 1, 2, or 3 independently selected R y groups.
  • each R y is independently selected from hydroxyl, cyano, nitro, C
  • the compound is a compound of Formula (Ilia) or (HIb), or pharmaceutically acceptable salt thereof, wherein: R 1 is selected from H; R a is selected from Ci. 6 alkyl; each R b is independently selected from H and Ci. 6 alkyl; Ar 1 is phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by a R y group and by n additional independently selected R y groups;
  • L 2 is straight chain Cs alkylene, which is optionally substituted by 1 or 2 independently selected R" groups; each R x is independently selected from halogen, C
  • the compound is a compound of Formula (HIa) or (HIb), or pharmaceutically acceptable salt thereof, wherein: R 1 is selected from H; R a is selected from Ci- ⁇ alkyl; each R b is independently selected from H and C
  • Ar 1 is phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; each of which is substituted by a R y group and by n additional independently selected R y groups;
  • L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 - each R y is independently selected from halogen, C
  • Ci -6 alkoxy, and Ci -6 haloalkoxy are each optionally substituted by a R y group; each R y is independently selected from hydroxyl, Ci -4 alkoxy, and CM haloalkoxy; and n is an integer selected from 0 and 1.
  • the compound is a compound of Formula (HIa) or (HIb), or pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from H; R a is selected from C ⁇ . ⁇ alkyl; each R b is independently selected from H and Ci- 6 alkyl; Ar 1 is phenyl;
  • L 2 is -CH 2 CH 2 CH 2 CH 2 CH 2 - each R y is independently selected from halogen, Ci_ 6 alkyl, Ci ⁇ haloalkyl, Ci.6 alkoxy, and Ci. 6 haloalkoxy; wherein said Ci- 6 alkyl, Ci. 6 haloalkyl, Ci_ 6 alkoxy, and Ci.6 haloalkoxy are each optionally substituted by a R y group; each R y is independently selected from hydroxyl, CM alkoxy, and Ci -4 haloalkoxy; and n is an integer selected from 0 and 1.
  • the compound is: 7,8-dioxo-N-p-tolylnonanamide or Nl- methyl-2-oxo-N8-p-tolyloctanediamide; or pharmaceutically acceptable salt thereof.
  • the compounds described herein may contain one or more asymmetric centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. While shown without respect to the stereochemistry in Formulas I-III, the present invention includes such optical isomers (enantiomers) and diastereomers (geometric isomers); as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. The use of these compounds is intended to cover the racemic mixture or either of the chiral enantiomers.
  • Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, and include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw- Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • the compounds described herein also include pharmaceutically acceptable salts of the compounds disclosed herein.
  • pharmaceutically acceptable salt refers to a salt formed by the addition of a pharmaceutically acceptable acid or base to a compound disclosed herein.
  • pharmaceutically acceptable refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient.
  • Pharmaceutically acceptable salts include, but are not limited to, those derived from organic and inorganic acids such as, but not limited to, acetic, lactic, (+)-L-tartaric, (+)- L-lactic, (+/-)-DL-lactic, glutaric, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids.
  • organic and inorganic acids such as, but not limited to, acetic, lactic, (+)-L-tartaric, (+)- L-lactic, (+/-)-DL-lactic, glutaric, citric, cinnamic, tartaric, succinic, fuma
  • the compounds are prodrugs.
  • prodrug refers to a moiety that releases a compound described herein when administered to a patient.
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Examples of prodrugs include compounds described herein as described herein that contain one or more molecular moieties appended to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compound, and that when administered to a patient, cleave in vivo to form the free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds described herein. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties.
  • the compounds described herein can be prepared in a variety of ways known to one skilled in the art of organic synthesis.
  • the compounds described herein can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.
  • the compounds described herein can be conveniently prepared in accordance with the procedures outlined in the schemes below, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C NMR) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • HPLC high performance liquid chromatography
  • Preparation of compounds can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4d. Ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety. Adjustments to the protecting groups and formation and cleavage methods described herein may be adjusted as necessary in light of the various substituents.
  • Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • the amide can then be reacted with a second amine (c) in the presence of coupling agent such l-(3-methylaminopropyl)-3-ethylcarbodiimide hydrochloride or O- benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (HBTU) in the presence of a tertiary amine such as triethylamino, 4-(N,N-dimethylamino)pyridine, or diisopropylethylamine (DIPEA) to produce the diamide compound (d).
  • coupling agent such l-(3-methylaminopropyl)-3-ethylcarbodiimide hydrochloride or O- benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (HBTU)
  • HBTU O- benzotriazole-N,N,
  • the J group on Ar 2 can be protected using an appropriate protecting group such as Fmoc (9H- fluoren-9-ylmethoxycarbonyl) before reaction in one of the steps of General Scheme I.
  • the protecting group can removed at the end of the synthesis by methods known in the art.
  • Fmoc can be removed by the used of piperidine.
  • the compounds of Formula (I) can be made by procedures such as those shown in General Scheme II.
  • a l -nitro-2-aminoaryl compound (a) (wherein J is an amino group) is first reacted to protect the amino group.
  • compound (a) can be treated with benzyl chloroformate to produce the carboxybenzyl (Cbz) protected amine (b).
  • J is hydroxyl group
  • other well-known protecting groups can be used in the alternative.
  • the nitro group of compound (b) can then be reduced to an amino compound (c).
  • Compound (c) can then be reacted with the carboxylic acid (d) in the presence of a coupling reagent to give compound (e).
  • the protecting group on compound (e) can then be removed under appropriate conditions.
  • a Cbz protecting group can be removed by the hydrogenation using palladium on carbon in methanol solvent.
  • the carboxylic acid (d) can be produced by the methods summarized above in General Scheme I (e.g., by reacting Ar 1 - L'N(R')H with a cyclic anhydride).
  • the ketone compound (d) can then be produced by treating compound (c) with concentrated hydrochloric acid.
  • compound (c) is instead treated with ozone at -78 0 C in the presence of pyridine to give the ester compound (e) which is then reacted with an amine to give the amide compound.
  • HDAC3 inhibitors described herein can be used prophylactically or as a treatment for various neurological conditions (e.g., neurological conditions associated with frataxin deficiency). More specifically, the HDAC3 inhibitors can be used to delay or prevent the onset of a neurodegenerative or neuromuscular condition, as well as to treat a mammal, such as a human subject, suffering from a neurological condition (e.g., a neurodegenerative or neuromuscular condition).
  • a neurological condition e.g., a neurodegenerative or neuromuscular condition.
  • neurodegenerative conditions include, without limitation, fragile X syndrome, Friedreich's ataxia, Huntington's disease, spinocerebellar ataxias, amyotrophic lateral sclerosis, Kennedy's disease, spinal and bulbar muscular atrophy and Alzheimer's disease.
  • neuromuscular conditions include spinal muscular atrophy and myotonic dystrophy.
  • Mammals, e.g. humans, to which HDAC3 inhibitors can be administered include those suffering from, or diagnosed as having, the conditions discussed herein as well as those who are at risk for developing the above conditions.
  • a mammal at risk for developing a neurodegenerative condition can be identified in numerous ways, including, for example, first determining (1) the length, extent, and/or number of repeats of particular nucleic acid sequences (e.g., a frataxin gene sequence, a huntingtin gene sequence, an ataxin gene sequence, a fragile X mental retardation (FMR]) gene sequence, a dystrophia myotonica protein kinase (DMPK) gene sequence, or an androgen receptor gene sequence) in the individual's genome; the degree of acetylation of core histones; or the expression level of a particular mRNA or protein (e.g., frataxin, huntingtin, brain derived neurotrophic factor (BDNF), peroxisome proliferator-activated receptor-gamma,
  • An individual at risk for developing a neurodegenerative or neuromuscular condition is one who has an aberrant number of repeats of a particular nucleic aid sequence, degree of acetylation of core histones or expression of a particular gene.
  • an animal or person at risk for developing Friedreich's ataxia can be identified by determining the length, extent, or number of repeats of a GAA triplet in the first intron of the frataxin gene.
  • a person would be at risk for Friedreich's ataxia if the above analysis indicates that there are more than 34 repeats of the GAA triplet, for example, if the person has more than 66 repeats of the GAA triplet.
  • a person at risk for Friedreich's ataxia could also be identified by determining the levels of frataxin mRNA or protein expressed in the person.
  • a person would be at risk for Friedreich's ataxia if the levels of frataxin mRNA or protein is lower than the level normally observed in a healthy individual such as for example, an unaffected sibling.
  • the DNA abnormality found in 98% of FRDA patients is an unstable hyper-expansion of a GAA triplet repeat in the first intron of the frataxin gene that results in a defect in transcription of the frataxin gene (see Campuzano et al., 1996, Science, 271 : 1423-27).
  • FRDA patients have a marked deficiency of frataxin mRNA, and the longer the GAA triplet repeats, the more profound the frataxin deficiency.
  • FRDA is typical of triplet repeat diseases: normal alleles have 6-34 repeats while FRDA patient alleles have 66-1700 repeats. Longer GAA triplet repeats are associated with earlier onset and increased severity of the disease.
  • HDAC3 inhibitors can increase frataxin mRNA and protein in lymphocytes from FRDA patients.
  • a "histone deacetylase 3 (HDAC3) inhibitor” is a small molecule that binds to HDAC3 to modulate the levels of acetylation of histones, non-histone chromosomal proteins, and other cellular proteins.
  • An HDAC3 inhibitor identified by the methods described herein may interact with a HDAC3 to modulate the level of acetylation of cellular targets.
  • a histone deacetylase can be any polypeptide having features characteristic of polypeptides that catalyze the removal of the acetyl group (deacetylation) from acetylated target proteins.
  • HDACs histone deacetylases
  • an HDAC can be a polypeptide that represses gene transcription by deacetylating the ⁇ -amino groups of conserved lysine residues located at the N-termini of histones, e.g., H3, H4, H2A, and H2B, that form the nucleosome.
  • HDACs also deacetylate other proteins such as p53, E2F, ⁇ - tubulin, and MyoD. See Annemieke et al., 2003, Biochem. J., 370:737. HDACs can also be localized to the nucleus and certain HDACs can be found in both the nucleus and also the cytoplasm.
  • HDAC3-specific inhibitors described herein may interact with any HDAC.
  • the HDAC3 inhibitors will have at least about 2-fold (e.g., at least about 5-fold, 10-fold, 15- fold, or 20- fold) greater activity to inhibit HDAC3 as compared to one or more other HDACs (e.g., one or more HDACs of class I or class II).
  • Class I HDACs are those that most closely resemble the yeast transcriptional regulator RPD3. Examples of class I HDACs include HDACs 1, 2, 3 and 8, as well as any HDAC that has a deacetylase domain exhibiting from 45 % to 93 % identity in amino acid sequence to HDACs 1, 2, 3 and 8.
  • Class II HDACs are those that most closely resemble the yeast HDACl enzyme. Examples of class II HDACs include HDACs 4, 5, 6, 7, 9 and 10.
  • the invention relates, inter alia, to the discovery that specific histone deacetylase 3 (HDAC3) inhibitors also increase expression of frataxin, and could therefore be useful in the treatment of neurological conditions (e.g., neurological conditions associated with reduced frataxin expression).
  • HDAC3 inhibitors e.g., HDAC3 inhibitors, methods of treating various chronic and/or acute neurological conditions such as, for example, Friedreich's ataxia, and methods of identifying compounds that could be used as therapeutics for various chronic and/or acute neurological conditions such as, for example, Friedreich's ataxia.
  • This application features methods of treating a neurological condition (e.g.,
  • Friedreich's ataxia myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease) that include administering an HDAC inhibitor described herein to a patient having a neurological condition.
  • This application also features the use of an HDAC inhibitor described herein in the preparation of, or for use as, a medicament for the treatment or prevention of a neurological condition (e.g., Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease).
  • a neurological condition e.g., Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease.
  • the present invention also provides a method of treating a cancer in patient in need thereof, comprising administering a therapeutically effective amount of an HDAC inhibitor as described herein, or pharmaceutically, acceptable salt thereof.
  • the cancer is a solid tumor, neoplasm, carcinoma, sarcoma, leukemia, or lymphoma.
  • leukemias include acute leukemias and chronicleukemias such as acute lymphocytic leukemia (ALL), acute myeloid leukemia chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) and Hairy Cell Leukemia; lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T-celllymphotrophic virus (fITLV) such as adult T-cell leukemia/lymphoma (ATLL), Hodgkin's disease and non-Hodgkin's lymphomas, large-cell lymphomas, diffuse large B-celllymphoma (DLBCL); Burkitt's lymphoma; primary central nervous system (CNS) lymphoma; multiple myeloma; childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilm's tumor, bone tumors, and soft-tissue s
  • ALL acute
  • the cancer is (a) Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; (b) Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma,
  • the present invention further provides methods of treating an inflammatory disorder in a patient in need thereof, comprising administering a therapeutically effective amount of an HDAC inhibitor as described herein, or pharmaceutically, acceptable salt thereof.
  • the inflammatory disorder is an acute and chronic inflammatory disease, autoimmune disease, allergic disease, disease associated with oxidative stress, and diseases characterized by cellular hyperproliferation.
  • Non-limiting examples are inflammatory conditions of a joint including rheumatoid arthritis (RA) and psoriatic arthritis; inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinphilic myositis, eosinophilic fasciitis; cancers with leukocyte infiltration of the skin or organs, ischemic injury, including cerebral ischemia (e.g., brain injury as a result of trauma, epilepsy, hemorrhage or stroke, each of which may lead to neurodegeneration); HIV, heart failure, chronic, acute or malignant
  • cytokine-induced toxicity e.g., septic shock, endotoxic shock
  • side effects from radiation therapy temporal mandibular joint disease, tumor metastasis; or an inflammatory condition resulting from strain, sprain, cartilage damage, trauma such as burn, orthopedic surgery, infection or other disease processes.
  • Allergic diseases and conditions include but are not limited to respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), delayed-type hypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies, and the like.
  • respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g.
  • HDAC inhibitors have been shown to have antimalarial activity (Andrews et al., 2000, Int. J. Parasitol., 30:761 -768; Andrews et al., Antimicrob. Agents Chemother., 52: 1454-61).
  • the present invention provides methods of treating a Plasmodium falciparum infection (e.g., malaria) in a patient in need thereof.
  • this application features use of an HDAC inhibitor described herein in the preparation of, or for use as, a medicament for the treatment or prevention of a cancer, an inflammatory disorder, or malaria.
  • an HDAC3 inhibitor can be administered to an animal or cellular model of a neurological condition.
  • an HDAC3 inhibitor is administered to an animal model with a naturally occurring or genetically engineered triplet repeat expansion. Exemplary animal models are described in Al-Mahdawi et al., 2006, Genomics, 88:580-590; Rai et al., 2008, PLoS ONE 3:el958 doi: 10.1371/journal.pone.0001958; Wang et al., 2006, Acta Pharmacol. Sin.
  • the amount of HDAC3 inhibitor to be administered to the individual can be any amount appropriate to restore the level of histone acetylation, or the level of mRNA or protein expression, in the afflicted individual to that typical of a healthy individual such as an unaffected sibling.
  • the amount of the HDAC3 inhibitor to be administered can be an effective dose or an appropriate fraction thereof, if administration is performed serially. Such amounts will depend on individual patient parameters including age, physical condition, size, weight, the condition being treated, the severity of the condition, and any concurrent treatment.
  • the effective dose range that is necessary to prevent or delay the onset of the neurodegenerative condition can be lower than the effective dose range for inhibiting the progression of the condition being treated.
  • Factors that determine appropriate dosages are well known to those of ordinary skill in the art and can be addressed with routine experimentation. For example, determination of the physicochemical, toxicological and pharmacokinetic properties can be made using standard chemical and biological assays and through the use of mathematical modeling techniques known in the chemical, pharmacological and toxicological arts. The therapeutic utility and dosing regimen can be extrapolated from the results of such techniques and through the use of appropriate pharmacokinetic and/or pharmacodynamic models. The precise amount of HDAC3 inhibitor administered to a patient will be the responsibility of the attendant physician.
  • HDAC3 inhibitors can be administered orally or by injection at a dose of from 0.1 to 30 mg per kg weight of the mammal, typically 2 to 15 mg/kg weight of the mammal.
  • the dose range for adult humans is generally from 8 to 2,400 mg/day, e.g., from 35 to 1,050 mg/day. If the salt of the compound is administered, then the amount of salt administered is calculated in terms of the base.
  • HDAC3 inhibitors can be administered in numerous ways.
  • the HDAC3 inhibitors can be administered orally, rectally, topically, or by intramuscular, intraperitoneal subcutaneous or intravenous injection.
  • the inhibitors are administered orally or by injection.
  • Other routes include intrathecal administration directly into spinal fluid and direct introduction onto, in the vicinity of, or within the target cells. The route of administration will depend on the condition being treated and its severity.
  • Toxicity and therapeutic efficacy of HDAC3 inhibitors can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compounds that exhibit high therapeutic indices are preferred.
  • the therapeutic index can be estimated by assaying the HDAC3 specific inhibitory activity of a HDAC3 inhibitor (the HDAC3 ICs 0 ) as compared to the growth inhibitory activity of the HDAC3 inhibitor on a cell in vitro, e.g., a HepG2 cell or other cell line (the growth ICs 0 ).
  • the ratio between the growth inhibitory (e.g., cytotoxic or cytostatic) effect and the HDAC3 specific inhibitory effect provides an estimate of the therapeutic index.
  • the invention features methods of identifying a candidate compound for treatment of a neurological condition by obtaining a test compound; assaying a first activity of the test compound to inhibit histone deacetylase activity of a histone deacetylase 3 (HDAC3); assaying a second activity of the test compound to inhibit histone deacetylase activity of a class I histone deacetylase other than the HDAC3 (e.g., HDACl, HDAC2, or HDAC8); and identifying the test compound as a candidate compound for treatment of a neurological condition associated with a frataxin deficiency if the first activity of the test compound is greater than the second activity of the test compound.
  • HDAC3 histone deacetylase 3
  • HDAC8 histone deacetylase 3
  • the invention features methods of identifying a candidate compound for treatment of a neurological condition by obtaining a test compound; assaying a first activity of the test compound to inhibit histone deacetylase activity of a HDAC3; assaying a second activity of the test compound to inhibit histone deacetylase activity of a HDACl ; assaying a third activity of the test compound to inhibit histone deacetylase activity of a HDAC2; assaying a fourth activity of the test compound to inhibit histone deacetylase activity of a HDAC8; and identifying the test compound as a candidate compound for treatment of a neurological condition if the first activity of the test compound is greater than each of the second, third, and fourth activities of the test compound.
  • the invention features methods of identifying a candidate compound for treatment of a neurological condition by obtaining a test compound; assaying a first activity of the test compound to inhibit histone deacetylase activity of a HDAC3; assaying a second activity of the test compound to inhibit histone deacetylase activity of a class I or class II histone deacetylase other than the HDAC3 (e.g., HDACl, HDAC2, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, or HDAClO); and identifying the test compound as a candidate compound for treatment of a neurological condition associated with a frataxin deficiency if the first activity of the test compound is greater than the second activity of the test compound.
  • this application features methods of identifying a candidate compound for treatment of a neurological condition by obtaining a test compound; assaying a first activity of the test compound to inhibit histone deacetylase activity of a HDAC3; assaying a set of activities of the test compound to inhibit histone deacetylase activity of each of histone deacetylases 1 , 2, 4, 5, 6, 7, 8, 9, and 10; and identifying the test compound as a candidate compound for treatment of a neurological condition if the first activity of the test compound is greater than each activity of the set of activities of the test compound.
  • one or more of the HDACs is a human HDAC (e.g., a human HDAC3).
  • the test compound is identified as a candidate compound for treatment of a neurological condition if the first activity is at least about 1.5-fold greater (e.g., at least about 2-fold, 3-fold, 4-fold, 5-fold, 10- fold, 15-fold, or 20-fold greater) than another activity (e.g., the second, third, or fourth activity, or each activity of the set of activities).
  • first activity is at least about 1.5-fold greater (e.g., at least about 2-fold, 3-fold, 4-fold, 5-fold, 10- fold, 15-fold, or 20-fold greater) than another activity (e.g., the second, third, or fourth activity, or each activity of the set of activities).
  • the neurological condition is Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease.
  • the neurological condition is associated with expansion of a triplet repeat (e.g., Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxias, or Kennedy's disease).
  • the methods further include assaying the activity of the candidate compound to increase expression of one or more genes whose expression is decreased in the neurological condition (e.g., frataxin, huntingtin, brain derived neurotrophic factor (BDNF), peroxisome proliferator-activated receptor-gamma, coactivator 1 , alpha (PGCl A), ataxin, fragile X mental retardation (FMRl), dystrophia myotonica protein kinase (DMPK), or androgen receptor).
  • the activity of the candidate compound to increase expression of one or more genes whose expression is decreased in the neurological condition is measured in an animal, e.g., an animal model of the neurological condition.
  • the method is repeated for a plurality of test compounds (e.g., at least 10, 20, 50, 100, 200, 500, or 1000 test compounds).
  • a plurality of test compounds e.g., at least 10, 20, 50, 100, 200, 500, or 1000 test compounds.
  • this application features methods of treating a neurological condition (e.g., Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxias, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease) that include performing any of the methods described herein, formulating the candidate compound in a pharmaceutical composition, and administering the pharmaceutical composition to a patient having a neurological condition.
  • a neurological condition e.g., Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxias, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease
  • HDAC3 Specific inhibitors of HDAC3 provide advantages for treatment of neurological conditions over the use of broad-spectrum HDAC inhibitors by reducing toxicities associated with inhibition of other HDACs. Such specific HDAC3 inhibitors provide a higher therapeutic index, resulting in better tolerance by patients during chronic or long-term treatment.
  • HDAC3 inhibitors are found by identifying test compounds (e.g., from a group of test compounds) that inhibit the activity of HDAC3 more, e.g., 2, 3, 4, 5, 10, or more times, than they inhibit the activity of one or more other HDACs.
  • HDAC inhibitory activity of test compounds can be assayed by standard means. Briefly, an assay typically involves incubating an acetylated HDAC substrate with a HDAC enzyme in the presence or absence of a test compound and detecting the removal of acetyl groups from the substrate. HDAC inhibition assays can be performed, e.g., in a cell, in a cell extract, or in a cell-free mixture.
  • HDAC inhibition assays are described in Perez-Balado et al., 2007, J. Med. Chem., 50:2497-2505; Herman et al., 2006, Nat. Chem. Biol., 2:551-558; and Beckers et al., 2007, Int. J. Cancer, 121 :1 138-48.
  • HDAC assay kits are commercially available from BIOMOL (Plymouth Meeting, PA) and Upstate (Charlottesville, VA).
  • BIOMOL Plymouth Meeting, PA
  • Upstate Chargesville, VA
  • a small molecule microarray method for screening for HDAC inhibitors is described in Vegas et al., 2007, Angew. Chem. Int. Ed. Engl., 46:7960-64.
  • HDAC3 and other HDAC enzymes can be provided, e.g., as purified proteins, partially purified proteins, purified recombinant proteins, in cells, or cell extracts. Purification or partial purification of HDAC3 and other HDAC enzymes can be performed by standard means, including affinity chromatography and immunoprecipitation.
  • the HDAC substrate can be a commercially available substrate (e.g., Fluor de LysTM, BIOMOL) or an acetylated cellular HDAC substrate, e.g., histone H2A, histone H2B, histone H3, histone H4, ⁇ -tubulin, NF ⁇ B-3, or p53.
  • exemplary substrates further include acetylated peptides of the preceding proteins, e.g., residues 2-24 or 1-18 of Histone H4.
  • the deacetylation of the HDAC substrate can be detected by standard means.
  • substrates are provided with fluorimetric or colorimetric reagents that detect deacetylated lysines.
  • the substrate can be 3 H-acetylated, and deacetylation is detected by measuring the release of 3 H from the substrate.
  • antibodies can be used to distinguish acetylated substrates from deacetylated substrates.
  • antibodies specific for acetylated ⁇ -tubulin are available from Sigma, and antibodies specific for acetylated histone H3 are available from Upstate.
  • HDAC3 inhibitors can be further tested for induction of expression of one or more genes that are underexpressed in a neurological disorder, e.g., frataxin (GenBank Accession No. NM OOO 144.3), huntingtin (GenBank Accession No. NM 0021 1 1.6), brain derived neurotrophic factor (BDNF; GenBank Accession No.
  • frataxin GenBank Accession No. NM OOO 144.3
  • huntingtin GeneBank Accession No. NM 0021 1 1.6
  • BDNF brain derived neurotrophic factor
  • NM l 70735.4 peroxisome proliferator-activated receptor-gamma, coactivator 1 , alpha
  • POCl A GenBank Accession No. NM 013261.3
  • ataxins e.g., ataxin 1 (GenBank Accession No. NM 000332.2
  • fragile X mental retardation FMRl ; GenBank Accession No.
  • NM 002024.3 dystrophia myotonica protein kinase
  • DMPK dystrophia myotonica protein kinase
  • NM_000044.2 dystrophia myotonica protein kinase
  • NM_000044.2 dystrophia myotonica protein kinase
  • any cells can be used, including primary cells obtained from a subject (e.g., a subject having a neurological disorder) or cells of a cell line.
  • exemplary cells include neural cells, neuronal cells, and lymphocytes.
  • the cells can be isolated and stored frozen in aliquots to provide ease in scaling the assay to allow multiple samples or multiple assays to be done with the same cell source.
  • the cells are lymphocytes (e.g., derived from Friedreich's ataxia patients), which are primary cells or cells of a lymphoblastoid cell line.
  • nucleic acid expression can be determined, e.g., by hybridization (e.g., Northern blotting), nucleic acid microarrays, PCR
  • Protein expression can be determined, e.g., by immunoblotting (e.g., Western blotting), immunoprecipitation, immunosorbent assay (e.g., ELISA or RIA), peptide microarrays, or fusion proteins (e.g., GFP fusions).
  • immunoblotting e.g., Western blotting
  • immunoprecipitation e.g., immunoprecipitation
  • immunosorbent assay e.g., ELISA or RIA
  • peptide microarrays e.g., GFP fusions.
  • Useful compounds for chronic treatment include those that inhibit HDAC3 at concentrations that do not show significant cytotoxic activity.
  • Cytotoxic activity can be measured by incubating compounds with an indicator cell line (e.g., the human transformed liver cell HepG2). Viable cell number is determined after an incubation period, typically between 24-72 hours following administration of the compound. Viable cells can be determined by many methods including but not limited to cell counting or using a substrate converted to a colored product by live cells such as MTS.
  • the ratio of HDAC3 activity to cytotoxicity can identify molecules that increase expression of gene products reduced by disease and are tolerable to administration over long periods of time.
  • HDAC3 inhibitors can be administered neat or formulated as pharmaceutical compositions.
  • Pharmaceutical compositions include an appropriate amount of the HDAC inhibitor in combination with an appropriate carrier and optionally as other useful ingredients.
  • Acceptable salts of HDAC inhibitors include, but are not limited to, those prepared from the following acids: alkyl, alkenyl, aryl, alkylaryl and alkenylaryl mono-, di- and tricarboxylic acids of 1 to 20 carbon atoms, optionally substituted by 1 to 4 hydroxyls; alkyl, alkenyl, aryl, alkylaryl and alkenylaryl mono-, di- and trisulfonic acids of 1 to 20 carbon atoms, optionally substituted by 1 to 4 hydroxyls; dibasic acids (e.g., fumaric; glutaric; maleic; salicyclic; tartaric (including (+)-L-tartaric); malonic; and succinic acids); and mineral acids.
  • dibasic acids e.g., fumaric; glutaric; maleic; salicyclic; tartaric (including (+)-L-tartaric); malonic; and succinic acids
  • mineral acids e.g., mineral acids
  • Examples include hydrochloric; hydrobromic; sulfuric; nitric; phosphoric; lactic (including (+)-L-lactic, (+/-)-DL-lactic); acetic; p- toluenesulfoniccitric; methanesulfonic; formic; malonic; succinic; naphthalene-2-sulfonic; and benzenesulfonic acid.
  • compositions of HDAC3 inhibitors suitable for oral administration can be in the form of (1) discrete units such as capsules, sachets, tablets, or lozenges each containing a predetermined amount of the HDAC3 inhibitor; (2) a powder or granules; (3) a bolus, electuary, or paste; (4) a solution or a suspension in an aqueous liquid or a nonaqueous liquid; or (5) an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • Compositions suitable for topical administration in the mouth, for example buccally or sublingually include lozenges.
  • Compositions suitable for parenteral administration include aqueous and non-aqueous sterile suspensions or injection solutions.
  • Compositions suitable for rectal administration can be presented as a suppository.
  • compositions of HDAC3 inhibitors can be formulated using a solid or liquid carrier.
  • the solid or liquid carrier should be compatible with the other ingredients of the formulation and not deleterious to the recipient. If the pharmaceutical composition is in tablet form, then the HDAC3 inhibitor is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. If the composition is in powder form, the carrier is a finely divided solid in admixture with the finely divided active ingredient. The powders and tablets can contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • a solid carrier can include one or more substances that can act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents.
  • a suitable carrier can also be an encapsulating material. If the composition is a solution, suspension, emulsion, syrup, elixir, or pressurized composition, then liquid carriers can be used.
  • the HDAC3 inhibitor is dissolved or suspended in a pharmaceutically acceptable liquid carrier.
  • suitable examples of liquid carriers for oral and parenteral administration include (1) water; (2) alcohols, e.g. monohydric alcohols and polyhydric alcohols such as glycols, and their derivatives; and (3) oils, e.g. fractionated coconut oil and arachis oil.
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Liquid carriers for pressurized compositions include halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers; emulsifiers; buffers; preservatives; sweeteners; flavoring agents; suspending agents; thickening agents; colors; viscosity regulators; stabilizers; osmo-regulators; cellulose derivatives such as sodium carboxymethyl cellulose; antioxidants; and bacteriostatics.
  • suitable pharmaceutical additives such as solubilizers; emulsifiers; buffers; preservatives; sweeteners; flavoring agents; suspending agents; thickening agents; colors; viscosity regulators; stabilizers; osmo-regulators; cellulose derivatives such as sodium carboxymethyl cellulose; antioxidants; and bacteriostatics.
  • Other carriers include those used for formulating lozenges such as sucrose, acacia, tragacanth, gelatin and glycerin as well as those used in formulating suppositories such as cocoa butter or polyethylene glycol.
  • solutions of the HDAC3 inhibitor can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the composition suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient, which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium as described above.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or 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. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the HDAC3 inhibitor in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze-drying techniques, which yield a powder of the HDAC3 inhibitor, plus any additional desired ingredient present in the previously sterile- filtered solutions.
  • compositions can be in unit-dose or multi-dose form or in a form that allows for slow or controlled release of the HDAC3 inhibitor.
  • Each unit-dose can be in the form of a tablet, capsule or packaged composition such as, for example, a packeted powder, vial, ampoule, prefilled syringe or sachet containing liquids.
  • the unit-dose form also can be the appropriate number of any such compositions in package form.
  • Pharmaceutical compositions in multi-dose form can be in packaged in containers such as sealed ampoules and vials.
  • the HDAC3 inhibitor can be stored in a freeze- dried (lyophilized) condition requiring only the addition of a sterile liquid carrier immediately prior to use.
  • extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.
  • the application also provides a kit for the treatment or prevention of a disorder selected from Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntingdon's disease, a spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Alzheimer's disease in a patient in need thereof, comprising (i) a compound described herein, or a pharmaceutically acceptable salt thereof; and (ii) instructions comprising a direction to administer said compound to said patient.
  • RGFA8 N l -(2-aminophenyl)-N 7 -/?-tolyl-l,7-heptanedioic acid diamide; WO 2007/058927
  • human lymphocytes isolated from peripheral blood from normal donors were incubated with 1-30 ⁇ M RGFA8.
  • Frataxin mR ⁇ A levels were measured with quantitative RT-PCR and normalized to expression levels of the housekeeping gene GADPH (Herman et al., Nat. Chem. Biol., 2:551-558, 2006).
  • RGFA8 increased expression of frataxin in normal lymphocytes or patient lymphocytes at all concentrations tested, with a maximum observed increase of about 16-fold compared to vehicle control (FIG. 1, normal lymphocytes). This example indicates that RGFA8 could be used to treat patients with Friedreich's ataxia by increasing frataxin expression.
  • RGF A8 is a Specific Inhibitor of HDAC3
  • RGFA8 was specific for any particular HDAC or subset of HDACs
  • activities of RGFA8 and known HDAC inhibitor trichostatin A were tested on a panel of individual purified HDAC enzymes and a nuclear extract, which contained a mixture of HDACs.
  • HDAC enzyme inhibition assays were performed using purified HDACs 1-10 essentially as described in Beckers et al., 2007, Int. J. Cancer.,
  • RGFA8 was most active on HDAC3, with a half-maximal inhibitory concentration (IC 50 ) of 0.20 ⁇ 0.23 ⁇ M (Table 1). At least 10-fold lesser activity was observed by RGFA8 on other HDACs or on nuclear extract.
  • TSA was found to be a more potent inhibitor of HDAC3 than RGF8, TSA had greater inhibitory activity on HDAC6 (IC 50 of 0.0014 ⁇ 0.0006) and HDACl (IC 50 of 0.0067 ⁇ 0.001 1) as compared to HDAC3 (IC 50 of 0.0096 ⁇ 0.0071). Sub-micromolar inhibition by TSA was observed for all HDACs tested.
  • HDAC inhibitors that are specific for HDAC3 can be used to treat neurological conditions (e.g., Friedreich's ataxia).
  • a chemical library was screened to identify compounds that specifically inhibited HDAC3, relative to other HDACs. Briefly, a chemical library of test compounds was created by standard organic chemistry methods, and the inhibitory activity of the compounds on purified HDACs 1 -10 was determined (see Example 2). Fourteen compounds were identified that had stronger inhibitory activity for HDAC3 as compared to one or more other HDACs. These compounds, their structures, and inhibitory activities for HDACl , HDAC2, HDAC3, HDAC5, are presented in Table 2, along with growth inhibitory activity on HepG2 cells. HDAC inhibitory activities were measured essentially as described in Example 2.
  • HepG2 cells Growth inhibition of HepG2 cells was measured by adding serial dilutions of the compounds to HepG2 cells at a density of 5* 10 4 cells/ml, and incubating the mixture for 72 hours at 37 0 C, 5% CO 2 . The viable cells were then measured using a CellTiter 96TM AQueous One Solution cell proliferation assay (Promega, Madison, WI). The activities of RGFA 8 and the known HDAC inhibitor MS 275 are also presented.
  • HDAC3 inhibitors were identified as above. The activities of the compounds to inhibit HDACl and HDAC3 are listed in Table 3.
  • Relative inhibitory activities for selected compounds were determined by dividing the IC 50 for HDACs 1 , 2, and 5 by the IC 50 for HDAC3 (Table 5).
  • the estimated therapeutic index for each compound was determined by dividing the HepG2 growth IC 50 by the IC50 for HDAC3 activity (Table 5).
  • FXN frataxin
  • Selected compounds were assayed by quantitative RT-PCR for their activity to increase expression of frataxin (FXN]) mRNA in human lymphocytes isolated from peripheral blood of normal donors (see Example 1). Briefly, the identified compounds were added to lymphocytes at a concentration of 10 ⁇ M, and increase in expression of FXNl mRNA was determined compared to vehicle control. The majority of the identified compounds increased frataxin mRNA expression at a concentration of 10 ⁇ M (Table 5), indicating that these compounds can be useful in treatment of Friedrich's ataxia and other neurological disorders described herein.
  • FXN frataxin
  • Compound B04 is administered to knock-in mice homozygous for a (GAA) 230 repeat in the first intron of the endogenous frataxin gene (Miranda et al., 2002, FEBS Lett., 512:291-297).
  • the mice are treated by subcutaneous daily injections with 150 mg/kg of
  • RNA is extracted from brain stem, heart, and/or cerebellum. Frataxin mRNA expression is determined by one step quantitative real-time PCR using the primers 5 '-CCTGGCCGAGTTCTTTGAAGO ' (SEQ ID NO: 1) and 5 '-GCCAGATTTGCTTGTTTGGO ' (SEQ ID NO:2). Frataxin mRNA is
  • Treatment with compound B04 increases knock-in frataxin mRNA to levels that do not significantly differ from wild-type, thus demonstrating correction of fxn defciciency in these animals.
  • Western blotting confirms that increased fxn mRNA levels result in higher frataxin protein level.
  • Treatment with compound B04 does not result in increased frataxin mRNA levels in wild-type animals, indicating that its effect is due to removal of the inhibition caused by the GAA expansion.
  • This compound was made by the process shown below.
  • This compound was made by the process shown below.
  • This compound was made by the process shown below.
  • This compound was made by the process shown below.
  • This compound was made by the process shown below.
  • Example 33 A Synthesis of B35. N 1 -(2-amino-4-fluorophenyI)-N 7 -(pyridin-2-yl)-l,7-heptanedioic acid diamide
  • This compound was made by the process shown below.
  • This compound was made by the process below.
  • This compound was made by the process below.
  • This compound was made by the process below.
  • This compound was made by the process below.
  • Example 38 Synthesis of B41 N 1 -(2-aminophenyl)-N 7 -(4-(pyridin-4-yl)thiazol-2-yl)-l,7-heptanedioic acid diamide This compound was made by the process below, starting from an intermediate from the synthesis of B36.
  • This compound was made by the process below.
  • This compound was made by the process below.
  • This compound was made by the process below.
  • This compound was synthesized by the process below.
  • This compound was synthesized by the process below.
  • This compound was made by the procedure below.
  • This compound was made by the procedure below.
  • This compound was made by the procedure below.
  • This compound was made by the procedure below.
  • Example 72 7V 1 -(2-aminophenyl)-4-oxo-./V 7 -/?-tolylheptanediamide (B77) was made according to the general Scheme 3.

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Abstract

L'invention porte sur des inhibiteurs de HDAC représentés par les Formules I, II et III. L'invention porte également sur des méthodes de traitement d'états neurologiques par l'administration des composés et sur l'utilisation des composés en tant que médicaments.
PCT/US2009/055954 2008-09-03 2009-09-03 Composés comprenant des dérivés d'acide pimélique en tant qu'inhibiteurs de hdac WO2010028193A1 (fr)

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CN102633668A (zh) * 2012-01-20 2012-08-15 天舒生物技术有限公司 化合物在转录因子失调相关疾病的治疗药物中的应用
WO2012117421A1 (fr) 2011-03-02 2012-09-07 Orchid Research Laboratories Ltd Inhibiteurs de l'histone désacétylase
CN103304474A (zh) * 2013-06-03 2013-09-18 石玉芳 ω,ω,ω’,ω’-四溴-2,6-二乙酰基吡啶及其合成方法
WO2014138508A1 (fr) * 2013-03-06 2014-09-12 C & C Biopharma, Llc Nouveaux modulateurs de facteurs de transcription
WO2015069810A1 (fr) * 2013-11-05 2015-05-14 C & C Biopharma, Llc Traitement de remodelage cardiaque et d'autres affections du cœur
US20150231049A1 (en) * 2011-10-31 2015-08-20 Avon Products, Inc. Cosmetic Use of N-Heteroarylbisamide Analogs and Related Compounds
WO2015168518A1 (fr) * 2014-05-02 2015-11-05 Torrey Pines Institute For Molecular Studies Composés et procédés de traitement de troubles neurologiques
WO2017028745A1 (fr) * 2015-08-17 2017-02-23 Chung-Wai Shiau Malonamides substitués et leur utilisation comme médicaments antibactériens
US9663529B2 (en) 2013-07-02 2017-05-30 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors
US9914740B2 (en) 2013-07-02 2018-03-13 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors
US20190241504A1 (en) * 2017-08-17 2019-08-08 Standard Llc Novel Myocyte Enhancer Factor 2 (MEF2) modulators
WO2023034440A1 (fr) 2021-09-01 2023-03-09 Case Western Reserve University Traitement de maladies neurodégénératives avec des inhibiteurs de hdac

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012117421A1 (fr) 2011-03-02 2012-09-07 Orchid Research Laboratories Ltd Inhibiteurs de l'histone désacétylase
US20150231049A1 (en) * 2011-10-31 2015-08-20 Avon Products, Inc. Cosmetic Use of N-Heteroarylbisamide Analogs and Related Compounds
US9545367B2 (en) * 2011-10-31 2017-01-17 Avon Products, Inc. Cosmetic use of N-heteroarylbisamide analogs and related compounds
CN102516067A (zh) * 2011-11-25 2012-06-27 宜宾学院 一种合成塞曲司特中间体6-苯甲酰基已酸的方法
CN102633668A (zh) * 2012-01-20 2012-08-15 天舒生物技术有限公司 化合物在转录因子失调相关疾病的治疗药物中的应用
CN102633668B (zh) * 2012-01-20 2015-05-06 天舒生物技术有限公司 化合物在转录因子失调相关疾病的治疗药物中的应用
US9133105B2 (en) 2013-03-06 2015-09-15 C&C Biopharma, Llc Transcription factor modulators
WO2014138508A1 (fr) * 2013-03-06 2014-09-12 C & C Biopharma, Llc Nouveaux modulateurs de facteurs de transcription
CN103304474A (zh) * 2013-06-03 2013-09-18 石玉芳 ω,ω,ω’,ω’-四溴-2,6-二乙酰基吡啶及其合成方法
US9663529B2 (en) 2013-07-02 2017-05-30 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors
US9914740B2 (en) 2013-07-02 2018-03-13 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors
WO2015069810A1 (fr) * 2013-11-05 2015-05-14 C & C Biopharma, Llc Traitement de remodelage cardiaque et d'autres affections du cœur
WO2015168518A1 (fr) * 2014-05-02 2015-11-05 Torrey Pines Institute For Molecular Studies Composés et procédés de traitement de troubles neurologiques
US9994536B2 (en) 2014-05-02 2018-06-12 Torrey Pines Institute For Molecular Studies Compounds and methods of treating neurological disorders
WO2017028745A1 (fr) * 2015-08-17 2017-02-23 Chung-Wai Shiau Malonamides substitués et leur utilisation comme médicaments antibactériens
US20190241504A1 (en) * 2017-08-17 2019-08-08 Standard Llc Novel Myocyte Enhancer Factor 2 (MEF2) modulators
US11230524B2 (en) * 2017-08-17 2022-01-25 Standard Llc Myocyte enhancer factor 2 (MEF2) modulators
WO2023034440A1 (fr) 2021-09-01 2023-03-09 Case Western Reserve University Traitement de maladies neurodégénératives avec des inhibiteurs de hdac

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