WO2010057833A1 - Compounds for treatment of duchenne muscular dystrophy - Google Patents

Compounds for treatment of duchenne muscular dystrophy Download PDF

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WO2010057833A1
WO2010057833A1 PCT/EP2009/065118 EP2009065118W WO2010057833A1 WO 2010057833 A1 WO2010057833 A1 WO 2010057833A1 EP 2009065118 W EP2009065118 W EP 2009065118W WO 2010057833 A1 WO2010057833 A1 WO 2010057833A1
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pyridin
phenyl
compound
optionally substituted
benzaldehyde
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PCT/EP2009/065118
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French (fr)
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Stephen Paul Wren
Graham Michael Wynne
Cristina Lecci
Francis Xavier Wilson
Paul James Davis
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Biomarin Iga, Ltd.
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Publication of WO2010057833A1 publication Critical patent/WO2010057833A1/en

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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/70—Sulfur atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • compositions comprising the compounds, and methods of use thereof.
  • a method for the treatment or prophylaxis of muscular dystrophy and related conditions including Duchenne muscular dystrophy.
  • DMD Duchenne muscular dystrophy
  • X-linked recessive disorder that affects 1 in 3,500 males caused by mutations in the dystrophin gene.
  • the gene is the largest in the human genome, encompassing 2.6 million base pairs of DNA and containing 79 exons.
  • Approximately 60% of dystrophin mutations are large insertion or deletions that lead to frameshift errors downstream, whereas approximately 40% are point mutations or small frameshift rearrangements.
  • Becker muscular dystrophy is a much milder form of DMD caused by reduction in the amount, or alteration in the size, of the dystrophin protein.
  • the high incidence of DMD (1 in 10,000 sperm or eggs) means that genetic screening will never eliminate the disease, so an effective therapy is highly desirable.
  • Dogs offer the best phenocopy for human disease, and are considered a high benchmark for preclinical studies. Unfortunately, breeding these animals is expensive and difficult, and the clinical time course can be variable among litters. [0005] The mdx mouse is the most widely used model due to availability, short gestation time, time to mature and relatively low cost (Bulf ⁇ eld et al., X Chromosome-Linked Muscular Dystrophy (max) in the Mouse, Proc. Natl. Acad. Sci. USA 81, 1189-92 (1984)). [0006] Since the discovery of the DMD gene about 20 years ago, varying degrees of success in the treatment of DMD have been achieved in preclinical animal studies, some of which are being followed up in humans.
  • Gene- and cell-based therapies offer the fundamental advantage of obviating the need to separately correct secondary defects/pathology (for example, contractures), especially if initiated early in the course of the disease.
  • secondary defects/pathology for example, contractures
  • these approaches face a number of technical hurdles.
  • Immunological responses against viral vectors, myoblasts and newly synthesized dystrophin have been reported, in addition to toxicity, lack of stable expression and difficulty in delivery.
  • Pharmacological approaches for the treatment of muscular dystrophy differ from gene- and cell-based approaches in not being designed to deliver either the missing gene and/or protein.
  • the pharmacological strategies use drugs/molecules in an attempt to improve the phenotype by means such as decreasing inflammation, improving calcium homeostasis and increasing muscle progenitor proliferation or commitment. These strategies offer the advantage that they are easy to deliver systemically and can circumvent many of the immunological and/or toxicity issues that are related to vectors and cell-based therapies.
  • Upregulation therapy is based on increasing the expression of alternative genes to replace a defective gene and is particularly beneficial when an immune response is mounted against a previously absent protein.
  • Upregulation of utrophin an autosomal paralogue of dystrophin has been proposed as a potential therapy for DMD (Perkins et al., Neuromuscul. Disord., Sl :S78-S89 (2002); Khurana et al, Nat. Rev. Drug Discov., 2:379-90 (2003)).
  • utrophin When utrophin is over- expressed in transgenic mdx mice, it localizes to the sarcolemma of muscle cells and restores the components of the dystrophin-associated protein complex (DAPC), which prevents the dystrophic development and in turn leads to functional improvement of skeletal muscle.
  • DAPC dystrophin-associated protein complex
  • Adenoviral delivery of utrophin in the dog has been shown to prevent pathology. Commencement of increased utrophin expression shortly after birth in the mouse model can be effective, and no toxicity is observed when utrophin is ubiquitously expressed, which is promising for the translation of this therapy to humans. Upregulation of endogenous utrophin to sufficient levels to decrease pathology might be achieved by the delivery of small diffusible compounds.
  • compositions comprising the compounds, and methods of use thereof.
  • compounds that upregulate endogenous utrophin and are useful in the treatment or prophylaxis of muscular dystrophy, including DMD.
  • R 1 , R 2 , R 3 , L 1 , L 2 , and Y are defined herein elsewhere, for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof for use in the treatment or prophylaxis of Duchenne muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof for use in the treatment or prophylaxis of Becker muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof for use in the treatment or prophylaxis of cachexia.
  • compositions comprising a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof; in combination with one or more pharmaceutically acceptable carriers or excipients.
  • the method treats, prevents, and/or manages one or more symptoms of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • the method treats, prevents, and/or manages one or more symptoms of Duchenne muscular dystrophy.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • the compounds of formula (I) are used in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. In another embodiment, the compounds of formula (I) are used in the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy. In another embodiment, the compounds of formula (I) are used in the treatment or prophylaxis of Duchenne muscular dystrophy.
  • alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted.
  • the alkyl is a linear saturated monovalent hydrocarbon radical of 1 to 20 (Ci-C 20 ), 1 to 15 (Ci-Ci 5 ), 1 to 10 (Ci-Ci 0 ), 1 to 6 (Ci-C 6 ), or 1 to 5 (C 1 - C 5 ) carbon atoms, or a branched saturated monovalent hydrocarbon radical of 3 to 20 (C 3 - C 20 ), 3 to 15 (C 3 -C 15 ), 3 to 10 (C 3 -Ci 0 ), 3 to 6 (C 3 -C 6 ), or 3 to 5 (C 3 -C 5 ) carbon atoms.
  • linear Ci-C 6 and branched C 3 -C 6 alkyl groups are also referred to as "lower alkyl.”
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec -butyl, t-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).
  • Ci-C 6 alkyl refers to an optionally substituted linear or branched saturated monovalent hydrocarbon radical having one to six carbon atoms, such as, e.g. , methyl, ethyl, n-propyl, isopropyl, t-butyl, and n-hexyl.
  • the Ci-C 6 alkyl is optionally substituted with one or more halo, such as, e.g., trifluoromethyl and 1,2- dichloroethyl.
  • Ci-C 6 haloalkyl refers to a Ci-C 6 alkyl group as defined herein elsewhere substituted by one or more halo.
  • C 1 -C 4 alkyl and “Ci-Ci 0 alkyl” have similar meanings as “Ci-C 6 alkyl” except that they contain respectively from one to four and from one to ten carbon atoms.
  • the alkyl may be optionally substituted as described herein.
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bond(s), wherein the alkenyl is optionally substituted.
  • alkenyl also embraces radicals having "cis” and “trans” configurations, or alternatively, "E” and "Z” configurations.
  • the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C 2 -C 20 ), 2 to 15 (C 2 -Ci 5 ), 2 to 10 (C 2 -Ci 0 ), 2 to 6 (C 2 -C 6 ), or 2 to 5 (C 2 -C 5 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (Cs-C 20 ), 3 to 15 (C 3 -C 15 ), 3 to 10 (C 3 -C 10 ), 3 to 6 (C 3-C 6 ), or 3 to 5 (C 3 -C 5 ) carbon atoms.
  • alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and A- methylbutenyl.
  • C 2 -C 6 alkenyl refers to an optionally substituted linear or branched monovalent hydrocarbon radical having from two to six carbon atoms and containing at least one carbon-carbon double bond, such as, e.g., ethenyl, 2-propenyl, and 3-hexenyl.
  • the C 2 -C 6 alkenyl is optionally substituted with one or more halo, such as, e.g., chloroethenyl and fluoroethenyl.
  • halo such as, e.g., chloroethenyl and fluoroethenyl.
  • the terms "C 2 -Ci 0 alkenyl" has similar meanings except that they contain from two to ten carbon atoms.
  • the alkenyl may be optionally substituted as described herein.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bond(s), wherein the alkynyl is optionally substituted.
  • the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C 2 -C 20 ), 2 to 15 (C 2 -Ci 5 ), 2 to 10 (C 2 -Ci 0 ), 2 to 6 (C 2 -C 6 ), or 2 to 5 (C 2 -C 5 ) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (Cs-C 20 ), 3 to 15 (C 3 -Ci 5 ), 3 to 10 (C 3 -Ci 0 ), 3 to 6 (C 3 -C 6 ), or 3 to 5 (C 3 -C 5 ) carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH).
  • C 2 -C 6 alkynyl refers to an optionally substituted linear or branched monovalent hydrocarbon radical having from two to six carbon atoms and containing at least one carbon-carbon triple bond, such as, e.g., ethynyl, 2-propynyl, and 3-hexynyl.
  • the C 2 -C 6 alkynyl is optionally substituted with one or more halo.
  • alkynyl As used herein, and unless otherwise specified, the terms “C 2 -Ci 0 alkynyl” has similar meanings except that they contain from two to ten carbon atoms. In certain embodiments, the alkynyl may be optionally substituted as described herein. [0022] As used herein, and unless otherwise specified, the term “alkylene” refers to a saturated linear or branched divalent hydrocarbon radical, wherein the alkylene is optionally substituted.
  • the alkylene is a saturated linear divalent hydrocarbon radical of 1 to 20 (Ci-C 20 ), 1 to 15 (Ci-Ci 5 ), 1 to 10 (Ci-Ci 0 ), 1 to 6 (Ci-C 6 ), or 1 to 5 (C 1 - C 5 ) carbon atoms, or a saturated branched divalent hydrocarbon radical of 3 to 20 (Cs-C 20 ), 3 to 15 (C 3 -C 15 ), 3 to 10 (C 3 -Ci 0 ), 3 to 6 (C 3 -C 6 ), or 3 to 5 (C 3 -C 5 ) carbon atoms.
  • linear Ci-C 6 and branched C 3 -C 6 alkylene groups are also referred to as "lower alkylene.”
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene (including all isomeric forms), isopropylene, butylene (including all isomeric forms), n-butylene, isobutylene, t-butylene, pentylene (including all isomeric forms), and hexylene (including all isomeric forms).
  • Ci-C 6 alkylene refers to a saturated optionally substituted linear divalent hydrocarbon radical of 1 to 6 carbon atoms or a saturated optionally substituted branched divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • Ci-C 3 alkylene refers to a saturated optionally substituted linear divalent hydrocarbon radical of 1 to 3 carbon atoms or a saturated optionally substituted branched divalent hydrocarbon radical of 3 carbon atoms, such as, e.g., -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, and -CH(CH 3 )-(CH 2 )-.
  • the alkylene may be optionally substituted as described herein.
  • alkenylene refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bond(s), wherein the alkenylene is optionally substituted.
  • alkenylene also embraces radicals having "cis” and “trans” configurations, or alternatively, "E” and "Z” configurations.
  • the alkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C 2 -C 20 ), 2 to 15 (C 2 -Ci 5 ), 2 to 10 (C 2 -Ci 0 ), or 2 to 6 (C 2 -C 6 ) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C 3 -C 20 ), 3 to 15 (C 3 -Ci 5 ), 3 to 10 (C 3 -Ci 0 ), or 3 to 6 (C 3 -C 6 ) carbon atoms.
  • alkenylene groups include, but are not limited to, ethenylene, allylene, propenylene, butenylene, and 4-methylbutenylene.
  • C 2 -C 6 alkenylene refers to an optionally substituted linear divalent hydrocarbon radical of 2 to 6 carbon atoms or an optionally substituted branched divalent hydrocarbon radical of 3 to 6 carbon atoms, which contains one or more carbon-carbon double bond.
  • the alkenylene may be optionally substituted as described herein.
  • alkynylene refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bond(s), wherein the alkynylene is optionally substituted.
  • the alkynylene is a linear divalent hydrocarbon radical of 2 to 20 (C 2 -C 20 ), 2 to 15 (C 2 -Ci 5 ), 2 to 10 (C 2 -Ci 0 ), or 2 to 6 (C 2 -C 6 ) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C 3 -C 20 ), 3 to 15 (C 3 -Ci 5 ), 3 to 10 (C 3 -Ci 0 ), or 3 to 6 (C 3 -C 6 ) carbon atoms.
  • C 2 -C 6 alkynylene refers to an optionally substituted linear divalent hydrocarbon radical of 2 to 6 carbon atoms or an optionally substituted branched divalent hydrocarbon radical of 3 to 6 carbon atoms, which contains one or more carbon-carbon triple bond.
  • the alkynylene may be optionally substituted as described herein.
  • the term “carbocyclic” refers to an optionally substituted aromatic or non-aromatic ring system wherein all of the ring atoms are carbon atoms.
  • the carbocyclic ring system is monocyclic or multicyclic.
  • the carbocyclic is optionally substituted with one or more halo.
  • the carbocyclic is an optionally substituted non-aromatic ring system having from 3 to 8 ring atoms, all of which are carbon atoms.
  • the carbocyclic contains one or more carbon-carbon double bond.
  • carbocyclic ring systems include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and cyclohexenyl.
  • carbocyclic ring systems also include, but are not limited to, phenyl, naphthyl, or indanyl. In certain embodiments, the carbocyclic may be optionally substituted as described herein.
  • heterocyclic refers to an optionally substituted aromatic or non-aromatic ring system wherein one or more of the ring atom(s) is a hetero atom independently selected from N, O, and S.
  • the heterocyclic ring system is monocyclic or multicyclic.
  • the heterocyclic is an optionally substituted non-aromatic ring system having 3 to 8 ring atoms, one or more of which is a hetero atom independently selected from N, O, and S.
  • Examples include, but are not limited to, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, imidazolinyl, dioxanyl, and pyrrolidinyl. Examples also include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, indolyl, and benzimidazolyl.
  • Examples also include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzimidazolinyl, benzodioxolyl, benzodioxanyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, thiazolyl, benzothiazolyl, benzoxazolyl, indazolyl, and imidazolyl.
  • the heterocyclic may be optionally substituted as described herein.
  • one or more ring N atom(s) may be replaced with N(O) to form an oxide.
  • one or more ring S atom(s) may be replaced with S(O) or S(O) 2 to form an oxide.
  • aromatic refers to an optionally substituted carbocyclic or heterocyclic ring system which contains at least one aromatic ring.
  • the aromatic ring system is monocyclic or multicyclic.
  • the aromatic ring is monocyclic or bicyclic and has from 5 to 10 ring atoms.
  • the aromatic is bicyclic with two fused rings, wherein one of the rings is aromatic and the other may be aromatic or partially saturated. Examples of aromatic ring systems include, but are not limited to, phenyl, naphthalenyl, and indanyl.
  • aromatic ring systems may also include, but are not limited to, pyridinyl, pyrimidinyl, furanyl, thienyl, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzimidazolinyl, benzodioxyl, benzodioxanyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, thiazolyl, benzothiazolyl, benzoxazolyl, indazolyl, and imidazolyl.
  • the aromatic ring system may be optionally substituted as described herein.
  • non-aromatic refers to an optionally substituted carbocyclic or heterocyclic ring system which may be fully or partially saturated.
  • the non-aromatic ring system is monocyclic or multicyclic.
  • the non-aromatic ring is monocyclic or bicyclic and has from 3 to 12 ring atoms.
  • Examples of non-aromatic ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, and pyrrolidinyl.
  • the non-aromatic ring system may be optionally substituted as described herein.
  • cycloalkyl or non- aromatic carbocyclic refers to a saturated bridged or non-bridged monovalent cyclic hydrocarbon radical, wherein the cycloalkyl or non-aromatic carbocyclic is optionally substituted.
  • the cycloalkyl or non-aromatic carbocyclic is monocyclic or multicyclic.
  • the cycloalkyl or non-aromatic carbocyclic is optionally substituted with one or more halo.
  • the cycloalkyl or non-aromatic carbocyclic has from 3 to 20 (C 3 -C 20 ), 3 to 15 (C 3 -Ci 5 ), 3 to 10 (C 3 -Ci 0 ), 3 to 8 (C 3 -C 8 ), 3 to 7 (C 3 -Cy), or 3 to 6 (C 3 -C 6 ) carbon atoms.
  • Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.
  • the cycloalkyl or non-aromatic carbocyclic may be optionally substituted as described herein.
  • aryl or “aromatic carbocyclic” refers to a monovalent monocyclic or multicyclic hydrocarbon radical that contains at least one aromatic ring, wherein the aryl or aromatic carbocyclic is optionally substituted.
  • the aryl has from 6 to 20 (C 6 -C 20 ), from 6 to 15 (C 6 - C 15 ), or from 6 to 10 (C 6 -Ci 0 ) ring atoms.
  • the aryl has a single ring or two fused rings and from 6 to 10 ring carbon atoms.
  • the aryl or aromatic carbocyclic is bicyclic, i.e., having two rings, wherein one of the rings is aromatic and the other ring may be aromatic or partially saturated.
  • the aryl or aromatic carbocyclic is bicyclic or tricyclic, wherein one of the rings is aromatic and the other of the ring(s) may be saturated, partially unsaturated, and/or aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and indanyl.
  • aryl groups also include, but are not limited to fluorenyl, azulenyl, anthryl, phenanthryl, and pyrenyl.
  • aryl groups also include, but are not limited to, dihydronaphthyl, indenyl, or tetrahydronaphthyl (tetralinyl).
  • the aryl or aromatic carbocyclic is optionally substituted with two or more substituents, wherein the two substituents are adjacent to each other and may be taken together with the atoms to which they are attached to form a fused partially saturated ring, which optionally contains one or more heteroatoms selected from N, O, and S, such as, e.g., benzodioxolyl and dihydrobenzofuran.
  • the aryl or aromatic carbocyclic may be optionally substituted as described herein.
  • aralkyl or “aryl-alkyl” refers to a monovalent alkyl group substituted with aryl. In certain embodiments, the alkyl and aryl moieties are optionally substituted with one or more substituents as described herein.
  • heteroaryl or “heteroaromatic” refers to a monovalent monocyclic or multicyclic radical that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N, and wherein the heteroaryl is optionally substituted.
  • each ring of the heteroaryl can contain one to two O atoms, one to two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • the heteroaryl or heteroaromatic has a single ring or two fused rings and from 5 to 10 ring atoms, at least one of which is a heteroatom selected from N, O, and S.
  • the heteroaryl or heteroaromatic is bicyclic, i.e., having two rings, wherein one of the rings is aromatic and the other ring may be aromatic or partially saturated.
  • monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
  • bicyclic heteroaryl groups include, but are not limited to, benzo furanyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimi
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
  • the heteroaryl may be optionally substituted as described herein.
  • heterocyclyl refers to a monovalent monocyclic or multicyclic radical that contains at least one non-aromatic ring, wherein at least one non-aromatic ring contains one or more heteroatoms independently selected from O, S, and N, and wherein the heterocyclyl is optionally substituted.
  • the heterocyclyl has from 3 to 20, from 3 to 15, from 3 to 12, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system.
  • the nitrogen or sulfur atom(s) in the heterocyclyl is optionally oxidized. In certain embodiments, the nitrogen atom(s) in the heterocyclyl is optionally quaternized. In certain embodiments, some of the rings in the heterocyclyl may be partially or fully saturated, or aromatic. In certain embodiments, the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclyl examples include, but are not limited to, azepinyl, benzimidazolinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, ⁇ -carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl
  • halo or halogen refers to fluoro, chloro, bromo, or iodo.
  • the term "optionally substituted” is intended to mean that a group, including but not limited to, alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl, may be substituted with one or more substituents independently selected from, e.g., (a) Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 cycloalkyl, C 6-14 aryl, C 7 _i5 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q 1 ; and (b) halo, cyano (-CN), nitro (-NO 2 ), -C(O)R a , -C(O)OR a , -C
  • the terms “optically active” and “enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
  • the compound comprises about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer based on the total weight of the racemate in question.
  • R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
  • the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
  • the (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
  • a chiral center or another form of isomeric center is present in a compound provided herein, all forms of such isomer or isomers, including stereoisomers, enantiomers and diastereoisomers, are intended to be within the scope of this disclosure.
  • Compounds provided herein containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or a diastereomerically enriched mixture, or the racemic mixture may be separated using known techniques and an individual enantiomer may be used alone.
  • solvate refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non- stoichiometric amount of solvent bound by non-covalent intermolecular forces.
  • the bound solvent is water
  • the solvate is a hydrate.
  • the term "pharmaceutically acceptable salt” refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids, organic acids, inorganic bases, and organic bases.
  • pharmaceutically acceptable salt When the compound provided herein contains an acidic or basic moiety, it may be provided as a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and Handbook of Pharmaceutical Salts, Properties, and Use; Stahl and Wermuth, Ed.; Wiley- VCH and VHCA: Zurich, Switzerland, 2002.
  • suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(15)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy- ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucohe
  • suitable bases for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, sodium hydroxide, and primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, JV-methyl-glucamine, hydrabamine, lH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-hydroxyethyl)
  • prodrug refers to a covalently bonded compound comprising a parent drug moiety and a pro-moiety, which undergoes bond cleavage reaction in vivo to release the active parent drug.
  • prodrug refers to a functional derivative of a parent compound, for example, a compound of formula (I), and is readily convertible into the parent compound in vivo.
  • a prodrug may be converted to the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See, e.g., Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al.
  • the term "subject” refers to an animal, including but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • a primate e.g., human
  • cow, pig, sheep, goat horse
  • dog cat
  • rabbit rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.
  • the terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • the terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.
  • the terms “manage,” “managing,” and “management” refer to preventing, reducing, or slowing the progression, spread, or worsening of a disease or disorder, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and/or therapeutic agent do not result in a complete cure of the disease or disorder. In this regard, the term “manage,” “managing,” or “management” encompasses treating a patient who had suffered from a particular disease to prevent, minimize, or slow the progression or recurrence of the disease.
  • the term “therapeutically effective amount” refers to the amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • the term “therapeutically effective amount” also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • prophylactically effective amount refers to the amount of a compound sufficient to prevent a disease or disorder, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease.
  • prophylactically effective amount can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • the term "pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • active ingredient and active substance refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or managing one or more symptoms of a condition, disorder, or disease.
  • active ingredient and active substance may be an optically active isomer of a compound described herein.
  • drug or “therapeutic agent” refers to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or managing one or more symptoms of a condition, disorder, or disease.
  • Y is CH or N, wherein the CH is optionally substituted
  • L 1 is a bond, -O-, -NR 4 -, -S-, -SO-, -SO 2 -, -NHC(O)NH-, -NHC(O)-, or -NHS(O) 2 -;
  • L 2 is a bond, -NHC(O)NH-, -NHC(O)-, -O-, -S-, or -NR 8 -;
  • R 1 is (i) R 5 ; or (ii) Ci-C 6 alkyl optionally substituted with one or more halo, R 5 , OR 6 , N(R 6 ) 2 , or C(O)N(R 6 ) 2 ; or when L 1 is a bond, R 1 may additionally be H;
  • R 2 is (i) Ci-C 6 alkyl; or (ii) aryl or heteroaryl, each of which is optionally substituted with one or more halo, R 9 , OR 9 , SR 9 , N(R 9 ) 2 , C(O)R 9 , CH 2 C(O)R 9 , NHC(O)R 9 , NR 9 C(O)R 9 , C(O)N(R 9 ) 2 , NHS(O) 2 R 9 , NHC(O)NHR 9 , or OR 10 ;
  • R 3 is H, halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or when L 1 is a bond and R 1 is H, R 3 may additionally be -L 3 -R ⁇ ;
  • L 3 is a bond, -0-, -NR 4 -, -S-, -SO-, -SO 2 -, -NHC(O)NH-, -NHC(O)-, or -NHS(O) 2 -;
  • R 4 is H or Ci-C 4 alkyl
  • R 5 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, OR 6 , N(R 6 ) 2 , S(O) 2 R 6 , R 7 , OR 7 , C(O)R 7 , NHC(O)R 7 , optionally substituted Ci-C 6 alkyl, or optionally substituted 0(Ci-C 6 alkyl), wherein the Ci-C 6 alkyl and 0(Ci-C 6 alkyl) are each independently optionally substituted with one or more OR 6 , N(R 6 ) 2 , or C(O)N(R 6 ) 2 ; or when R 5 is a partially or fully saturated ring, R 5 may additionally be substituted with one or more oxo; each occurrence of R 6 is independently H or Ci-C 4 alkyl;
  • R 7 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, OH, N(R 6 ) 2 , optionally substituted Ci-C 6 alkyl, or optionally substituted 0(Ci-C 6 alkyl), wherein the Ci-C 6 alkyl and 0(Ci-C 6 alkyl) are each independently optionally substituted with one or more OR 6 or N(R 6 ) 2 ; or when R 7 is a partially or fully saturated ring, R 7 may additionally be substituted with one or more oxo;
  • R 8 is H or Ci-C 4 alkyl; each occurrence of R 9 is independently H or Ci-C 4 alkyl;
  • R 10 is aryl or heteroaryl, each of which is optionally substituted with one or more halo;
  • R 11 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, R 9 , OR 9 , N(R 9 ) 2 , C(O)R 9 , NHC(O)R 9 , or C(O)N(R 9 ) 2 ; and each occurrence Of Ci-C 4 alkyl and Ci-C 6 alkyl may independently be further substituted with one or more halo; for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia.
  • Y is CH or N
  • L 1 is a bond, -O-, -NR 4 -, -S-, -SO-, -SO 2 -, -NHC(O)NH-, -NHC(O)-, or -NHS(O) 2 -;
  • L 2 is a bond, -NHC(O)NH-, -NHC(O)-, -0-, -S-, or -NR 8 -;
  • R 1 is (i) R 5 ; or (ii) Ci-C 6 alkyl optionally substituted with one or more halo, R 5 , OR 6 , N(R 6 ) 2 , or C(O)N(R 6 ) 2 ; or when L 1 is a bond, R 1 may additionally be H;
  • R 2 is (i) Ci-C 6 alkyl; or (ii) aryl or heteroaryl, each of which is optionally substituted with one or more halo, R 9 , OR 9 , N(R 9 ) 2 , C(O)R 9 , NHC(O)R 9 , C(O)N(R 9 ) 2 , NHC(O)NHR 9 , or OR 10 ;
  • R 3 is H, halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or when L 1 is a bond and R 1 is H, R 3 may additionally be -L 3 -R ⁇ ;
  • L 3 is a bond, -0-, -NR 4 -, -S-, -SO-, -SO 2 -, -NHC(O)NH-, -NHC(O)-, or -NHS(O) 2 -;
  • R 4 is H or Ci-C 4 alkyl
  • R 5 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more OR 6 , N(R 6 ) 2 , R 7 , OR 7 , C(O)R 7 , NHC(O)R 7 , optionally substituted Ci-C 6 alkyl, or optionally substituted 0(Ci-C 6 alkyl), wherein the Ci-C 6 alkyl and 0(Ci-C 6 alkyl) are each independently optionally substituted with one or more halo, OR 6 , N(R 6 ) 2 , or C(O)N(R 6 ) 2 ; or when R 5 is a partially or fully saturated ring, R 5 may additionally be substituted with one or more oxo; each occurrence of R 6 is independently H or Ci-C 4 alkyl;
  • R 7 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, OH, N(R 6 ) 2 , optionally substituted Ci-C 6 alkyl, or optionally substituted 0(Ci-C 6 alkyl), wherein the Ci-C 6 alkyl and 0(Ci-C 6 alkyl) are each independently optionally substituted with one or more OR 6 or N(R 6 ) 2 ; or when R 7 is a partially or fully saturated ring, R 7 may additionally be substituted with one or more oxo;
  • R 8 is H or Ci-C 4 alkyl; each occurrence of R 9 is independently H or C 1 -C 4 alkyl;
  • R 10 is aryl or heteroaryl, each of which is optionally substituted with one or more halo;
  • R 11 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, R 9 , OR 9 , N(R 9 ) 2 , C(O)R 9 , NHC(O)R 9 , or C(O)N(R 9 ) 2 ; for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia.
  • R 9 , OR 9 N(R 9 ) 2 , C(O)R 9 , NHC(O)R 9 , or C(O)N(R 9 ) 2 ; for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia.
  • Y is CH or N
  • L 1 is a bond, -O-, -NR 4 -, -S-, -SO-, -SO 2 -, -NHC(O)NH-, -NHC(O)-, or -NHS(O) 2 -;
  • L 2 is a bond, -NHC(O)NH-, -NHC(O)-, -O-, -S-, or -NR 8 -;
  • R 1 is (i) R 5 ; or (ii) Ci-C 6 alkyl optionally substituted with one or more halo, R 5 , OR 6 , N(R 6 ) 2 , or C(O)N(R 6 ) 2 ; or when L 1 is a bond, R 1 may additionally be H;
  • R 2 is (i) Ci-C 6 alkyl; or (ii) aryl or heteroaryl, each of which is optionally substituted with one or more halo, R 9 , OR 9 , N(R 9 ) 2 , C(O)R 9 , NHC(O)R 9 , C(O)N(R 9 ) 2 , or OR 10 ;
  • R 3 is H, halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; or when L 1 is a bond and R 1 is H, R 3 may additionally be -L 3 -R ⁇ ;
  • L 3 is a bond, -0-, -NR 4 -, -S-, -SO-, -SO 2 -, -NHC(O)NH-, -NHC(O)-, or -NHS(O) 2 -;
  • R 4 is H or Ci-C 4 alkyl
  • R 5 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more OR 6 , N(R 6 ) 2 , R 7 , OR 7 , C(O)R 7 , NHC(O)R 7 , optionally substituted Ci-C 6 alkyl, or optionally substituted 0(Ci-C 6 alkyl), wherein the Ci-C 6 alkyl and 0(Ci-C 6 alkyl) are each independently optionally substituted with one or more OR 6 , N(R 6 ) 2 , or C(O)N(R 6 ) 2 ; or when R 5 is a partially or fully saturated ring, R 5 may additionally be substituted with one or more oxo; each occurrence of R 6 is independently H or C 1 -C 4 alkyl;
  • R 7 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, OH, N(R 6 )2, optionally substituted Ci-C 6 alkyl, or optionally substituted 0(Ci-C 6 alkyl), wherein the Ci-C 6 alkyl and 0(Ci-C 6 alkyl) are each independently optionally substituted with one or more OR 6 or N(R 6 ) 2 ; or when R 7 is a partially or fully saturated ring, R 7 may additionally be substituted with one or more oxo;
  • R 8 is H or Ci-C 4 alkyl; each occurrence of R 9 is independently H or Ci-C 4 alkyl;
  • R 10 is aryl or heteroaryl, each of which is optionally substituted with one or more halo;
  • R 11 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, R 9 , OR 9 , N(R 9 ) 2 , C(O)R 9 , NHC(O)R 9 , or C(O)N(R 9 ) 2 ; for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof for use in the treatment or prophylaxis of Duchenne muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof for use in the treatment or prophylaxis of Duchenne muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof for use in the treatment or prophylaxis of Duchenne muscular dystrophy.
  • each occurrence of alkyl is independently optionally substituted with one or more halo. In one embodiment, each occurrence of alkyl is independently optionally substituted with one or more fluoro.
  • the left hand side of the linker as written is linked to the pyridyl or pyrimidine ring, and the right hand side of the linker as written is linked to the R 1 , R 2 , or R 11 group.
  • Y is CH. In one embodiment, Y is N.
  • L 1 is a bond. In one embodiment, L 1 is -O-. In one embodiment, L 1 is -NR 4 -. In one embodiment, L 1 is -S-. In one embodiment, L 1 is -SO-. In one embodiment, L 1 is -SO 2 -. In one embodiment, L 1 is -NHC(O)NH-. In one embodiment, L 1 is -NHC(O)-. In one embodiment, L 1 is -NHS(O) 2 -.
  • L 2 is a bond. In one embodiment, L 2 is -NHC(O)NH-. In one embodiment, L 2 is -NHC(O)-. In one embodiment, L 2 is -O-. In one embodiment, L 2 is
  • L 2 is -NR 8 -.
  • R 1 is R 5 .
  • R 1 is Ci-C 6 alkyl optionally substituted with one or more halo, R 5 , OR 6 , N(R 6 ) 2 , or C(O)N(R 6 ) 2 .
  • R 1 is Ci-C 6 alkyl optionally substituted with one or more halo.
  • R 1 is Ci-C 6 alkyl optionally substituted with one or more R 5 .
  • R 1 is Ci-C 6 alkyl optionally substituted with one or more OR 6 .
  • R 1 is Ci-C 6 alkyl optionally substituted with one or more N(R 6 ) 2 .
  • R 1 is Ci-C 6 alkyl optionally substituted with one or more C(O)N (R 6 ) 2 .
  • L 1 is a bond
  • R 1 is
  • L 1 is a bond
  • R 1 is H, R 5 , or Ci-C 6 alkyl optionally substituted with one or more halo, R 5 , OR 6 , N(R 6 ) 2 , or C(O)N(R 6 ) 2 .
  • R 2 is Ci-C 6 alkyl. In one embodiment, R 2 is Ci-C 6 alkyl optionally substituted with one or more halo.
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more halo, R 9 , OR 9 , SR 9 , N(R 9 ) 2 , C(O)R 9 , CH 2 C(O)R 9 , NHC(O)R 9 ,
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more halo, R 9 , OR 9 ,
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more halo, R 9 , OR 9 ,
  • R 2 is aryl optionally substituted with one or more halo, R 9 ,
  • R 2 is aryl optionally substituted with one or more halo, R 9 , OR 9 , N(R 9 ) 2 , C(O)R 9 , NHC(O)R 9 , C(O)N(R 9 ) 2 , NHC(O)NHR 9 , or OR 10 .
  • R 2 is aryl optionally substituted with one or more halo, R 9 , OR 9 , N(R 9 ) 2 ,
  • R 2 is heteroaryl optionally substituted with one or more halo
  • R 9 OR 9 , SR 9 , N(R 9 ) 2 , C(O)R 9 , CH 2 C(O)R 9 , NHC(O)R 9 , NR 9 C(O)R 9 , C(O)N(R 9 ) 2 ,
  • R 2 is heteroaryl optionally substituted with one or more halo, R 9 , OR 9 , N(R 9 ) 2 , C(O)R 9 , NHC(O)R 9 , C(O)N(R 9 ) 2 , NHC(O)NHR 9 , or OR 10 .
  • R 2 is heteroaryl optionally substituted with one or more halo, R 9 , OR 9 , N(R 9 ) 2 , C(O)R 9 , NHC(O)R 9 , C(O)N(R 9 ) 2 , or OR 10 .
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more halo. In one embodiment, R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more R 9 . In one embodiment, R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more OR 9 . In one embodiment, R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more SR 9 . In one embodiment, R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more N(R 9 ) 2 .
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more C(O)R 9 .
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more CH 2 C(O)R 9 .
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more NHC(O)R 9 .
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more NR 9 C(O)R 9 .
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more C(O)N(R 9 ) 2 .
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more NHS(O) 2 R 9 . In one embodiment, R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more NHC(O)NHR 9 . In one embodiment, R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more OR 10 .
  • R 3 is H. In one embodiment, R 3 is halo. In one embodiment, R 3 is Ci-C 6 alkyl. In one embodiment, R 3 is Ci-C 6 alkyl optionally substituted with one or more halo. In one embodiment, R is C 2 -C 6 alkenyl. In one embodiment, R is C 2 -C 6 alkynyl. In one embodiment, L 1 is a bond and R 1 is H, R 3 is -L 3 -R ⁇ .
  • L 1 is a bond and R 1 is H, R 3 is H, halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or -L 3 -R ⁇ .
  • L 3 is a bond.
  • L 3 is -O-.
  • L 3 is -NR 4 -.
  • L 3 is -S-.
  • L 3 is -SO-.
  • L 3 is -SO 2 -.
  • L 3 is -NHC(O)NH-.
  • L 3 is -NHC(O)-.
  • L 3 is -NHS(O) 2 -.
  • R 4 is H. In one embodiment, R 4 is C 1 -C 4 alkyl. In one embodiment, R 4 is Ci-C 4 alkyl optionally substituted with one or more halo.
  • R 5 is optionally substituted cycloalkyl. In one embodiment, R 5 is optionally substituted heterocyclyl. In one embodiment, R 5 is optionally substituted aryl. In one embodiment, R 5 is optionally substituted heteroaryl.
  • R 5 is optionally substituted with one or more halo, OR 6 , N(R 6 ) 2 , S(O) 2 R 6 , R 7 , OR 7 , C(O)R 7 , NHC(O)R 7 , optionally substituted Ci-C 6 alkyl, or optionally substituted 0(Ci-C 6 alkyl), wherein the Ci-C 6 alkyl and 0(Ci-C 6 alkyl) are each independently optionally substituted with one or more halo, OR 6 , N(R 6 ) 2 , or C(O)N(R 6 ) 2 .
  • R 5 is optionally substituted with one or more OR 6 , N(R 6 ) 2 , R 7 , OR 7 , C(O)R 7 , NHC(O)R 7 , optionally substituted Ci-C 6 alkyl, or optionally substituted 0(Ci-C 6 alkyl), wherein the Ci-C 6 alkyl and 0(Ci-C 6 alkyl) are each independently optionally substituted with one or more OR 6 , N(R 6 ) 2 , or C(O)N(R 6 ) 2 .
  • R 5 is optionally substituted with one or more halo.
  • R 5 is optionally substituted with one or more OR 6 .
  • R 5 is optionally substituted with one or more N(R 6 ) 2 . In one embodiment, R 5 is optionally substituted with one or more S(O) 2 R 6 . In one embodiment, R 5 is optionally substituted with one or more R 7 . In one embodiment, R 5 is optionally substituted with one or more OR 7 . In one embodiment, R 5 is optionally substituted with one or more C(O)R 7 . In one embodiment, R 5 is optionally substituted with one or more NHC(O)R 7 .
  • R 5 is optionally substituted with one or more Ci-C 6 alkyl, which is optionally substituted with one or more halo, OR 6 , N(R 6 ) 2 , or C(O)N(R 6 ) 2 . In one embodiment, R 5 is optionally substituted with one or more 0(Ci-C 6 alkyl), which is optionally substituted with one or more halo, OR 6 , N(R 6 ) 2 , or C(O)N(R 6 ) 2 .
  • R 5 when R 5 is a partially or fully saturated ring, such as, e.g., cycloalkyl, heterocyclyl, and/or partially or fully saturated fused ring system, R 5 is optionally substituted with one or more oxo, e.g., forming cyclic ketone, cyclic ester, or cyclic amide derivatives.
  • R 5 is optionally substituted with one or more oxo, e.g., forming cyclic ketone, cyclic ester, or cyclic amide derivatives.
  • R 6 is H. In one embodiment, R 6 is C 1 -C 4 alkyl. In one embodiment, R 6 is Ci-C 4 alkyl optionally substituted with one or more halo. [0078] In one embodiment, R 7 is optionally substituted cycloalkyl. In one embodiment, R 7 is optionally substituted heterocyclyl. In one embodiment, R 7 is optionally substituted aryl. In one embodiment, R 7 is optionally substituted heteroaryl.
  • R 7 is optionally substituted with one or more halo, OH, N(R 6 ) 2 , optionally substituted Ci-C 6 alkyl, or optionally substituted 0(Ci-C 6 alkyl), wherein the Ci-C 6 alkyl and 0(Ci-C 6 alkyl) are each independently optionally substituted with one or more halo, OR 6 , or N(R 6 ) 2 .
  • R 7 is optionally substituted with one or more halo, OH, N(R 6 ) 2 , optionally substituted Ci-C 6 alkyl, or optionally substituted 0(Ci-C 6 alkyl), wherein the Ci-C 6 alkyl and 0(Ci-C 6 alkyl) are each independently optionally substituted with one or more OR 6 or N(R 6 ) 2 .
  • R 7 is optionally substituted with one or more halo.
  • R 7 is optionally substituted with one or more OH.
  • R 7 is optionally substituted with one or more N(R 6 ) 2 .
  • R 7 is optionally substituted with one or more Ci-C 6 alkyl, which is optionally substituted with one or more halo, OR 6 , or N(R 6 ) 2 . In one embodiment, R 7 is optionally substituted with one or more 0(Ci-C 6 alkyl), which is optionally substituted with one or more halo, OR 6 , or N(R 6 ) 2 .
  • R 7 when R 7 is a partially or fully saturated ring, such as, e.g., cycloalkyl, heterocyclyl, and/or partially or fully saturated fused ring system, R 7 is optionally substituted with one or more oxo, e.g., forming cyclic ketone, cyclic ester, or cyclic amide derivatives.
  • R 7 is optionally substituted with one or more oxo, e.g., forming cyclic ketone, cyclic ester, or cyclic amide derivatives.
  • R 8 is H. In one embodiment, R 8 is C 1 -C 4 alkyl. In one embodiment, R 8 is Ci-C 4 alkyl optionally substituted with one or more halo.
  • R 9 is H. In one embodiment, R 9 is Ci-C 4 alkyl. In one embodiment, R 9 is Ci-C 4 alkyl optionally substituted with one or more halo.
  • R 10 is aryl optionally substituted with one or more halo. In one embodiment, R 10 is heteroaryl optionally substituted with one or more halo. [0083] In one embodiment, R 11 is optionally substituted cycloalkyl.
  • R 11 is optionally substituted heterocyclyl. In one embodiment, R 11 is optionally substituted aryl. In one embodiment, R 11 is optionally substituted heteroaryl. In one embodiment, R 11 is optionally substituted with one or more halo, R 9 , OR 9 , N(R 9 ) 2 , C(O)R 9 , NHC(O)R 9 , or C(O)N(R 9 ) 2 . In one embodiment, R 11 is optionally substituted with one or more halo. In one embodiment, R 11 is optionally substituted with one or more R 9 . In one embodiment, R 11 is optionally substituted with one or more OR 9 .
  • R 11 is optionally substituted with one or more N(R 9 ) 2 . In one embodiment, R 11 is optionally substituted with one or more C(O)R 9 . In one embodiment, R 11 is optionally substituted with one or more NHC(O)R 9 . In one embodiment, R 11 is optionally substituted with one or more C(O)N(R 9 ) 2 . [0084] In one embodiment, provided herein is a compound of formula (Ia):
  • L 1 is a bond, -NHC(O)NH-, -NHC(O)-, -O-, -S-, -NR 4 -, or -NHS(O) 2 -. In one embodiment, L 1 is a bond, -NHC(O)NH-, -NHC(O)-, -O-, -S-, or
  • L 2 is a bond or -O-.
  • R 3 is H.
  • L 1 is a bond, -NHC(O)NH-, -NHC(O)-, -O-, -S-, or -NR 4 -; L 2 is a bond or
  • L 1 is a bond and R 1 is H.
  • L 2 is a bond or
  • R 3 is -L 3 -R ⁇ , wherein L 3 is a bond, -NHC(O)NH-, -NHC(O)-,
  • L 1 is a bond; R 1 is H; L 2 is a bond or -O-; and R 3 is -iA-R 11 , wherein L 3 is a bond, -NHC(O)NH-, -NHC(O)-, -O-, -S-, or -NR 4 -.
  • -L 2 -R 2 is at the 5 -position of the pyridyl or pyrimidinyl ring and -I ⁇ -R 1 is at the 2-position of the pyridyl or pyrimidinyl ring.
  • R 2 is C 1 -C 4 alkyl or haloalkyl, such as, e.g., methyl or trifluoromethyl.
  • R 2 is aryl or heteroaryl, such as, e.g., phenyl, naphthalenyl, pyridyl, furyl, thienyl, benzofuranyl, benzodioxolyl, benzoxazolyl, benzothiazolyl, or indolinone, each of which is optionally substituted.
  • R 2 is aryl or heteroaryl, such as, e.g., phenyl, naphthalenyl, pyridyl, furyl, thienyl, benzofuranyl, or benzodioxolyl, each of which is optionally substituted.
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more halo, CH 3 , CF 3 , C(O)CH 3 , C(O)H, OCH 3 , OCF 3 , SCH 3 , N(CH 3 ) 2 , OH, NHC(O)CH 3 , NHC(O)CF 3 , NCH 3 C(O)CH 3 , NHC(O)-ethyl, NHC(O)-isopropyl, C(O)NHCH 3 , C(O)NH 2 , CH 2 C(O)CH 3 , NHS(O) 2 CH 3 , NHC(O)NHCH 3 , or phenoxy.
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with one or more halo, CH 3 , CF 3 , C(O)CH 3 , C(O)H, OCH 3 , OCF 3 , SCH 3 , N(CH 3 ) 2 , OH, NHC(O)CH 3 , NHC(O)-ethyl, NHC(O)-isopropyl, C(O)NHCH 3 , or phenoxy.
  • L 1 is -NHC(O)NH-
  • R 1 is cycloalkyl, such as, e.g., cyclopentyl or cyclohexyl.
  • L 1 is -NHC(O)- or -NHS(O) 2 -, and R 1 is aryl or heteroaryl, each of which is optionally substituted as described herein.
  • L 1 is -NHC(O)-, and R 1 is aryl or heteroaryl, each of which is optionally substituted as described herein.
  • R 1 is optionally substituted phenyl or heteroaryl.
  • R 1 is phenyl, pyrazolyl, oxazolyl, or isoxazolyl, each of which is optionally substituted.
  • R 1 is aryl or heteroaryl optionally substituted with one or more C 1 -C 4 alkyl, CF 3 , OCF 3 , or aryl. In one embodiment, R 1 is aryl or heteroaryl optionally substituted with one or more C 1 -C 4 alkyl or aryl, such as, e.g., methyl, ethyl, or phenyl.
  • L 1 is a bond, and R 1 is heterocyclyl, which is optionally substituted as described herein.
  • R 1 is piperazinyl, piperidinyl, or morpholinyl, and R 1 is attached to the L 1 bond via a ring nitrogen atom.
  • R 1 is heterocyclyl optionally substituted with one or more alkyl.
  • R 1 is heterocyclyl optionally substituted with one or more (i) aryl or heteroaryl, such as, e.g., phenyl or pyridyl; or (ii) C(O)-heterocyclyl, such as, e.g., C(O)-tetrahydrofuranyl.
  • the aryl, heteroaryl, and C(O)-heterocyclyl substituents are further optionally substituted with one or more halo, OH, or C 1 -C 4 alkyl optionally substituted with halo or OH.
  • the aryl, heteroaryl, and C(O)-heterocyclyl substituents are further optionally substituted with one or more OH or C 1 -C 4 alkyl optionally substituted with halo or OH.
  • L 1 is S
  • R 1 is Ci-C 6 alkyl
  • L 1 is -NR 4 -, wherein R 4 is hydrogen or methyl.
  • L 1 is -NH-.
  • L 1 is -NR 4 - or -0-, and R 1 is Ci-C 6 alkyl, aryl, or heteroaryl, each of which is optionally substituted as described herein.
  • L 1 is -O- or -NR 4 -, and R 1 is alkyl optionally substituted with one or more F, 0(Ci-C 4 alkyl), or C(O)N(Ci-C 4 alkyl) 2 .
  • L 1 is -O- or -NR 4 -
  • R 1 is alkyl optionally substituted with aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionally substituted as defined herein.
  • R 1 is alkyl optionally substituted with aryl, heteroaryl, cycloalkyl, or heterocyclyl, such as, e.g., phenyl, pyridyl, cyclopropyl, pyrrolidinyl, or morpholinyl.
  • R 1 is alkyl optionally substituted with aryl or heteroaryl, each of which is optionally substituted with one or more halo, phenoxy, oxo, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.
  • L 1 is -O- or -NR 4 -
  • R 1 is aryl or heteroaryl, such as, e.g., phenyl, dihydro-lH-indenyl, pyridyl, benzodioxolyl, or dihydrobenzodioxinyl.
  • R 1 is optionally substituted with one or more halo, OR 6 , N(R 6 ) 2 , S(O) 2 R 6 , R 7 , OR 7 , C(O)R 7 , NHC(O)R 7 , Ci-C 6 alkyl optionally substituted with one or more fluoro, or 0(Ci-C 6 alkyl) optionally substituted with C(O)N(R 6 ) 2 or one or more fluoro, wherein R 6 and R 7 are as defined herein elsewhere.
  • R 1 is optionally substituted with one or more halo, OR 6 , N(R 6 ) 2 , R 7 , OR 7 , C(O)R 7 , NHC(O)R 7 , Ci-C 6 alkyl, or 0(Ci-C 6 alkyl) optionally substituted with C(O)N(R 6 ) 2 , wherein R 6 and R 7 are as defined herein elsewhere.
  • R 1 is optionally substituted with one or more halo, phenyl, heterocyclyl, methyl, trifluoromethyl, phenoxy, methoxy, trifluoromethoxy, dimethylamino, OCH 2 C(O)N(CHs) 2 , or NHC(O)R 7 , where R 7 may be phenyl optionally substituted with methoxy.
  • R 3 when L 1 is a bond and R 1 is -H, R 3 is -L 3 -R ⁇ . In one embodiment, L 3 is -O- or -NR 4 -.
  • R 11 is aryl or heteroaryl, such as, e.g., phenyl, dihydro-lH-indenyl, pyridyl, or benzodioxolyl. In one embodiment, R 11 is optionally substituted with one or more halo, OR 9 , N(R 6 ) 2 , C(O)R 9 , NHC(O)R 9 , wherein R 9 is H or C 1 -C 4 alkyl optionally substituted with one or more fluoro.
  • R 11 is optionally substituted with one or more halo, OR 9 , N(R 6 ) 2 , C(O)R 9 , NHC(O)R 9 , wherein R 9 is H or C 1 -C 4 alkyl.
  • R 11 is optionally substituted with one or more halo, methyl, trifluoromethyl, methoxy, trifluoromethoxy, or dimethylamino.
  • specific examples of compounds of formula (I) include, but are not limited to, the following: 1. 1 -cyclohexyl-3 -(5 -methylpyridin-2-yl)urea,
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof in the preparation of an agent for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof in the preparation of an agent for the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy.
  • a method of making a compound of formula (I) is provided herein.
  • the compounds of formula (I) can be synthesized from commercially available starting materials using the following methods.
  • compounds of formula (I) may be prepared by reacting a compound of formula (II):
  • reaction with a compound of formula (III) or formula (IV) may take place in the presence of l,l-bis(diphenylphosphino)ferrocene palladium (II) chloride complex in dichloromethane, and in the presence of a base, such as, e.g., potassium carbonate.
  • a base such as, e.g., potassium carbonate.
  • compounds of formula (II) in which L 1 is -NR 4 - may be prepared by reacting a compound of formula (V):
  • the reaction when Y is C, the reaction may be conducted at elevated temperature, such as, e.g., between 100 and 200 0 C. In one embodiment, such reaction is carried out in the absence of a solvent. In another embodiment, the reaction may be carried out at lower temperature, such as, e.g., 10-30 0 C, such as, room temperature, under basic conditions, for example, in the presence of a base, such as, e.g., sodium hydride, and in an organic solvent, such as, e.g., ⁇ /, ⁇ /-dimethylformamide.
  • a base such as, e.g., sodium hydride
  • organic solvent such as, e.g., ⁇ /, ⁇ /-dimethylformamide.
  • the reaction may be carried out under acidic conditions, such as, e.g., in hydrochloric acid, and in an organic solvent, such as, e.g., a mixture of dioxane and n-butanol.
  • acidic conditions such as, e.g., in hydrochloric acid
  • organic solvent such as, e.g., a mixture of dioxane and n-butanol.
  • the reaction under acidic conditions may be conducted at elevated temperature, such as, e.g., between 100 and 200 0 C.
  • the reaction when Y is N, the reaction may be carried out in industrial methylated spirits (IMS) at a temperature of from about 120 to about 17O 0 C and with the use of microwave irradiation.
  • IMS industrial methylated spirits
  • compounds of formulae (V) and (VI) are known and are readily available or may be prepared by methods known to those of skill in the art.
  • compounds of formula (II) in which L 1 is -NHC(O)- may be prepared by reacting a compound of formula (VII):
  • the reaction may be carried out in the presence of a coupling agent, such as, e.g., benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), and a base, such as, e.g., JV,jV-diisopropylethylamine (DIPEA).
  • a coupling agent such as, e.g., benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP)
  • a base such as, e.g., JV,jV-diisopropylethylamine (DIPEA).
  • DIPEA JV,jV-diisopropylethylamine
  • the reaction is carried out in an organic solvent, such as, e.g., N,N- dimethy lformamide .
  • compounds of formula (II) in which L 1 is -NHSO 2 - may be prepared from compounds of formula (VIII) as defined herein elsewhere by reacting with compounds of formula (XI):
  • reaction may be carried out under basic conditions, such as, e.g., in the presence of triethylamine, in an organic solvent such as, e.g., dichloromethane.
  • organic solvent such as, e.g., dichloromethane.
  • compounds of formula (I) may also be prepared by reacting a compound of formula (IX)
  • R 1 , L 1 , R 3 , and Y are as defined herein elsewhere, and R 12 is H or Ci-C 6 alkyl, or the two R 12 groups together with the B and O atoms form a heterocyclyl group, such as, e.g., a 5- or 6-membered heterocyclyl, which may be substituted with methyl groups, for example forming a tetramethyl dioxaborolanyl group; with a compound of formula (X):
  • the reaction may be carried out in the presence of a catalytic agent, such as tetrakis(triphenylphosphine) palladium, and in a solvent, such as, e.g., DMF.
  • a catalytic agent such as tetrakis(triphenylphosphine) palladium
  • a solvent such as, e.g., DMF.
  • compounds of formula (X) are known and are readily available or may be prepared by methods known to those of skill in the art.
  • compounds of formula (IX) may be prepared by reacting a compound of formula (II) as defined herein with bis(pinacolato)diboron in the presence of, for example, dichlorobis(triphenylphosphine) palladium (II).
  • R 3 is -L 3 -R ⁇ may be prepared from compounds of formula (XII):
  • X 3 (XII) wherein Y, L 2 and R 2 are as defined herein elsewhere, and X 3 is a leaving group, such as, e.g., halo, such as, bromo, by methods analogous to those described for the preparation of other compounds of formula (I).
  • compounds of formula (I) in which L 1 is a bond, R 1 is H, and R 3 is -NH-R 11 may be prepared by reacting a compound of formula (XII) as defined herein with a compound of formula (XIII):
  • the reaction may be carried out in the presence of a palladium compound, such as, e.g., palladium acetate, and a chelating agent, such as, e.g., Xantphos TM , at elevated temperature, such as, e.g., 120 to 17O 0 C, and in an organic solvent, such as, e.g., dioxane.
  • a palladium compound such as, e.g., palladium acetate
  • a chelating agent such as, e.g., Xantphos TM
  • organic solvent such as, e.g., dioxane.
  • compounds of formula (XII) may be prepared from compounds of formula (XIV):
  • the reaction of a compound of formula (XIV) with a compound of formula (III) may take place in the presence of a palladium complex, and a base, such as, e.g., potassium carbonate, in an aqueous solvent.
  • a base such as, e.g., potassium carbonate
  • suitable protecting groups may be used, as understood by one of ordinary skills in the art. One skilled in the art would also be able to choose the appropriate protecting groups and the conditions to introduce and remove such protecting groups. Information concerning protecting groups is available, for example, in Theodora W. Greene and Peter G. M. Wuts, "Protecting Groups in Organic Synthesis", 4 th Edition, Wiley Interscience, 2006.
  • the compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof is administered in the form of a pharmaceutical composition.
  • the compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia is administered in the form of a pharmaceutical composition.
  • the compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in the treatment or prophylaxis of Duchenne muscular dystrophy is administered in the form of a pharmaceutical composition.
  • a pharmaceutical composition comprising a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, and at least one pharmaceutically acceptable excipient or carrier.
  • a pharmaceutical composition comprising a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises less than about 80% w/w, less than about 50% w/w, less than about 20% w/w, or between about 0.1 and about 20% w/w, of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in admixture with at least one pharmaceutically acceptable excipient, diluent, or carrier.
  • a process for the production of a pharmaceutical composition which comprises mixing the ingredients.
  • examples of pharmaceutical formulations or compositions, and suitable diluents or carriers include, but are not limited to, the following: for intravenous injection or infusion — purified water or saline solution; for inhalation compositions — coarse lactose; for tablets, capsules, and dragees — microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin; and for suppositories — natural or hardened oils or waxes.
  • the compound provided herein is used in aqueous solution, e.g., for intravenous infusion
  • the pharmaceutical composition containing the compound provided herein may further comprise one or more excipients.
  • the excipients include, but are not limited to, chelating or sequestering agents, antioxidants, tonicity adjusting agents, pH-modifying agents, and buffering agents.
  • solutions containing a compound of formula (I) may, if desired, be evaporated, e.g., by freeze drying or spray drying, to give a solid composition, which may be reconstituted prior to use.
  • the compound provided herein is not used in a solution.
  • the compound of formula (I) is in a form having a mass median diameter of from about 0.01 to about 10 ⁇ m.
  • the pharmaceutical composition comprising the compound of formula (I) may further contain one or more preserving, stabilizing, and/or wetting agents, solubilisers, e.g., a water soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water soluble glycol such as propylene glycol, sweetening and/or coloring agents, and/or flavorings.
  • the compositions may be formulated in sustained release form.
  • the pharmaceutical composition comprises a compound of formula (I) in between about 0.01% and about 99.9% w/w, relative to the entire preparation. In certain embodiments, the pharmaceutical composition comprises a compound of formula (I) in between about 0.1% and about 50% w/w, relative to the entire preparation. [00135] In one embodiment, provided herein is a pharmaceutical composition comprising a compound of formula (I), and at least one pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser.
  • the pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser is non-toxic and does not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be oral or by injection, such as cutaneous, subcutaneous, or intravenous injection.
  • the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions provided herein that are formulated for oral administration may be in tablet, capsule, powder, or liquid form.
  • a tablet may comprise a solid carrier or an adjuvant.
  • Liquid pharmaceutical compositions may comprise a liquid carrier, such as water, petroleum, animal or vegetable oils, or mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol may be included. A capsule may comprise a solid carrier such as gelatin. [00138] In another embodiment, the pharmaceutical compositions are provided in a dosage form for parenteral administration, and one or more pharmaceutically acceptable excipients or carriers.
  • compositions may be formulated for intravenous, cutaneous or subcutaneous injection
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution, which is pyrogen-free and has a suitable pH, isotonicity, and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has a suitable pH, isotonicity, and stability.
  • isotonic vehicles such as Sodium Chloride injection, Ringer's injection, or Lactated Ringer's injection.
  • Preservatives, stabilisers, buffers, antioxidants, and/or other additives may be included as required.
  • compositions are provided in a dosage form for topical administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • modified release dosage forms including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (See, e.g., Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd Edition, Rathbone et al, Eds., Marcel Dekker, Inc.: New York, NY, 2008).
  • the pharmaceutical compositions provided herein can be provided in a unit-dosage form or multiple-dosage form.
  • a unit-dosage form refers to physically discrete a unit suitable for administration to a human and animal subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of a unit- dosage form include an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof.
  • a multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or gallons.
  • the pharmaceutical compositions provided herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • the pharmaceutical compositions provided herein further comprise one or more therapeutic agents for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. In one embodiment, the pharmaceutical compositions provided herein further comprise one or more therapeutic agents for the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy. In one embodiment, the pharmaceutical compositions provided herein further comprise one or more therapeutic agents for the treatment or prophylaxis of Duchenne muscular dystrophy.
  • a compound of formula (I) in another embodiment, provided herein is the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. In one embodiment, provided herein is the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy. In one embodiment, provided herein is the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prophylaxis of Duchenne muscular dystrophy. In certain embodiments, the medicament is in tablet, capsule, powder, or liquid form. In certain embodiments, the medicament is formulated as described herein.
  • oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration.
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye -migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • binders fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye -migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression.
  • Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the amount of a binder or filler in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
  • Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
  • the amount of a diluent in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation- exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross- linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; micro crystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof.
  • the amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
  • Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL ® 200 (W.R.
  • Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB- O-SIL ® (Cabot Co. of Boston, MA), and asbestos-free talc.
  • Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof.
  • a color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.
  • Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.
  • Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.
  • Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN ® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN ® 80), and triethanolamine oleate.
  • Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
  • Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup.
  • Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil.
  • Suitable organic acids include, but are not limited to, citric and tartaric acid.
  • Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.
  • compositions provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets.
  • Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach.
  • Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.
  • Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.
  • Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material.
  • Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating.
  • Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
  • the tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • the pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry-filled capsule (DFC)
  • DFC dry-filled capsule
  • the soft elastic capsule is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the soft gelatin shells may contain a preservative to prevent the growth of microorganisms.
  • Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid.
  • the liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule.
  • Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • compositions provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.
  • An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in- water or water-in- oil.
  • Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative.
  • Suspensions may include a pharmaceutically acceptable suspending agent and preservative.
  • Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol.
  • Elixirs are clear, sweetened, and hydroalcoholic solutions.
  • Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative.
  • a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
  • Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly- alkylene glycol, including, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • a dialkylated mono- or poly- alkylene glycol including, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene
  • formulations can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • compositions provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non- effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents can be used in all of the dosage forms provided herein.
  • compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
  • compositions provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (See, Remington: The Science and Practice of Pharmacy, supra).
  • compositions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
  • aqueous vehicles water-miscible vehicles
  • non-aqueous vehicles non-aqueous vehicles
  • antimicrobial agents or preservatives against the growth of microorganisms stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emuls
  • Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection.
  • Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil.
  • Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N- methyl-2-pyrrolidone, NN-dimethylacetamide, and dimethyl sulfoxide.
  • Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propylparabens, and sorbic acid.
  • Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose.
  • Suitable buffering agents include, but are not limited to, phosphate and citrate.
  • Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite.
  • Suitable local anesthetics include, but are not limited to, procaine hydrochloride.
  • Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable emulsifying agents are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable complexing agents include, but are not limited to, cyclodextrins, including ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7- ⁇ -cyclodextrin
  • the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
  • the pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions.
  • the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile suspensions.
  • the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile emulsions.
  • compositions provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • compositions provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot.
  • the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
  • Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
  • Suitable outer polymeric membranes include but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
  • compositions provided herein can be administered topically to the skin, orifices, or mucosa.
  • topical administration includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
  • compositions provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches.
  • the topical formulation of the pharmaceutical compositions provided herein can also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.
  • Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
  • compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECTTM (Chiron Corp., Emeryville, CA), and BIOJECTTM (Bioject Medical Technologies Inc., Tualatin, OR).
  • electroporation iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection
  • BIOJECTTM Bioject Medical Technologies Inc., Tualatin, OR
  • Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in- water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (See, Remington: The Science and Practice of Pharmacy, supra).
  • Suitable cream base can be oil-in-water or water-in-oil.
  • Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase.
  • the oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
  • Gels are semisolid, suspension-type systems. Single -phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL ® ; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin.
  • dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
  • compositions provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas.
  • These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.
  • Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices.
  • Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite.
  • Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid;. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.
  • compositions provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.
  • pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract.
  • the pharmaceutical compositions can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2- tetrafluoroethane or 1,1, 1,2,3, 3,3-heptafluoropropane.
  • atomizer such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer
  • a suitable propellant such as 1,1,1,2- tetrafluoroethane or 1,1, 1,2,3, 3,3-heptafluoropropane.
  • the pharmaceutical compositions can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops.
  • the powder can comprise a bioadhesive agent, including chitosan or cyclod
  • Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein; a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less.
  • Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as /- leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate.
  • Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
  • the pharmaceutical compositions provided herein for inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.
  • compositions provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.
  • modified release dosage form refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route.
  • Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof.
  • the release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s).
  • modified release examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500.
  • compositions provided herein in a modified release dosage form can be fabricated using a matrix controlled release device known to those skilled in the art (See, Takada et ⁇ l. in “Encyclopedia of Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).
  • a matrix controlled release device known to those skilled in the art (See, Takada et ⁇ l. in "Encyclopedia of Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).
  • the pharmaceutical compositions provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose
  • the pharmaceutical compositions provided herein are formulated with a non-erodible matrix device.
  • the active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered.
  • materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate -methyl methacrylate copolymers, ethylene- vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plastic
  • the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
  • compositions provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.
  • compositions provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • an osmotic controlled release device including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • AMT asymmetric membrane technology
  • ECS extruding core system
  • such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semi-permeable membrane with at least one delivery port, which encapsulates the core.
  • the semi-permeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
  • the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device.
  • osmotic agents water- swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels.”
  • Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic mono
  • PEO polyethylene oxide
  • PEG poly
  • the other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating.
  • Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raff ⁇ nose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid
  • Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form.
  • amorphous sugars such as MANNOGEM EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time.
  • the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
  • the core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
  • Materials useful in forming the semi-permeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water- permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking.
  • Suitable polymers useful in forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copo
  • Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Patent No. 5,798,119.
  • Such hydrophobic but water- vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • the delivery port(s) on the semi-permeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220.
  • the total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semi-permeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
  • the pharmaceutical compositions in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
  • the osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (See, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 55, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).
  • the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers.
  • AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
  • the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers.
  • compositions provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 ⁇ m to about 3 mm, about 50 ⁇ m to about 2.5 mm, or from about 100 ⁇ m to about 1 mm in diameter.
  • multiparticulates can be made by the processes known to those skilled in the art, including wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, e.g., Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.
  • excipients or carriers as described herein can be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates.
  • the resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers.
  • the multiparticulates can be further processed as a capsule or a tablet.
  • compositions provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Patent Nos.
  • E. Methods of Use [00211] In one embodiment, provided herein are compounds that upregulate endogenous utrophin, and therefore, are useful in the treatment or prophylaxis of muscular dystrophy, including DMD, and other similar conditions.
  • a compound of formula (I) for use in medicine, for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • a method for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • the dose of the compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof is determined with consideration of age, body weight, general health condition, diet, administration time, administration method, clearance rate, combination of drugs, the level of disease for which the patient is under treatment for, and other factors. In one embodiment, the dose varies depending on the target disease, condition, subject of administration, administration method, and the like.
  • the pharmaceutical composition comprising a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, is administered orally as a therapeutic agent for the treatment or prophylaxis of Duchenne muscular dystrophy in a patient suffering from such a disease.
  • a therapeutic agent for the treatment or prophylaxis of Duchenne muscular dystrophy in a patient suffering from such a disease.
  • from about 0.01 mg to about 1O g of the compound is administered.
  • from about 0.1 mg to about 100 mg of the compound is administered.
  • the compound is administered in a single dose per day.
  • the compound is administered in 2 or 3 portions per day.
  • a method of treating, preventing, and/or managing a disorder or symptoms related to Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia comprising administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • a method of treating, preventing, and/or managing a disorder or symptoms related to Duchenne muscular dystrophy or Becker muscular dystrophy comprising administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • provided herein is a method of treating, preventing, and/or managing Duchenne muscular dystrophy. In another embodiment, provided herein is a method of treating, preventing, and/or managing Becker muscular dystrophy. In another embodiment, provided herein is a method of treating, preventing, and/or managing cachexia. [00221] In one embodiment, provided herein is the use of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in the manufacturing of a medicament for the treatment, prevention, and/or management of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • provided herein is the use of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in the manufacturing of a medicament for the treatment, prevention, and/or management of Duchenne muscular dystrophy or Becker muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof in the manufacturing of a medicament for the treatment, prevention, and/or management of Duchenne muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof in the manufacturing of a medicament for the treatment, prevention, and/or management of Becker muscular dystrophy.
  • a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof in the manufacturing of a medicament for the treatment, prevention, and/or management of cachexia.
  • the method comprises administering to a subject (e.g., a human) a therapeutically or prophylactically effective amount of a composition of a compound of formula (I).
  • a subject e.g., a human
  • the subject is a human.
  • the subject is a mammal.
  • the subject is a non- human primate, a farm animal, such as cattle, a sport animal, or a pet such as a horse, dog, or cat.
  • compound activity can be assessed by functional assays described herein elsewhere.
  • the efficacious concentration of the compounds provided herein is less than about 0.1 nM, less than about 1 nM, less than about 10 nM, less than about 100 nM, less than about 1 ⁇ M, less than about 10 ⁇ M, less than about 100 ⁇ M, or less than about 1 mM.
  • compounds' activity may be assessed in various art-recognized animal models as described herein elsewhere.
  • the compounds provided herein are active in at least one model, which can be used to measure the activity of the compounds and estimate their efficacy in treating Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • the compounds are active in, for example, the mdx mouse model, when compared to the effect of a vehicle.
  • the compounds provided herein are active in a dose-dependent manner.
  • the compounds or pharmaceutical compositions provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration, and can be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration. Also provided is administration of the compounds or pharmaceutical compositions provided herein in a depot formulation, in which the active ingredient is released over a predefined time period.
  • an appropriate dosage level in the treatment, prevention, and/or management of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level generally is ranging from about 0.001 to about 1000 mg per kg subject body weight per day (mg/kg per day), from about 0.001 to about 300 mg/kg per day, from about 0.001 to about 100 mg/kg per day, from about 0.01 to about 75 mg/kg per day, from about 0.1 to about 50 mg/kg per day, from about 0.5 to about 25 mg/kg per day, from about 1 to about 20 mg/kg per day, from about 0.01 to about 1000 mg/kg per day, from about 0.1 to about 1000 mg/kg per day, from about 1 to about 1000 mg/kg per day, from about 10 to about 1000 mg/kg per day, from about 100 to about 1000 mg/kg per day, or from about 100 to about 300 mg/kg per day, which can be administered in single or multiple doses per day.
  • the dosage can be ranging from about 0.005 to about 0.05, from about 0.05 to about 0.5, from about 0.5 to about 5.0, from about 1 to about 15, from about 1 to about 20, from about 1 to about 50, from about 5 to about 50, from about 10 to about 100, from about 20 to about 200, from about 30 to about 300, or from about 50 to about 500 mg/kg per day.
  • an appropriate dosage level is less than about 0.001 mg/kg per day, less than about 0.01 mg/kg per day, less than about 0.1 mg/kg per day, less than about 0.5 mg/kg per day, less than about 1 mg/kg per day, less than about 5 mg/kg per day, less than about 10 mg/kg per day, less than about 15 mg/kg per day, less than about 20 mg/kg per day, less than about 25 mg/kg per day, less than about 50 mg/kg per day, less than about 75 mg/kg per day, less than about 100 mg/kg per day, less than about 200 mg/kg per day, less than about 500 mg/kg per day, less than about 1 g/kg per day, less than about 3 g/kg per day, less than about 5 g/kg per day, or less than about 10 g/kg per day.
  • the pharmaceutical compositions provided herein can be formulated in the form of tablets containing from about 1.0 to about 1,000 mg of the active ingredient, in one embodiment, about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, or about 1,000 mg, of the active ingredient, for the symptomatic adjustment of the dosage to the patient to be treated.
  • the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day.
  • the compounds provided herein can be combined or used in combination with other agents or therapies useful in the treatment, prevention, and/or management of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • Suitable other therapeutic agents include, but are not limited to, corticosteroids, such as, e.g., prednisone and deflazacort.
  • other therapies that may be used in combination with the compounds provided herein include, but are not limited to, physical therapy, gene therapy, and/or orthopedic appliances, such as, e.g., braces and wheelchairs.
  • such other agents or drugs can be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with the compounds provided herein, or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • a pharmaceutical composition containing such other drugs in addition to the compound provided herein can be utilized, but is not required.
  • the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound provided herein.
  • the weight ratio of a compound provided herein to the second active ingredient can be varied, and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the weight ratio of the compound provided herein to the corticosteroid can range from about 1 ,000: 1 to about 1 : 1 ,000, from about 200: 1 to about 1 :200, from about 100:1 to about 1 :100, from about 10:1 to about 1 :10, from about 5:1 to about 1 :5, or from about 2:1 to about 1 :2.
  • combinations of a compound provided herein and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compounds provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Patent Nos. 5,323,907; 5,052,558; and 5,033,252.
  • packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject.
  • the kit provided herein includes a container and a dosage form of a compound provided herein.
  • the kit includes a container comprising a dosage form of the compound provided herein, or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in a container comprising one or more other therapeutic agent(s) described herein.
  • kits provided herein can further include devices that are used to administer the active ingredients.
  • devices include, but are not limited to, syringes, needle-less injectors drip bags, patches, and inhalers.
  • kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
  • the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • Examples of pharmaceutically acceptable vehicles include, but are not limited to, aqueous vehicles, including but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles including but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles including but not limited to, ethyl alcohol
  • HPLC-UV-MS was performed on a Gilson 321 HPLC with detection performed by a Gilson 170 DAD and a Finnigan AQA mass spectrometer operating in electrospray ionization mode.
  • the HPLC column used is a Phenomenex Gemini Cl 8 150x4.6 mm.
  • Preparative HPLC was performed on a Gilson 321 with detection performed by a Gilson 170 DAD. Fractions were collected using a Gilson 215 fraction collector or a Dionex Ultimate 3000 system.
  • the preparative HPLC column used is a Phenomenex Gemini Cl 8 15 Ox 10mm and the mobile phase is acetonitrile/water.
  • N-(3-(6-(p-Tolylamino)pyridin-3-yl)phenyl)acetamide [00244] A solution of 5-bromo- ⁇ /-/?-tolylpyridine-2-amine (0.8Og, 3.1mmol), 3- acetamidophenylboronic acid (1.1 Ig, 6.2mmol), 1,1 -Bis(diphenylphosphino)ferrocene palladium(II) chloride, complex with DCM (0.06g, O. ⁇ mmol), and potassium carbonate (1.61g, 15.5mmol) dissolved in DME (15mL) and H 2 O (ImL) were heated using microwave irradiation at 130 0 C for 10 minutes.
  • Step 1 Preparation of 5-Bromo-A/-methyl-N-(3-(trifluoromethyl)phenyl) pyridin-2-amine [00257]
  • LHMDS 0.79g 4.7mmol
  • a solution of 5-bromo- ⁇ /-/?-tolylpyridine-2-amine (0.5Og, 1.6mmol) 3 in dry DMSO was stirred at room temperature for 3 hours before methyl iodide (0.25g, 1.7mmol) was added slowly.
  • the solution was stirred at room temperature overnight.
  • the solution was poured carefully into water, and diluted with DCM.
  • Step l 5 Bromo- ⁇ /-(3 -(trifluoromethoxy)phenyl)pyridin-2-amine
  • 6-(6-(3-(Trifluoromethoxy)phenylamino)pyridin-3-yl)indolin-2-one (6) (Compound 131) [00279] A mixture of 6-(3-(trifluoromethoxy)phenylamino)pyridin-3-ylboronic acid and 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethoxy)phenyl)pyridin-2- amine (1.761 g), 6-bromoindolin-2-one (783 mg, 4.0 mmol), tetrakis(triphenylphosphine)- palladium (428 mg, 0.4 mmol), potassium acetate (1086 mg, 12.0 mmol) and a mixture of DMF, IMS and H 2 O (2:1 :1, 16 mL) were combined and heated with stirring, under microwave activation, at 15O 0 C for 20 minutes.
  • Step 1 l-Methyl-3-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-vPphenvPurea
  • Step 2 jV-Methyl-iV-(3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)phenyl)acetamide (Compound 137)
  • N-Methyl-N-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetamide (766 mg, 2.78 mmol), 5-bromo-N-(3-(trifluoromethoxy)phenyl)pyridin-2-amine (464 mg, 1.39 mmol), 1,1' Bis(diphenylphosphino)ferrocene palladium (II) chloride (227 mg, 0.28 mmol), potassium carbonate (960 mg, 6.95 mmol) and DMEZH 2 O (4:1, 15 mL) were combined and heated with stirring, under microwave activation, at 13O 0 C for 15 minutes.
  • Example 13 Preparation of A/-(3-(5-(3-(trifluoromethoxy)phenylamino)pyridin-3- vDphenvDacetamide (Compound 152) [00296] A mixture of 3,5 -dibromopyridine (2.0Og, 8.44mmol), 3-acetamidophenylboronic acid (1.5 Ig, 8.44mmol), potassium carbonate (1.17g, 8.44mmol) and palladium (tetrakis)triphenylphosphine (294mg, 0.025mmol) in DME/H 2 0 (4OmL, 3:1) was refluxed for 16h.
  • This material (1.2Og, 4.12mmol), 3- (trifluoromethoxy)aniline (66IuL, 4.95mmol), cesium carbonate (3.36g, 10.3mmol), palladium bis-acetate (47mg, 0.21mmol) and Xantphos (238mg, 0.41mmol) were dissolved in dioxane (7.5mL) and the resulting mixture was heated, under microwave activation, at 15O 0 C for 20mins. The crude mixture was partitioned between EtOAc (10OmL) and brine (10OmL) and the two layers were separated. The aqueous layer was extracted further with EtOAc (10OmL), the combined layers were dried over anhydrous MgSO 4 and evaporated to dryness.
  • the cell line used for the screen was an immortalized mdx mouse H2K cell line that had been stably transfected with a plasmid containing ⁇ 5kb fragment of the Utrophin A promoter including the first untranslated exon linked to a luciferase reporter gene.
  • the cells Under conditions of low temperature and interferon containing media, the cells remained as myoblasts. These were plated into 96 well plates and cultured in the presence of compound for three days. The level of luciferase was then determined by cell lysis and reading of the light output from the expressed luciferase gene utilizing a plate luminometer. Luciferase Assay for 96 Well Plates

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Abstract

Compounds of formula (I): wherein R1, R2, R3, L1, L2, and Y are as defined herein, are useful for the treatment or prophylaxis of conditions such as Duchenne muscular dystrophy, Becker muscular dystrophy, and cachexia.

Description

COMPOUNDS FOR TREATMENT OF DUCHENNE MUSCULAR DYSTROPHY
[0001] This application claims priority to U.K. Patent Application No. GB0821307.6, filed November 21, 2008, the content of which is incorporated by reference herein in its entirety.
FIELD
[0002] Provided herein are compounds for the treatment or prophylaxis of muscular dystrophy and related conditions, including Duchenne muscular dystrophy, compositions comprising the compounds, and methods of use thereof. Also provided herein is a method for the treatment or prophylaxis of muscular dystrophy and related conditions, including Duchenne muscular dystrophy.
BACKGROUND
[0003] Duchenne muscular dystrophy (DMD) is a common, genetic neuromuscular disease associated with the progressive deterioration of muscle function, first described over 150 years ago by the French neurologist, Duchenne de Boulogne, after whom the disease is named. DMD has been characterized as an X-linked recessive disorder that affects 1 in 3,500 males caused by mutations in the dystrophin gene. The gene is the largest in the human genome, encompassing 2.6 million base pairs of DNA and containing 79 exons. Approximately 60% of dystrophin mutations are large insertion or deletions that lead to frameshift errors downstream, whereas approximately 40% are point mutations or small frameshift rearrangements. The vast majority of DMD patients lack the dystrophin protein. Becker muscular dystrophy is a much milder form of DMD caused by reduction in the amount, or alteration in the size, of the dystrophin protein. The high incidence of DMD (1 in 10,000 sperm or eggs) means that genetic screening will never eliminate the disease, so an effective therapy is highly desirable.
[0004] A number of natural and engineered animal models of DMD exist, and provide a mainstay for preclinical studies (Allamand et al., Animal Models for Muscular Dystrophy: Valuable Tools for the Development of Therapies, Hum. MoI. Genet. 9, 2459-67 (2000)). Although the mouse, cat and dog models all have mutations in the DMD gene and exhibit a biochemical dystrophinopathy similar to that seen in humans, they show surprising and considerable variation in terms of their phenotype. Like humans, the canine (golden retriever muscular dystrophy and German short-haired pointer) models have a severe phenotype; these dogs typically die of cardiac failure. Dogs offer the best phenocopy for human disease, and are considered a high benchmark for preclinical studies. Unfortunately, breeding these animals is expensive and difficult, and the clinical time course can be variable among litters. [0005] The mdx mouse is the most widely used model due to availability, short gestation time, time to mature and relatively low cost (Bulfϊeld et al., X Chromosome-Linked Muscular Dystrophy (max) in the Mouse, Proc. Natl. Acad. Sci. USA 81, 1189-92 (1984)). [0006] Since the discovery of the DMD gene about 20 years ago, varying degrees of success in the treatment of DMD have been achieved in preclinical animal studies, some of which are being followed up in humans. Present therapeutic strategies can be broadly divided into three groups: first, gene therapy approaches; second, cell therapy; and last, pharmacological therapy. Gene- and cell-based therapies offer the fundamental advantage of obviating the need to separately correct secondary defects/pathology (for example, contractures), especially if initiated early in the course of the disease. Unfortunately, these approaches face a number of technical hurdles. Immunological responses against viral vectors, myoblasts and newly synthesized dystrophin have been reported, in addition to toxicity, lack of stable expression and difficulty in delivery.
[0007] Pharmacological approaches for the treatment of muscular dystrophy differ from gene- and cell-based approaches in not being designed to deliver either the missing gene and/or protein. In general, the pharmacological strategies use drugs/molecules in an attempt to improve the phenotype by means such as decreasing inflammation, improving calcium homeostasis and increasing muscle progenitor proliferation or commitment. These strategies offer the advantage that they are easy to deliver systemically and can circumvent many of the immunological and/or toxicity issues that are related to vectors and cell-based therapies. Although investigations with corticosteroids and sodium cromoglycate, to reduce inflammation, dantrolene to maintain calcium homeostasis and clenbuterol to increase muscle strength, have produced promising results, none of these potential therapies has yet been shown to be effective in treating DMD.
[0008] An alternative pharmacological approach is upregulation therapy. Upregulation therapy is based on increasing the expression of alternative genes to replace a defective gene and is particularly beneficial when an immune response is mounted against a previously absent protein. Upregulation of utrophin, an autosomal paralogue of dystrophin has been proposed as a potential therapy for DMD (Perkins et al., Neuromuscul. Disord., Sl :S78-S89 (2002); Khurana et al, Nat. Rev. Drug Discov., 2:379-90 (2003)). When utrophin is over- expressed in transgenic mdx mice, it localizes to the sarcolemma of muscle cells and restores the components of the dystrophin-associated protein complex (DAPC), which prevents the dystrophic development and in turn leads to functional improvement of skeletal muscle. Adenoviral delivery of utrophin in the dog has been shown to prevent pathology. Commencement of increased utrophin expression shortly after birth in the mouse model can be effective, and no toxicity is observed when utrophin is ubiquitously expressed, which is promising for the translation of this therapy to humans. Upregulation of endogenous utrophin to sufficient levels to decrease pathology might be achieved by the delivery of small diffusible compounds.
[0009] Earlier applications, PCT/GB2007/050055, PCT/GB2007/050056, UK Patent Application No. 0617739.8, UK Patent Application No. 0619282.7, UK Patent Application No. 0623985.9, UK Patent Application No. 0617740.6, UK Patent Application No. 0619283.5, UK Patent Application No. 0803906.7, and UK Patent Application No. 0806130.1, disclosed compounds which upregulate endogenous utrophin in predictive screens, and thus, may be useful in the treatment of DMD.
SUMMARY
[0010] Provided herein are compounds for the treatment or prophylaxis of muscular dystrophy and related conditions, including DMD, compositions comprising the compounds, and methods of use thereof. In one embodiment, provided herein are compounds that upregulate endogenous utrophin, and are useful in the treatment or prophylaxis of muscular dystrophy, including DMD. [0011] In one embodiment, provided herein is a compound of formula (I):
Figure imgf000004_0001
(I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof; wherein R1, R2, R3, L1, L2, and Y are defined herein elsewhere, for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. [0012] In one embodiment, provided herein is a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in the treatment or prophylaxis of Duchenne muscular dystrophy. In one embodiment, provided herein is a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in the treatment or prophylaxis of Becker muscular dystrophy. In one embodiment, provided herein is a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in the treatment or prophylaxis of cachexia. In one embodiment, provided herein is a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in the treatment or prophylaxis of Duchenne muscular dystrophy, or Becker muscular dystrophy.
[0013] In certain embodiments, provided herein is a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
[0014] Also provided herein are pharmaceutical compositions comprising a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof; in combination with one or more pharmaceutically acceptable carriers or excipients.
[0015] Also provided herein is a method for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. In one embodiment, the method treats, prevents, and/or manages one or more symptoms of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. In one embodiment, the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
[0016] Also provided herein is a method for the treatment or prophylaxis of Duchenne muscular dystrophy. In one embodiment, the method treats, prevents, and/or manages one or more symptoms of Duchenne muscular dystrophy. In one embodiment, the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
[0017] In one embodiment, the compounds of formula (I) are used in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. In another embodiment, the compounds of formula (I) are used in the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy. In another embodiment, the compounds of formula (I) are used in the treatment or prophylaxis of Duchenne muscular dystrophy.
DETAILED DESCRIPTION
A. Definitions
[0018] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
[0019] As used herein, and unless otherwise specified, the term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical of 1 to 20 (Ci-C20), 1 to 15 (Ci-Ci5), 1 to 10 (Ci-Ci0), 1 to 6 (Ci-C6), or 1 to 5 (C1- C5) carbon atoms, or a branched saturated monovalent hydrocarbon radical of 3 to 20 (C3- C20), 3 to 15 (C3-C15), 3 to 10 (C3-Ci0), 3 to 6 (C3-C6), or 3 to 5 (C3-C5) carbon atoms. As used herein, and unless otherwise specified, linear Ci-C6 and branched C3-C6 alkyl groups are also referred to as "lower alkyl." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec -butyl, t-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). As used herein, and unless otherwise specified, the term "Ci-C6 alkyl" refers to an optionally substituted linear or branched saturated monovalent hydrocarbon radical having one to six carbon atoms, such as, e.g. , methyl, ethyl, n-propyl, isopropyl, t-butyl, and n-hexyl. In some embodiments, the Ci-C6 alkyl is optionally substituted with one or more halo, such as, e.g., trifluoromethyl and 1,2- dichloroethyl. As used herein, and unless otherwise specified, the term "Ci-C6 haloalkyl" refers to a Ci-C 6 alkyl group as defined herein elsewhere substituted by one or more halo. As used herein, and unless otherwise specified, the terms "C1-C4 alkyl" and "Ci-Ci0 alkyl" have similar meanings as "Ci-C6 alkyl" except that they contain respectively from one to four and from one to ten carbon atoms. In certain embodiments, the alkyl may be optionally substituted as described herein. [0020] As used herein, and unless otherwise specified, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bond(s), wherein the alkenyl is optionally substituted. As used herein, and unless otherwise specified, the term "alkenyl" also embraces radicals having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-C20), 2 to 15 (C2-Ci5), 2 to 10 (C2-Ci0), 2 to 6 (C2-C6), or 2 to 5 (C2-C5) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (Cs-C20), 3 to 15 (C3-C15), 3 to 10 (C3-C10), 3 to 6 (C 3-C6), or 3 to 5 (C3-C5) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and A- methylbutenyl. As used herein, and unless otherwise specified, the term "C2-C6 alkenyl" refers to an optionally substituted linear or branched monovalent hydrocarbon radical having from two to six carbon atoms and containing at least one carbon-carbon double bond, such as, e.g., ethenyl, 2-propenyl, and 3-hexenyl. In some embodiments, the C2-C6 alkenyl is optionally substituted with one or more halo, such as, e.g., chloroethenyl and fluoroethenyl. As used herein, and unless otherwise specified, the terms "C2-Ci0 alkenyl" has similar meanings except that they contain from two to ten carbon atoms. In certain embodiments, the alkenyl may be optionally substituted as described herein.
[0021] As used herein, and unless otherwise specified, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bond(s), wherein the alkynyl is optionally substituted. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-C20), 2 to 15 (C2-Ci5), 2 to 10 (C2-Ci0), 2 to 6 (C2-C6), or 2 to 5 (C2-C5) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (Cs-C20), 3 to 15 (C3-Ci5), 3 to 10 (C3-Ci0), 3 to 6 (C3-C6), or 3 to 5 (C3-C5) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH) and propargyl (-CH2C≡CH). As used herein, and unless otherwise specified, the term "C2-C6 alkynyl" refers to an optionally substituted linear or branched monovalent hydrocarbon radical having from two to six carbon atoms and containing at least one carbon-carbon triple bond, such as, e.g., ethynyl, 2-propynyl, and 3-hexynyl. In some embodiments, the C2-C6 alkynyl is optionally substituted with one or more halo. As used herein, and unless otherwise specified, the terms "C2-Ci0 alkynyl" has similar meanings except that they contain from two to ten carbon atoms. In certain embodiments, the alkynyl may be optionally substituted as described herein. [0022] As used herein, and unless otherwise specified, the term "alkylene" refers to a saturated linear or branched divalent hydrocarbon radical, wherein the alkylene is optionally substituted. In certain embodiments, the alkylene is a saturated linear divalent hydrocarbon radical of 1 to 20 (Ci-C20), 1 to 15 (Ci-Ci5), 1 to 10 (Ci-Ci0), 1 to 6 (Ci-C6), or 1 to 5 (C1- C5) carbon atoms, or a saturated branched divalent hydrocarbon radical of 3 to 20 (Cs-C20), 3 to 15 (C3-C15), 3 to 10 (C3-Ci0), 3 to 6 (C3-C6), or 3 to 5 (C3-C5) carbon atoms. As used herein, unless otherwise specified, linear Ci-C6 and branched C3-C6 alkylene groups are also referred to as "lower alkylene." Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene (including all isomeric forms),
Figure imgf000008_0001
isopropylene, butylene (including all isomeric forms), n-butylene, isobutylene, t-butylene, pentylene (including all isomeric forms), and hexylene (including all isomeric forms). As used herein, unless otherwise specified, "Ci-C6 alkylene" refers to a saturated optionally substituted linear divalent hydrocarbon radical of 1 to 6 carbon atoms or a saturated optionally substituted branched divalent hydrocarbon radical of 3 to 6 carbon atoms. As used herein, unless otherwise specified, "Ci-C3 alkylene" refers to a saturated optionally substituted linear divalent hydrocarbon radical of 1 to 3 carbon atoms or a saturated optionally substituted branched divalent hydrocarbon radical of 3 carbon atoms, such as, e.g., -CH2-, -(CH2)2-, -(CH2)3-, and -CH(CH3 )-(CH2)-. In certain embodiments, the alkylene may be optionally substituted as described herein.
[0023] As used herein, and unless otherwise specified, the term "alkenylene" refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bond(s), wherein the alkenylene is optionally substituted. As used herein, and unless otherwise specified, the term "alkenylene" also embraces radicals having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In certain embodiments, the alkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2-C20), 2 to 15 (C2-Ci5), 2 to 10 (C2-Ci0), or 2 to 6 (C2-C6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C3-C20), 3 to 15 (C3-Ci5), 3 to 10 (C3-Ci0), or 3 to 6 (C3-C6) carbon atoms. Examples of alkenylene groups include, but are not limited to, ethenylene, allylene, propenylene, butenylene, and 4-methylbutenylene. As used herein, and unless otherwise specified, "C2-C6 alkenylene" refers to an optionally substituted linear divalent hydrocarbon radical of 2 to 6 carbon atoms or an optionally substituted branched divalent hydrocarbon radical of 3 to 6 carbon atoms, which contains one or more carbon-carbon double bond. As used herein, and unless otherwise specified, the term "C2-C3 alkenylene" refers to an optionally substituted linear or branched divalent hydrocarbon radical of 2 to 3 carbon atoms having one carbon-carbon double bond, such as, e.g., -CH=CH- and -CH2-CH=CH-. In certain embodiments, the alkenylene may be optionally substituted as described herein.
[0024] As used herein, and unless otherwise specified, the term "alkynylene" refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon triple bond(s), wherein the alkynylene is optionally substituted. In certain embodiments, the alkynylene is a linear divalent hydrocarbon radical of 2 to 20 (C2-C20), 2 to 15 (C2-Ci5), 2 to 10 (C2-Ci0), or 2 to 6 (C2-C6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C3-C20), 3 to 15 (C3-Ci5), 3 to 10 (C3-Ci0), or 3 to 6 (C3-C6) carbon atoms. Examples of alkynylene groups include, but are not limited to, ethynylene (-C≡C-) and propargylene (-CH2C=C-). As used herein, and unless otherwise specified, "C2-C6 alkynylene" refers to an optionally substituted linear divalent hydrocarbon radical of 2 to 6 carbon atoms or an optionally substituted branched divalent hydrocarbon radical of 3 to 6 carbon atoms, which contains one or more carbon-carbon triple bond. In certain embodiments, the alkynylene may be optionally substituted as described herein.
[0025] As used herein, and unless otherwise specified, the term "carbocyclic" refers to an optionally substituted aromatic or non-aromatic ring system wherein all of the ring atoms are carbon atoms. In one embodiment, the carbocyclic ring system is monocyclic or multicyclic. In some embodiments, the carbocyclic is optionally substituted with one or more halo. In some embodiments, the carbocyclic is an optionally substituted non-aromatic ring system having from 3 to 8 ring atoms, all of which are carbon atoms. In some embodiments, the carbocyclic contains one or more carbon-carbon double bond. Examples of carbocyclic ring systems include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Examples of carbocyclic ring systems also include, but are not limited to, phenyl, naphthyl, or indanyl. In certain embodiments, the carbocyclic may be optionally substituted as described herein.
[0026] As used herein, and unless otherwise specified, the term "heterocyclic" refers to an optionally substituted aromatic or non-aromatic ring system wherein one or more of the ring atom(s) is a hetero atom independently selected from N, O, and S. In one embodiment, the heterocyclic ring system is monocyclic or multicyclic. In some embodiments, the heterocyclic is an optionally substituted non-aromatic ring system having 3 to 8 ring atoms, one or more of which is a hetero atom independently selected from N, O, and S. Examples include, but are not limited to, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, imidazolinyl, dioxanyl, and pyrrolidinyl. Examples also include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, indolyl, and benzimidazolyl. Examples also include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzimidazolinyl, benzodioxolyl, benzodioxanyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, thiazolyl, benzothiazolyl, benzoxazolyl, indazolyl, and imidazolyl. In certain embodiments, the heterocyclic may be optionally substituted as described herein.
[0027] Unless otherwise specified, in the carbocyclic and heterocyclic ring systems, one or more ring CH2 group(s) may be replaced with C=O, to form a cyclic ketone, amide, ester, or other carboxyl derivatives. Unless otherwise specified, in the heterocyclic ring systems, one or more ring N atom(s) may be replaced with N(O) to form an oxide. Unless otherwise specified, in the heterocyclic ring systems, one or more ring S atom(s) may be replaced with S(O) or S(O)2 to form an oxide.
[0028] As used herein, and unless otherwise specified, the term "aromatic" refers to an optionally substituted carbocyclic or heterocyclic ring system which contains at least one aromatic ring. In one embodiment, the aromatic ring system is monocyclic or multicyclic. In some embodiments, the aromatic ring is monocyclic or bicyclic and has from 5 to 10 ring atoms. In some embodiments, the aromatic is bicyclic with two fused rings, wherein one of the rings is aromatic and the other may be aromatic or partially saturated. Examples of aromatic ring systems include, but are not limited to, phenyl, naphthalenyl, and indanyl. Examples of aromatic ring systems may also include, but are not limited to, pyridinyl, pyrimidinyl, furanyl, thienyl, indolyl, isoindolyl, benzofuranyl, benzimidazolyl, benzimidazolinyl, benzodioxyl, benzodioxanyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, thiazolyl, benzothiazolyl, benzoxazolyl, indazolyl, and imidazolyl. In certain embodiments, the aromatic ring system may be optionally substituted as described herein.
[0029] As used herein, and unless otherwise specified, the term "non-aromatic" refers to an optionally substituted carbocyclic or heterocyclic ring system which may be fully or partially saturated. In one embodiment, the non-aromatic ring system is monocyclic or multicyclic. In some embodiments, the non-aromatic ring is monocyclic or bicyclic and has from 3 to 12 ring atoms. Examples of non-aromatic ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, and pyrrolidinyl. In certain embodiments, the non-aromatic ring system may be optionally substituted as described herein. [0030] As used herein, and unless otherwise specified, the term "cycloalkyl" or "non- aromatic carbocyclic" refers to a saturated bridged or non-bridged monovalent cyclic hydrocarbon radical, wherein the cycloalkyl or non-aromatic carbocyclic is optionally substituted. In one embodiment, the cycloalkyl or non-aromatic carbocyclic is monocyclic or multicyclic. In some embodiments, the cycloalkyl or non-aromatic carbocyclic is optionally substituted with one or more halo. In certain embodiments, the cycloalkyl or non-aromatic carbocyclic has from 3 to 20 (C3-C20), 3 to 15 (C3-Ci5), 3 to 10 (C3-Ci0), 3 to 8 (C3-C8), 3 to 7 (C3-Cy), or 3 to 6 (C3-C6) carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl. In certain embodiments, the cycloalkyl or non-aromatic carbocyclic may be optionally substituted as described herein. [0031] As used herein, and unless otherwise specified, the term "aryl" or "aromatic carbocyclic" refers to a monovalent monocyclic or multicyclic hydrocarbon radical that contains at least one aromatic ring, wherein the aryl or aromatic carbocyclic is optionally substituted. In certain embodiments, the aryl has from 6 to 20 (C6-C20), from 6 to 15 (C6- C15), or from 6 to 10 (C6-Ci0) ring atoms. In some embodiments, the aryl has a single ring or two fused rings and from 6 to 10 ring carbon atoms. In some embodiments, the aryl or aromatic carbocyclic is bicyclic, i.e., having two rings, wherein one of the rings is aromatic and the other ring may be aromatic or partially saturated. In some embodiments, the aryl or aromatic carbocyclic is bicyclic or tricyclic, wherein one of the rings is aromatic and the other of the ring(s) may be saturated, partially unsaturated, and/or aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and indanyl. Examples of aryl groups also include, but are not limited to fluorenyl, azulenyl, anthryl, phenanthryl, and pyrenyl. Examples of aryl groups also include, but are not limited to, dihydronaphthyl, indenyl, or tetrahydronaphthyl (tetralinyl). In some embodiments, the aryl or aromatic carbocyclic is optionally substituted with two or more substituents, wherein the two substituents are adjacent to each other and may be taken together with the atoms to which they are attached to form a fused partially saturated ring, which optionally contains one or more heteroatoms selected from N, O, and S, such as, e.g., benzodioxolyl and dihydrobenzofuran. In certain embodiments, the aryl or aromatic carbocyclic may be optionally substituted as described herein.
[0032] As used herein, and unless otherwise specified, the term "aralkyl" or "aryl-alkyl" refers to a monovalent alkyl group substituted with aryl. In certain embodiments, the alkyl and aryl moieties are optionally substituted with one or more substituents as described herein. [0033] As used herein, and unless otherwise specified, the term "heteroaryl" or "heteroaromatic" refers to a monovalent monocyclic or multicyclic radical that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N, and wherein the heteroaryl is optionally substituted. In one embodiment, each ring of the heteroaryl can contain one to two O atoms, one to two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. In some embodiments, the heteroaryl or heteroaromatic has a single ring or two fused rings and from 5 to 10 ring atoms, at least one of which is a heteroatom selected from N, O, and S. In some embodiments, the heteroaryl or heteroaromatic is bicyclic, i.e., having two rings, wherein one of the rings is aromatic and the other ring may be aromatic or partially saturated. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzo furanyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, thienopyridyl, 6,7-dihydro-5H-cyclopenta[δ]pyridinyl, and 6,7-dihydro-5H- cyclopenta[c]pyridinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl may be optionally substituted as described herein. [0034] As used herein, and unless otherwise specified, the terms "heterocyclyl" refers to a monovalent monocyclic or multicyclic radical that contains at least one non-aromatic ring, wherein at least one non-aromatic ring contains one or more heteroatoms independently selected from O, S, and N, and wherein the heterocyclyl is optionally substituted. In certain embodiments, the heterocyclyl has from 3 to 20, from 3 to 15, from 3 to 12, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system. In certain embodiments, the nitrogen or sulfur atom(s) in the heterocyclyl is optionally oxidized. In certain embodiments, the nitrogen atom(s) in the heterocyclyl is optionally quaternized. In certain embodiments, some of the rings in the heterocyclyl may be partially or fully saturated, or aromatic. In certain embodiments, the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of heterocyclyl include, but are not limited to, azepinyl, benzimidazolinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1 ,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl may be optionally substituted as described herein.
[0035] As used herein, and unless otherwise specified, the terms "halo" or "halogen" refers to fluoro, chloro, bromo, or iodo.
[0036] The term "optionally substituted" is intended to mean that a group, including but not limited to, alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl, may be substituted with one or more substituents independently selected from, e.g., (a) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i5 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (b) halo, cyano (-CN), nitro (-NO2), -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(NRa)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(=NRa)NRbRc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(=NRd)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, Cβ-u aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heteroaryl or heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1. As used herein, all groups that can be substituted are "optionally substituted," unless otherwise specified.
[0037] In one embodiment, each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; and (b) Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_7 cycloalkyl, C6- 14 aryl, C7_i5 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)OR6, -C(O)NRfRg, -C(NRe)NRfRg, -ORe, -OC(O)R6, -OC(O)OR6, -0C(0)NRfRg, -0C(=NR6)NRfRg, -OS(O)R6, -OS(O)2R6, -0S(0)NRfRg, -0S(0)2NRfRg, -NRfRg, -NR6C(0)Rh, -NR6C(0)0Rh, -NR6C(0)NRfRg, -NR6C(=NRh)NRfRg, -NR6S(0)Rh, -NR6S(O)2R11, -NR6S(0)NRfRg, -NR6S(O)2NRfRg, -SR6, -S(O)R6, -S(O)2R6, -S(0)NRfRg, and -S(0)2NRfRg; wherein each R6, Rf, Rg, and Rh is independently (i) hydrogen; (ii) Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_7 cycloalkyl, C6-I4 aryl, C7_i5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heteroaryl or heterocyclyl.
[0038] As used herein, and unless otherwise specified, the terms "optically active" and "enantiomerically active" refer to a collection of molecules, which has an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer based on the total weight of the racemate in question.
[0039] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the molecule, R and S. [0040] If a chiral center or another form of isomeric center is present in a compound provided herein, all forms of such isomer or isomers, including stereoisomers, enantiomers and diastereoisomers, are intended to be within the scope of this disclosure. Compounds provided herein containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or a diastereomerically enriched mixture, or the racemic mixture may be separated using known techniques and an individual enantiomer may be used alone.
[0041] As used herein, and unless otherwise specified, the term "solvate" refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non- stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the bound solvent is water, the solvate is a hydrate.
[0042] As used herein, and unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids, organic acids, inorganic bases, and organic bases. When the compound provided herein contains an acidic or basic moiety, it may be provided as a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and Handbook of Pharmaceutical Salts, Properties, and Use; Stahl and Wermuth, Ed.; Wiley- VCH and VHCA: Zurich, Switzerland, 2002. In one embodiment, suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(15)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy- ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene- 1,5- disulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid. In one embodiment, suitable bases for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, sodium hydroxide, and primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, JV-methyl-glucamine, hydrabamine, lH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-hydroxyethyl)- pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, JV-methyl-D-glucamine, and 2-amino-2-(hydroxymethyl)-l,3-propanediol. [0043] Salts which are not pharmaceutically acceptable may still be valuable as intermediates.
[0044] As used herein, and unless otherwise specified, the term "prodrug" refers to a covalently bonded compound comprising a parent drug moiety and a pro-moiety, which undergoes bond cleavage reaction in vivo to release the active parent drug. In one embodiment, the term "prodrug" refers to a functional derivative of a parent compound, for example, a compound of formula (I), and is readily convertible into the parent compound in vivo. A prodrug may be converted to the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See, e.g., Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. in Design of Biophartnaceutical Properties through Prodrugs and Analogs; Roche Ed., APHA Acad. Pharm. ScL: 1977; Gangwar et al, Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Farquhar et al, J. Pharm. Sci. 1983, 72, 324-325; Wernuth in Drug Design: Fact or Fantasy; Jolles et al Eds.; Academic Press: London, 1984; pp 47-72; Design of Prodrugs; Bundgaard et al Eds.; Elsevier: 1985; Fleisher et al, Methods Enzymol 1985, 112, 360-381; Stella et al, Drugs 1985, 29, 455-473; Bioreversible Carriers in Drug in Drug Design, Theory and Application; Roche Ed.; APHA Acad. Pharm. Sci.: 1987; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Waller et al, Br. J. Clin. Pharmac. 1989, 28, 497-507; Balant et al, Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Freeman et al, J. Chem. Soc, Chem. Commun. 1991, 875-877; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Nathwani and Wood, Drugs 1993, 45, 866-94; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Fleisher et al, Adv. Drug Delivery Rev. 1996, 19, 115-130; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Gaignault et al, Pract. Med. Chem. 1996, 671-696; Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al, Pharm. Biotech. 1998, 11, 345-365; Wiebe and Knaus, A dv. Drug Delivery Rev. 1999, 39, 63-80; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Wang et al, Curr. Pharm. Design 1999, 5, 265-287; Han et al, AAPS Pharmsci. 2000, 2, 1-11; Asgharnejad in Transport Processes in Pharmaceutical Systems; Amidon et al, Eds.; Marcell Dekker: 2000; pp 185-218; Sinha et al, Pharm. Res. 2001, 18, 557-564; Anand et al, Expert Opin. Biol. Ther. 2002, 2, 607-620; Rao, Resonace 2003, 19-27; Sloan et al, Med. Res. Rev. 2003, 23, 763-793; Patterson et al, Curr. Pharm. Des. 2003, 9, 2131-2154; Hu, IDrugs 2004, 7, 736-742; Robinson et al, Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 14527-14532; Erion et al, J. Pharmacol. Exp. Ther. 2005, 312, 554- 560; Fang et al, Curr. Drug Discov. Technol 2006, 3, 211-224; Stanczak et al, Pharmacol. Rep. 2006, 58, 599-613; Sloan et al, Pharm. Res. 2006, 23, 2729-2747; Stella et al, Adv. DrugDeliv. Rev. 2007, 59, 677-694; Gomes et al, Molecules 2007, 12, 2484-2506; Krafz et al, ChemMedChem 2008, 3, 20-53; Rautio et al, AAPSJ. 2008, 10, 92-102; Rautio et al, Nat. Rev. Drug. Discov. 2008, 7, 255-270; Pavan et al, Molecules, 2008, 13, 1035-1065; Sandros et al, Molecules 2008, 13, 1156-1178; Singh et al, Curr. Med. Chem. 2008, 15, 1802-1826; Onishi et al, Molecules, 2008, 13, 2136-2155; Huttunen et al, Curr. Med. Chem. 2008, 15, 2346-2365; and Serafϊn et al, Mini Rev. Med. Chem. 2009, 9, 481-497. [0045] As used herein, and unless otherwise specified, the term "subject" refers to an animal, including but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.
[0046] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. [0047] As used herein, and unless otherwise specified, the terms "prevent," "preventing," and "prevention" are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition. [0048] As used herein, and unless otherwise specified, the terms "manage," "managing," and "management" refer to preventing, reducing, or slowing the progression, spread, or worsening of a disease or disorder, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and/or therapeutic agent do not result in a complete cure of the disease or disorder. In this regard, the term "manage," "managing," or "management" encompasses treating a patient who had suffered from a particular disease to prevent, minimize, or slow the progression or recurrence of the disease. [0049] As used herein, and unless otherwise specified, the term "therapeutically effective amount" refers to the amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician. [0050] As used herein, and unless otherwise specified, the term "prophylactically effective amount" refers to the amount of a compound sufficient to prevent a disease or disorder, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
[0051] As used herein, and unless otherwise specified, the term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al, eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash & Ash eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson ed., CRC Press LLC: Boca Raton, FL, 2009.
[0052] As used herein, and unless otherwise specified, the term "about" or "approximately" means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
[0053] As used herein, and unless otherwise specified, the terms "active ingredient" and "active substance" refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or managing one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient" and "active substance" may be an optically active isomer of a compound described herein.
[0054] As used herein, and unless otherwise specified, the term "drug" or "therapeutic agent" refers to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or managing one or more symptoms of a condition, disorder, or disease.
B. Compounds
[0055] Provided herein is a compound of formula (I):
Figure imgf000019_0001
(I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein
Y is CH or N, wherein the CH is optionally substituted;
L1 is a bond, -O-, -NR4-, -S-, -SO-, -SO2-, -NHC(O)NH-, -NHC(O)-, or -NHS(O)2-;
L2 is a bond, -NHC(O)NH-, -NHC(O)-, -O-, -S-, or -NR8-; R1 is (i) R5; or (ii) Ci-C6 alkyl optionally substituted with one or more halo, R5, OR6, N(R6)2, or C(O)N(R6)2; or when L1 is a bond, R1 may additionally be H;
R2 is (i) Ci-C6 alkyl; or (ii) aryl or heteroaryl, each of which is optionally substituted with one or more halo, R9, OR9, SR9, N(R9)2, C(O)R9, CH2C(O)R9, NHC(O)R9, NR9C(O)R9, C(O)N(R9)2, NHS(O)2R9, NHC(O)NHR9, or OR10;
R3 is H, halo, Ci-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; or when L1 is a bond and R1 is H, R3 may additionally be -L3-Rπ;
L3 is a bond, -0-, -NR4-, -S-, -SO-, -SO2-, -NHC(O)NH-, -NHC(O)-, or -NHS(O)2-;
R4 is H or Ci-C4 alkyl;
R5 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, OR6, N(R6)2, S(O)2R6, R7, OR7, C(O)R7, NHC(O)R7, optionally substituted Ci-C6 alkyl, or optionally substituted 0(Ci-C6 alkyl), wherein the Ci-C6 alkyl and 0(Ci-C6 alkyl) are each independently optionally substituted with one or more OR6, N(R6)2, or C(O)N(R6)2; or when R5 is a partially or fully saturated ring, R5 may additionally be substituted with one or more oxo; each occurrence of R6 is independently H or Ci-C4 alkyl;
R7 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, OH, N(R6)2, optionally substituted Ci-C6 alkyl, or optionally substituted 0(Ci-C6 alkyl), wherein the Ci-C6 alkyl and 0(Ci-C6 alkyl) are each independently optionally substituted with one or more OR6 or N(R6)2; or when R7 is a partially or fully saturated ring, R7 may additionally be substituted with one or more oxo;
R8 is H or Ci-C4 alkyl; each occurrence of R9 is independently H or Ci-C4 alkyl;
R10 is aryl or heteroaryl, each of which is optionally substituted with one or more halo;
R11 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, R9, OR9, N(R9)2, C(O)R9, NHC(O)R9, or C(O)N(R9)2; and each occurrence Of Ci-C4 alkyl and Ci-C6 alkyl may independently be further substituted with one or more halo; for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia. [0056] In one embodiment, provided herein is a compound of formula (I):
Figure imgf000021_0001
(I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein
Y is CH or N;
L1 is a bond, -O-, -NR4-, -S-, -SO-, -SO2-, -NHC(O)NH-, -NHC(O)-, or -NHS(O)2-;
L2 is a bond, -NHC(O)NH-, -NHC(O)-, -0-, -S-, or -NR8-;
R1 is (i) R5; or (ii) Ci-C6 alkyl optionally substituted with one or more halo, R5, OR6, N(R6)2, or C(O)N(R6)2; or when L1 is a bond, R1 may additionally be H;
R2 is (i) Ci-C6 alkyl; or (ii) aryl or heteroaryl, each of which is optionally substituted with one or more halo, R9, OR9, N(R9)2, C(O)R9, NHC(O)R9, C(O)N(R9)2, NHC(O)NHR9, or OR10;
R3 is H, halo, Ci-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; or when L1 is a bond and R1 is H, R3 may additionally be -L3-Rπ;
L3 is a bond, -0-, -NR4-, -S-, -SO-, -SO2-, -NHC(O)NH-, -NHC(O)-, or -NHS(O)2-;
R4 is H or Ci-C4 alkyl;
R5 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more OR6, N(R6)2, R7, OR7, C(O)R7, NHC(O)R7, optionally substituted Ci-C6 alkyl, or optionally substituted 0(Ci-C6 alkyl), wherein the Ci-C6 alkyl and 0(Ci-C6 alkyl) are each independently optionally substituted with one or more halo, OR6, N(R6)2, or C(O)N(R6)2; or when R5 is a partially or fully saturated ring, R5 may additionally be substituted with one or more oxo; each occurrence of R6 is independently H or Ci-C4 alkyl;
R7 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, OH, N(R6)2, optionally substituted Ci-C6 alkyl, or optionally substituted 0(Ci-C6 alkyl), wherein the Ci-C6 alkyl and 0(Ci-C6 alkyl) are each independently optionally substituted with one or more OR6 or N(R6)2; or when R7 is a partially or fully saturated ring, R7 may additionally be substituted with one or more oxo;
R8 is H or Ci-C4 alkyl; each occurrence of R9 is independently H or C1-C4 alkyl;
R10 is aryl or heteroaryl, each of which is optionally substituted with one or more halo; and
R11 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, R9, OR9, N(R9)2, C(O)R9, NHC(O)R9, or C(O)N(R9)2; for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia. [0057] In one embodiment, provided herein is a compound of formula (I):
Figure imgf000022_0001
(I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein
Y is CH or N;
L1 is a bond, -O-, -NR4-, -S-, -SO-, -SO2-, -NHC(O)NH-, -NHC(O)-, or -NHS(O)2-;
L2 is a bond, -NHC(O)NH-, -NHC(O)-, -O-, -S-, or -NR8-;
R1 is (i) R5; or (ii) Ci-C6 alkyl optionally substituted with one or more halo, R5, OR6, N(R6)2, or C(O)N(R6)2; or when L1 is a bond, R1 may additionally be H;
R2 is (i) Ci-C6 alkyl; or (ii) aryl or heteroaryl, each of which is optionally substituted with one or more halo, R9, OR9, N(R9)2, C(O)R9, NHC(O)R9, C(O)N(R9)2, or OR10;
R3 is H, halo, Ci-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; or when L1 is a bond and R1 is H, R3 may additionally be -L3-Rπ;
L3 is a bond, -0-, -NR4-, -S-, -SO-, -SO2-, -NHC(O)NH-, -NHC(O)-, or -NHS(O)2-;
R4 is H or Ci-C4 alkyl;
R5 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more OR6, N(R6)2, R7, OR7, C(O)R7, NHC(O)R7, optionally substituted Ci-C6 alkyl, or optionally substituted 0(Ci-C6 alkyl), wherein the Ci-C6 alkyl and 0(Ci-C6 alkyl) are each independently optionally substituted with one or more OR6, N(R6)2, or C(O)N(R6)2; or when R5 is a partially or fully saturated ring, R5 may additionally be substituted with one or more oxo; each occurrence of R6 is independently H or C1-C4 alkyl;
R7 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, OH, N(R6)2, optionally substituted Ci-C6 alkyl, or optionally substituted 0(Ci-C6 alkyl), wherein the Ci-C6 alkyl and 0(Ci-C6 alkyl) are each independently optionally substituted with one or more OR6 or N(R6)2; or when R7 is a partially or fully saturated ring, R7 may additionally be substituted with one or more oxo;
R8 is H or Ci-C4 alkyl; each occurrence of R9 is independently H or Ci-C4 alkyl;
R10 is aryl or heteroaryl, each of which is optionally substituted with one or more halo; and
R11 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, R9, OR9, N(R9)2, C(O)R9, NHC(O)R9, or C(O)N(R9)2; for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia.
[0058] In one embodiment, provided herein is a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy.
[0059] In one embodiment, provided herein is a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in the treatment or prophylaxis of Duchenne muscular dystrophy. [0060] In certain embodiments, provided herein is a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
[0061] In one embodiment, each occurrence of alkyl is independently optionally substituted with one or more halo. In one embodiment, each occurrence of alkyl is independently optionally substituted with one or more fluoro.
[0062] In one embodiment, in the linker L1, L2, and L3 as described herein, the left hand side of the linker as written is linked to the pyridyl or pyrimidine ring, and the right hand side of the linker as written is linked to the R1, R2, or R11 group. [0063] In one embodiment, Y is CH. In one embodiment, Y is N. [0064] In one embodiment, L1 is a bond. In one embodiment, L1 is -O-. In one embodiment, L1 is -NR4-. In one embodiment, L1 is -S-. In one embodiment, L1 is -SO-. In one embodiment, L1 is -SO2-. In one embodiment, L1 is -NHC(O)NH-. In one embodiment, L1 is -NHC(O)-. In one embodiment, L1 is -NHS(O)2-.
[0065] In one embodiment, L2 is a bond. In one embodiment, L2 is -NHC(O)NH-. In one embodiment, L2 is -NHC(O)-. In one embodiment, L2 is -O-. In one embodiment, L2 is
-S-. In one embodiment, L2 is -NR8-.
[0066] In one embodiment, R1 is R5. In one embodiment, R1 is Ci-C6 alkyl optionally substituted with one or more halo, R5, OR6, N(R6)2, or C(O)N(R6)2. In one embodiment, R1 is Ci-C6 alkyl optionally substituted with one or more halo. In one embodiment, R1 is Ci-C6 alkyl optionally substituted with one or more R5. In one embodiment, R1 is Ci-C6 alkyl optionally substituted with one or more OR6. In one embodiment, R1 is Ci-C6 alkyl optionally substituted with one or more N(R6)2. In one embodiment, R1 is Ci-C6 alkyl optionally substituted with one or more C(O)N (R6)2. In one embodiment, L1 is a bond, R1 is
H. In one embodiment, L1 is a bond, R1 is H, R5, or Ci-C6 alkyl optionally substituted with one or more halo, R5, OR6, N(R6)2, or C(O)N(R6)2.
[0067] In one embodiment, R2 is Ci-C6 alkyl. In one embodiment, R2 is Ci-C6 alkyl optionally substituted with one or more halo.
[0068] In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more halo, R9, OR9, SR9, N(R9)2, C(O)R9, CH2C(O)R9, NHC(O)R9,
NR9C(O)R9, C(O)N(R9)2, NHS(O)2R9, NHC(O)NHR9, or OR10. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more halo, R9, OR9,
N(R9)2, C(O)R9, NHC(O)R9, C(O)N(R9)2, NHC(O)NHR9, or OR10. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more halo, R9, OR9,
N(R9)2, C(O)R9, NHC(O)R9, C(O)N(R9)2, or OR10.
[0069] In one embodiment, R2 is aryl optionally substituted with one or more halo, R9,
OR9, SR9, N(R9)2, C(O)R9, CH2C(O)R9, NHC(O)R9, NR9C(O)R9, C(O)N(R9)2, NHS(O)2R9,
NHC(O)NHR9, or OR10. In one embodiment, R2 is aryl optionally substituted with one or more halo, R9, OR9, N(R9)2, C(O)R9, NHC(O)R9, C(O)N(R9)2, NHC(O)NHR9, or OR10. In one embodiment, R2 is aryl optionally substituted with one or more halo, R9, OR9, N(R9)2,
C(O)R9, NHC(O)R9, C(O)N(R9)2, or OR10.
[0070] In one embodiment, R2 is heteroaryl optionally substituted with one or more halo,
R9, OR9, SR9, N(R9)2, C(O)R9, CH2C(O)R9, NHC(O)R9, NR9C(O)R9, C(O)N(R9)2,
NHS(O)2R9, NHC(O)NHR9, or OR10. In one embodiment, R2 is heteroaryl optionally substituted with one or more halo, R9, OR9, N(R9)2, C(O)R9, NHC(O)R9, C(O)N(R9)2, NHC(O)NHR9, or OR10. In one embodiment, R2 is heteroaryl optionally substituted with one or more halo, R9, OR9, N(R9)2, C(O)R9, NHC(O)R9, C(O)N(R9)2, or OR10. [0071] In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more halo. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more R9. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more OR9. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more SR9. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more N(R9)2. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more C(O)R9. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more CH2C(O)R9. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more NHC(O)R9. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more NR9C(O)R9. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more C(O)N(R9)2. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more NHS(O)2R9. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more NHC(O)NHR9. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more OR10.
[0072] In one embodiment, R3 is H. In one embodiment, R3 is halo. In one embodiment, R3 is Ci-C6 alkyl. In one embodiment, R3 is Ci-C6 alkyl optionally substituted with one or more halo. In one embodiment, R is C2-C6 alkenyl. In one embodiment, R is C2-C6 alkynyl. In one embodiment, L1 is a bond and R1 is H, R3 is -L3-Rπ. In one embodiment, L1 is a bond and R1 is H, R3 is H, halo, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -L3-Rπ. [0073] In one embodiment, L3 is a bond. In one embodiment, L3 is -O-. In one embodiment, L3 is -NR4-. In one embodiment, L3 is -S-. In one embodiment, L3 is -SO-. In one embodiment, L3 is -SO2-. In one embodiment, L3 is -NHC(O)NH-. In one embodiment, L3 is -NHC(O)-. In one embodiment, L3 is -NHS(O)2-. [0074] In one embodiment, R4 is H. In one embodiment, R4 is C1-C4 alkyl. In one embodiment, R4 is Ci-C4 alkyl optionally substituted with one or more halo. [0075] In one embodiment, R5 is optionally substituted cycloalkyl. In one embodiment, R5 is optionally substituted heterocyclyl. In one embodiment, R5 is optionally substituted aryl. In one embodiment, R5 is optionally substituted heteroaryl. In one embodiment, R5 is optionally substituted with one or more halo, OR6, N(R6)2, S(O)2R6, R7, OR7, C(O)R7, NHC(O)R7, optionally substituted Ci-C6 alkyl, or optionally substituted 0(Ci-C6 alkyl), wherein the Ci-C6 alkyl and 0(Ci-C6 alkyl) are each independently optionally substituted with one or more halo, OR6, N(R6)2, or C(O)N(R6)2. In one embodiment, R5 is optionally substituted with one or more OR6, N(R6)2, R7, OR7, C(O)R7, NHC(O)R7, optionally substituted Ci-C6 alkyl, or optionally substituted 0(Ci-C6 alkyl), wherein the Ci-C6 alkyl and 0(Ci-C6 alkyl) are each independently optionally substituted with one or more OR6, N(R6)2, or C(O)N(R6)2. In one embodiment, R5 is optionally substituted with one or more halo. In one embodiment, R5 is optionally substituted with one or more OR6. In one embodiment, R5 is optionally substituted with one or more N(R6)2. In one embodiment, R5 is optionally substituted with one or more S(O)2R6. In one embodiment, R5 is optionally substituted with one or more R7. In one embodiment, R5 is optionally substituted with one or more OR7. In one embodiment, R5 is optionally substituted with one or more C(O)R7. In one embodiment, R5 is optionally substituted with one or more NHC(O)R7. In one embodiment, R5 is optionally substituted with one or more Ci-C6 alkyl, which is optionally substituted with one or more halo, OR6, N(R6)2, or C(O)N(R6)2. In one embodiment, R5 is optionally substituted with one or more 0(Ci-C6 alkyl), which is optionally substituted with one or more halo, OR6, N(R6)2, or C(O)N(R6)2.
[0076] In one embodiment, when R5 is a partially or fully saturated ring, such as, e.g., cycloalkyl, heterocyclyl, and/or partially or fully saturated fused ring system, R5 is optionally substituted with one or more oxo, e.g., forming cyclic ketone, cyclic ester, or cyclic amide derivatives.
[0077] In one embodiment, R6 is H. In one embodiment, R6 is C1-C4 alkyl. In one embodiment, R6 is Ci-C4 alkyl optionally substituted with one or more halo. [0078] In one embodiment, R7 is optionally substituted cycloalkyl. In one embodiment, R7 is optionally substituted heterocyclyl. In one embodiment, R7 is optionally substituted aryl. In one embodiment, R7 is optionally substituted heteroaryl. In one embodiment, R7 is optionally substituted with one or more halo, OH, N(R6)2, optionally substituted Ci-C6 alkyl, or optionally substituted 0(Ci-C6 alkyl), wherein the Ci-C6 alkyl and 0(Ci-C6 alkyl) are each independently optionally substituted with one or more halo, OR6, or N(R6)2. In one embodiment, R7 is optionally substituted with one or more halo, OH, N(R6)2, optionally substituted Ci-C6 alkyl, or optionally substituted 0(Ci-C6 alkyl), wherein the Ci-C6 alkyl and 0(Ci-C6 alkyl) are each independently optionally substituted with one or more OR6 or N(R6)2. In one embodiment, R7 is optionally substituted with one or more halo. In one embodiment, R7 is optionally substituted with one or more OH. In one embodiment, R7 is optionally substituted with one or more N(R6)2. In one embodiment, R7 is optionally substituted with one or more Ci-C6 alkyl, which is optionally substituted with one or more halo, OR6, or N(R6)2. In one embodiment, R7 is optionally substituted with one or more 0(Ci-C6 alkyl), which is optionally substituted with one or more halo, OR6, or N(R6)2. [0079] In one embodiment, when R7 is a partially or fully saturated ring, such as, e.g., cycloalkyl, heterocyclyl, and/or partially or fully saturated fused ring system, R7 is optionally substituted with one or more oxo, e.g., forming cyclic ketone, cyclic ester, or cyclic amide derivatives.
[0080] In one embodiment, R8 is H. In one embodiment, R8 is C1-C4 alkyl. In one embodiment, R8 is Ci-C4 alkyl optionally substituted with one or more halo. [0081] In one embodiment, R9 is H. In one embodiment, R9 is Ci-C4 alkyl. In one embodiment, R9 is Ci-C4 alkyl optionally substituted with one or more halo. [0082] In one embodiment, R10 is aryl optionally substituted with one or more halo. In one embodiment, R10 is heteroaryl optionally substituted with one or more halo. [0083] In one embodiment, R11 is optionally substituted cycloalkyl. In one embodiment, R11 is optionally substituted heterocyclyl. In one embodiment, R11 is optionally substituted aryl. In one embodiment, R11 is optionally substituted heteroaryl. In one embodiment, R11 is optionally substituted with one or more halo, R9, OR9, N(R9)2, C(O)R9, NHC(O)R9, or C(O)N(R9)2. In one embodiment, R11 is optionally substituted with one or more halo. In one embodiment, R11 is optionally substituted with one or more R9. In one embodiment, R11 is optionally substituted with one or more OR9. In one embodiment, R11 is optionally substituted with one or more N(R9)2. In one embodiment, R11 is optionally substituted with one or more C(O)R9. In one embodiment, R11 is optionally substituted with one or more NHC(O)R9. In one embodiment, R11 is optionally substituted with one or more C(O)N(R9)2. [0084] In one embodiment, provided herein is a compound of formula (Ia):
Figure imgf000027_0001
or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein L1, L2, R1, R2, R3, and Y are as defined herein elsewhere. [0085] In one embodiment, provided herein is a compound of formula (Ib):
Figure imgf000028_0001
(Ib), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein L1, L2, R1, R2, and Y are as defined herein elsewhere. [0086] In one embodiment, provided herein is a compound of formula (Ic):
Figure imgf000028_0002
(Ic), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein L2, L3, R2, and R11 are as defined herein elsewhere.
[0087] Any combinations of L1, L2, L3, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and Y are encompassed by this disclosure and specifically provided herein.
[0088] In one embodiment, L1 is a bond, -NHC(O)NH-, -NHC(O)-, -O-, -S-, -NR4-, or -NHS(O)2-. In one embodiment, L1 is a bond, -NHC(O)NH-, -NHC(O)-, -O-, -S-, or
-NR4-. In one embodiment, L2 is a bond or -O-. In one embodiment, R3 is H. In one embodiment, L1 is a bond, -NHC(O)NH-, -NHC(O)-, -O-, -S-, or -NR4-; L2 is a bond or
-O-; and R3 is H.
[0089] In one embodiment, L1 is a bond and R1 is H. In one embodiment, L2 is a bond or
-O-. In one embodiment, R3 is -L3-Rπ, wherein L3 is a bond, -NHC(O)NH-, -NHC(O)-,
-O-, -S-, or -NR4-. In one embodiment, L1 is a bond; R1 is H; L2 is a bond or -O-; and R3 is -iA-R11, wherein L3 is a bond, -NHC(O)NH-, -NHC(O)-, -O-, -S-, or -NR4-.
[0090] In one embodiment, -L2-R2 is at the 5 -position of the pyridyl or pyrimidinyl ring and -I^-R1 is at the 2-position of the pyridyl or pyrimidinyl ring.
[0091] In one embodiment, R2 is C1-C4 alkyl or haloalkyl, such as, e.g., methyl or trifluoromethyl.
[0092] In one embodiment, R2 is aryl or heteroaryl, such as, e.g., phenyl, naphthalenyl, pyridyl, furyl, thienyl, benzofuranyl, benzodioxolyl, benzoxazolyl, benzothiazolyl, or indolinone, each of which is optionally substituted. In one embodiment, R2 is aryl or heteroaryl, such as, e.g., phenyl, naphthalenyl, pyridyl, furyl, thienyl, benzofuranyl, or benzodioxolyl, each of which is optionally substituted. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more halo, CH3, CF3, C(O)CH3, C(O)H, OCH3, OCF3, SCH3, N(CH3)2, OH, NHC(O)CH3, NHC(O)CF3, NCH3C(O)CH3, NHC(O)-ethyl, NHC(O)-isopropyl, C(O)NHCH3, C(O)NH2, CH2C(O)CH3, NHS(O)2CH3, NHC(O)NHCH3, or phenoxy. In one embodiment, R2 is aryl or heteroaryl, each of which is optionally substituted with one or more halo, CH3, CF3, C(O)CH3, C(O)H, OCH3, OCF3, SCH3, N(CH3)2, OH, NHC(O)CH3, NHC(O)-ethyl, NHC(O)-isopropyl, C(O)NHCH3, or phenoxy.
[0093] In one embodiment, L1 is -NHC(O)NH-, and R1 is cycloalkyl, such as, e.g., cyclopentyl or cyclohexyl.
[0094] In one embodiment, L1 is -NHC(O)- or -NHS(O)2-, and R1 is aryl or heteroaryl, each of which is optionally substituted as described herein. In one embodiment, L1 is -NHC(O)-, and R1 is aryl or heteroaryl, each of which is optionally substituted as described herein. In one embodiment, R1 is optionally substituted phenyl or heteroaryl. In one embodiment, R1 is phenyl, pyrazolyl, oxazolyl, or isoxazolyl, each of which is optionally substituted. In one embodiment, R1 is aryl or heteroaryl optionally substituted with one or more C1-C4 alkyl, CF3, OCF3, or aryl. In one embodiment, R1 is aryl or heteroaryl optionally substituted with one or more C1-C4 alkyl or aryl, such as, e.g., methyl, ethyl, or phenyl. [0095] In one embodiment, L1 is a bond, and R1 is heterocyclyl, which is optionally substituted as described herein. In one embodiment, R1 is piperazinyl, piperidinyl, or morpholinyl, and R1 is attached to the L1 bond via a ring nitrogen atom. In one embodiment, R1 is heterocyclyl optionally substituted with one or more alkyl. In one embodiment, R1 is heterocyclyl optionally substituted with one or more (i) aryl or heteroaryl, such as, e.g., phenyl or pyridyl; or (ii) C(O)-heterocyclyl, such as, e.g., C(O)-tetrahydrofuranyl. In one embodiment, the aryl, heteroaryl, and C(O)-heterocyclyl substituents are further optionally substituted with one or more halo, OH, or C1-C4 alkyl optionally substituted with halo or OH. In one embodiment, the aryl, heteroaryl, and C(O)-heterocyclyl substituents are further optionally substituted with one or more OH or C1-C4 alkyl optionally substituted with halo or OH.
[0096] In one embodiment, L1 is S, and R1 is Ci-C6 alkyl.
[0097] In one embodiment, L1 is -NR4-, wherein R4 is hydrogen or methyl. In one embodiment, L1 is -NH-. In one embodiment, L1 is -NR4- or -0-, and R1 is Ci-C6 alkyl, aryl, or heteroaryl, each of which is optionally substituted as described herein. [0098] In one embodiment, L1 is -O- or -NR4-, and R1 is alkyl optionally substituted with one or more F, 0(Ci-C4 alkyl), or C(O)N(Ci-C4 alkyl)2. In one embodiment, L1 is -O- or -NR4-, and R1 is alkyl optionally substituted with aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionally substituted as defined herein. In one embodiment, R1 is alkyl optionally substituted with aryl, heteroaryl, cycloalkyl, or heterocyclyl, such as, e.g., phenyl, pyridyl, cyclopropyl, pyrrolidinyl, or morpholinyl. In one embodiment, R1 is alkyl optionally substituted with aryl or heteroaryl, each of which is optionally substituted with one or more halo, phenoxy, oxo, methyl, trifluoromethyl, methoxy, or trifluoromethoxy. [0099] In one embodiment, L1 is -O- or -NR4-, and R1 is aryl or heteroaryl, such as, e.g., phenyl, dihydro-lH-indenyl, pyridyl, benzodioxolyl, or dihydrobenzodioxinyl. In one embodiment, R1 is optionally substituted with one or more halo, OR6, N(R6)2, S(O)2R6, R7, OR7, C(O)R7, NHC(O)R7, Ci-C6 alkyl optionally substituted with one or more fluoro, or 0(Ci-C6 alkyl) optionally substituted with C(O)N(R6)2 or one or more fluoro, wherein R6 and R7 are as defined herein elsewhere. In one embodiment, R1 is optionally substituted with one or more halo, OR6, N(R6)2, R7, OR7, C(O)R7, NHC(O)R7, Ci-C6 alkyl, or 0(Ci-C6 alkyl) optionally substituted with C(O)N(R6)2, wherein R6 and R7 are as defined herein elsewhere. In one embodiment, R1 is optionally substituted with one or more halo, phenyl, heterocyclyl, methyl, trifluoromethyl, phenoxy, methoxy, trifluoromethoxy, dimethylamino, OCH2C(O)N(CHs)2, or NHC(O)R7, where R7 may be phenyl optionally substituted with methoxy.
[00100] In one embodiment, when L1 is a bond and R1 is -H, R3 is -L3-Rπ. In one embodiment, L3 is -O- or -NR4-. In one embodiment, R11 is aryl or heteroaryl, such as, e.g., phenyl, dihydro-lH-indenyl, pyridyl, or benzodioxolyl. In one embodiment, R11 is optionally substituted with one or more halo, OR9, N(R6)2, C(O)R9, NHC(O)R9, wherein R9 is H or C1-C4 alkyl optionally substituted with one or more fluoro. In one embodiment, R11 is optionally substituted with one or more halo, OR9, N(R6)2, C(O)R9, NHC(O)R9, wherein R9 is H or C1-C4 alkyl. In one embodiment, R11 is optionally substituted with one or more halo, methyl, trifluoromethyl, methoxy, trifluoromethoxy, or dimethylamino. [00101] In one embodiment, specific examples of compounds of formula (I) include, but are not limited to, the following: 1. 1 -cyclohexyl-3 -(5 -methylpyridin-2-yl)urea,
Figure imgf000030_0001
2. 5-methyl-N-(5-methylpyridin-2-yl)-3-phenylisoxazole-4-carboxamide,
Figure imgf000031_0001
3. ((2S,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)(4-(5- (trifluoromethyl)pyridin-2-yl)piperazin- 1 -yl)methanone,
Figure imgf000031_0002
4. N-phenethyl-5 -(4-(trifluoromethoxy)phenyl)pyridin-2-amine,
Figure imgf000031_0003
5. 4-(2-(5-(benzo[d][l,3]dioxol-5-yl)pyridin-2-yloxy)phenyl)morpholine,
Figure imgf000031_0004
6. 3 -(6-( 1 -phenylethylamino)pyridin-3 -yl)benzaldehyde,
7. 4-(6-(2-(pyridin-4-yl)ethylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000031_0006
8. 2-(6-(2,3-dihydrobenzo[b][l,4]dioxin-6-ylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000031_0007
9. 5-(4-phenoxyphenyl)-2-(3-(pyridin-2-yl)propoxy)pyridine,
Figure imgf000031_0008
10. 1 -(5 -(trifluoromethyl)pyridin-2-yl)-4-(5 -(3 ,4,5 -trimethoxyphenyl)pyridin-2- yl)piperazine,
Figure imgf000032_0001
11. 3-(6-(2,6-difluorophenylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000032_0002
12. 2-(3-(5-(4-formylphenyl)pyridin-2-ylamino)phenoxy)-N,N-dimethylacetamide,
Figure imgf000032_0003
13. Nl-(6'-methoxy-3,3'-bipyridin-6-yl)-N3,N3-dimethylbenzene-l,3-diamine,
Figure imgf000032_0004
14. N 1 ,N 1 -dimethyl-N3 -(5 -(2-(methylthio)phenyl)pyridin-2-yl)benzene- 1 ,3 -diamine,
Figure imgf000032_0005
15. 5 -(furan-2-yl)-N-(3 -phenoxyphenyl)pyridin-2-amine,
Figure imgf000032_0006
16. N-(2,6-difluorophenyl)-5-(4-(trifluoromethoxy)phenyl)pyridin-2-amine,
Figure imgf000032_0007
17. 3 -(6-(cyclopropylmethylamino)pyridin-3 -yl)benzaldehyde,
Figure imgf000033_0001
18. l-(3-(trifluoromethyl)phenyl)-4-(5-(3,4,5-trimethoxyphenyl)pyridin-2-yl)piperazine,
Figure imgf000033_0002
19. N-(3-(6-(3,5-dichlorophenylamino)pyridin-3-yl)phenyl)acetamide,
Figure imgf000033_0003
20. 1 -(3 -(6-(3 -(dimethylamino)phenylamino)pyridin-3 -yl)phenyl)ethanone,
Figure imgf000033_0004
21. 2-(6-(pyridin-3-ylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000033_0005
22. 4-(6-(4-(3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)pyridin-3 -yl)benzaldehyde,
Figure imgf000033_0006
23. 3-(6-morpholinopyridin-3-yl)benzaldehyde,
Figure imgf000033_0007
24. N-(2-morpholinoethyl)-3,3'-bipyridin-6-amine,
Figure imgf000033_0008
25. N-(3-(6-(2-morpholinoethylamino)pyridin-3-yl)phenyl)acetamide,
Figure imgf000034_0001
26. N-(I -(4-fluorophenyl)ethyl)-5-p-tolylpyridin-2-amine,
Figure imgf000034_0002
27. 3-(6-(2-(pyridin-4-yl)ethylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000034_0003
28. N-(2-(pyridin-2-yl)ethyl)-5 -p-tolylpyridin-2-amine,
Figure imgf000034_0004
29. 3 -(6-(pyridin-2-ylmethoxy)pyridin-3 -yl)benzaldehyde,
Figure imgf000034_0005
30. 4-(6-(2,2,2-trifluoroethylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000034_0006
31. 3-(6-(3,4-dichlorophenylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000034_0007
32. 2-(3-phenoxybenzyloxy)-5-(thiophen-2-yl)pyridine,
Figure imgf000034_0008
33. l-(5-(6-(3 ,4,5 -trimethoxyphenylamino)pyridin-3 -yl)thiophen-2-yl)ethanone,
Figure imgf000035_0001
34. 3-(6-(2-morpholinoethoxy)pyridin-3-yl)benzaldehyde,
Figure imgf000035_0002
35. 3-(6-(2-(pyridin-2-yl)ethylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000035_0003
36. 2-(6-(phenethylamino)pyridin-3 -yl)benzaldehyde,
Figure imgf000035_0004
37. 2-(3 -phenoxybenzyloxy)-5 -(3 ,4,5 -trimethoxyphenyl)pyridine,
Figure imgf000035_0005
38. l-(3,5-dichloropyridin-4-yl)-4-(5-(3,4,5-trimethoxyphenyl)pyridin-2-yl)piperazine,
Figure imgf000035_0006
39. 2-(6-( 1 -phenylethylamino)pyridin-3 -yl)benzaldehyde,
Figure imgf000035_0007
40. 2-(6-(3 -(trifluoromethyl)phenylamino)pyridin-3 -yl)benzaldehyde,
Figure imgf000035_0008
41. 1 -(2-(5-p-tolylpyridin-2-yloxy)ethyl)pyrrolidin-2-one,
Figure imgf000036_0001
42. 3-(6-(4-methylpiperazin- 1 -yl)pyridin-3-yl)benzaldehyde,
Figure imgf000036_0002
43. 3-(6-(isopropylthio)pyridin-3-yl)benzaldehyde,
Figure imgf000036_0003
44. 4-(6-(3 -phenoxyphenylamino)pyridin-3 -yl)phenol,
Figure imgf000036_0004
45. N-(2,6-difluorobenzyl)-5-(2-(methylthio)phenyl)pyridin-2-amine,
Figure imgf000036_0005
46. l-(5-(2-fluorophenyl)pyridin-2-yl)-4-(pyridin-2-yl)piperazine,
Figure imgf000036_0006
47. N-(3-(trifluoromethoxy)phenyl)-3,3'-bipyridin-6-amine,
Figure imgf000036_0007
48. 4-(6-(2-morpholinoethylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000036_0008
49. 5-(2-fluorophenyl)-N-(2-(pyridin-2-yl)ethyl)pyridin-2-amine,
Figure imgf000037_0001
50. 4-(2-(5-(2-chlorophenyl)pyridin-2-yloxy)ethyl)morpholine,
Figure imgf000037_0002
51. 3-(6-(3-(pyridin-2-yl)propoxy)pyridin-3-yl)benzaldehyde,
Figure imgf000037_0003
52. N-(2-(pyridin-2-yl)ethyl)-3,3'-bipyridin-6-amine,
Figure imgf000037_0004
53. 5-(2-methoxyphenyl)-N-(3-(trifluoromethoxy)phenyl)pyridin-2-amine,
Figure imgf000037_0005
54. N 1 -(5 -(4-methoxyphenyl)pyridin-2-yl)-N3 ,N3 -dimethylbenzene- 1 ,3 -diamine,
Figure imgf000037_0006
55. 3 -(6-(2-methoxyethylamino)pyridin-3 -yl)benzaldehyde,
Figure imgf000037_0007
56. N-(3,5-dichlorophenyl)-3,3'-bipyridin-6-amine,
Figure imgf000037_0008
57. 1 -(5 -(6-(3 -(dimethylamino)phenylamino)pyridin-3 -yl)thiophen-2-yl)ethanone,
Figure imgf000037_0009
58. 2-(6-(6-methoxypyridin-3 -ylamino)pyridin-3 -yl)benzaldehyde,
Figure imgf000038_0001
59. Nl-(5-(3-chlorophenyl)pyridin-2-yl)-N3,N3-dimethylbenzene-l,3-diamine,
Figure imgf000038_0002
60. 4-(2-(5-p-tolylpyridin-2-yloxy)phenyl)morpholine,
Figure imgf000038_0003
61. N-(3-(6-(2-phenoxyphenylamino)pyridin-3-yl)phenyl)acetamide,
Figure imgf000038_0004
62. 2-(3 -phenoxybenzyloxy)-5 -phenylpyridine,
Figure imgf000038_0005
63. 2-(6-(4-(5 -(trifluoromethyl)pyridin-2-yl)piperazin- 1 -yl)pyridin-3 -yl)benzaldehyde,
Figure imgf000038_0006
64. 2-(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)benzaldehyde,
Figure imgf000038_0007
65. N 1 -(5 -(3 -methoxyphenyl)pyridin-2-yl)-N3 ,N3 -dimethylbenzene- 1 ,3 -diamine,
Figure imgf000039_0001
66. 2-(6-morpholinopyridin-3-yl)benzaldehyde,
Figure imgf000039_0002
67. 5 -(3 -methoxyphenyl)-2-(pyridin-2-ylmethoxy)pyridine,
Figure imgf000039_0003
68. l-(5-(2-fluorophenyl)pyridin-2-yl)-4-methylpiperazine,
Figure imgf000039_0004
69. l-(5-(6-(2-phenoxyphenylamino)pyridin-3-yl)thiophen-2-yl)ethanone,
Figure imgf000039_0005
70. 5-(2-chlorophenyl)-N-(2,2,2-trifluoroethyl)pyridin-2-amine,
Figure imgf000039_0006
71. N-(3 -(trifluoromethyl)phenyl)-5 -(4-(trifluoromethyl)phenyl)pyridin-2-amine,
Figure imgf000039_0007
72. N-(3-(6-(2-(pyridin-4-yl)ethylamino)pyridin-3-yl)phenyl)acetamide,
Figure imgf000039_0008
73. 2-(6-(4-(pyridin-2-yl)piperazin- 1 -yl)pyridin-3-yl)benzaldehyde,
Figure imgf000040_0001
74. N-(3 -(6-(3 -(trifluoromethyl)phenylamino)pyridin-3 -yl)phenyl)acetamide,
Figure imgf000040_0002
75. 5-(benzofuran-2-yl)-N-(2-phenoxybenzyl)pyridin-2-amine,
Figure imgf000040_0003
76. 5 -(4-methoxyphenyl)-N-(2-(pyridin-4-yl)ethyl)pyridin-2-amine,
Figure imgf000040_0004
77. N-(3,4-dichlorophenyl)-5-(thiophen-2-yl)pyridin-2-amine,
Figure imgf000040_0005
78. l-(5-(2-chlorophenyl)pyridin-2-yl)-4-(pyridin-2-yl)piperazine,
Figure imgf000040_0006
79. 2-(2-phenoxybenzyloxy)-5 -(3 ,4,5 -trimethoxyphenyl)pyridine,
Figure imgf000040_0007
80. N-(2,3-dihydro-lH-inden-l-yl)-5-phenylpyridin-2-amine,
Figure imgf000040_0008
81. 3-(6-(2,3-dihydro-lH-inden-l-ylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000041_0001
82. 2-(6-(pyridin-2-ylmethoxy)pyridin-3-yl)benzaldehyde,
Figure imgf000041_0002
83. 4-(6-(isopropylthio)pyridin-3-yl)benzaldehyde,
Figure imgf000041_0003
84. 2-(6-(3,4-dichlorophenylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000041_0004
85. 3-(6-(2,2,2-trifluoroethylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000041_0005
86. 5-(3-(trifluoromethyl)phenyl)-N-(3,4,5-trimethoxyphenyl)pyridin-2-amine,
Figure imgf000041_0006
87. N-(2,6-difluorobenzyl)-5-p-tolylpyridin-2-amine,
Figure imgf000041_0007
88. N-(2,3 -dihydro- 1 H-inden- 1 -yl)-5 -p-tolylpyridin-2-amine,
Figure imgf000041_0008
89. 2-(6-(2-(pyridin-2-yl)ethylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000042_0001
90. 2-(3-(5-(2-formylphenyl)pyridin-2-ylamino)phenoxy)-N,N-dimethylacetamide,
Figure imgf000042_0002
91. 4-(6-(4-methylpiperazin- 1 -yl)pyridin-3-yl)benzaldehyde,
Figure imgf000042_0003
92. 5 -(3 -fluorophenyl)-2-(3 -(pyridin-2-yl)propoxy)pyridine,
Figure imgf000042_0004
93. 4-(6-(3-phenoxyphenylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000042_0005
94. 4-(2-(5-(3-fluorophenyl)pyridin-2-yloxy)ethyl)morpholine,
Figure imgf000042_0006
95. 2-(6-(cyclopropylmethylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000042_0007
96. 3 -(6-(4-(3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)pyridin-3 -yl)benzaldehyde,
Figure imgf000042_0008
97. 2-(6-(2,2,2-trifluoroethylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000043_0001
98. 3-(6-(3-(trifluoromethoxy)phenylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000043_0002
99. 5-(benzo[d] [ 1 ,3]dioxol-5-yl)-N-(l -(4-fluorophenyl)ethyl)pyridin-2-amine,
Figure imgf000043_0003
100. 4-(5-(2-chlorophenyl)pyridin-2-yl)morpholine,
Figure imgf000043_0004
101. 4-(6-(2-morpholinoethoxy)pyridin-3-yl)benzaldehyde,
Figure imgf000043_0005
102. N 1 ,N 1 -dimethyl-N3 -(5 -(thiophen-2-yl)pyridin-2-yl)benzene- 1 ,3 -diamine,
Figure imgf000043_0006
103. N-(3-(6-(2-(pyridin-2-yl)ethylamino)pyridin-3-yl)phenyl)acetamide,
Figure imgf000043_0007
104. 4-(6-(3,5-dichlorophenylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000043_0008
105. N-(I -phenylethyl)-3,3'-bipyridin-6-amine,
Figure imgf000044_0001
106. N-(3 -(5 -(3 -acetamidophenyl)pyridin-2-ylamino)phenyl)-3 -methoxybenzamide,
Figure imgf000044_0002
107. 5-(2-methoxyphenyl)-2-(pyridin-2-ylmethoxy)pyridine,
Figure imgf000044_0003
108. 2-(6-(3-phenoxyphenylamino)pyridin-3-yl)benzaldehyde,
Figure imgf000044_0004
109. 3 -methoxy-N-(3 -(5 -(2-(methylthio)phenyl)pyridin-2-ylamino)phenyl)benzamide,
Figure imgf000044_0005
110. 5 -(3 -methoxyphenyl)-2-(3 -phenoxybenzyloxy)pyridine,
Figure imgf000044_0006
111. 5-(2-fluorophenyl)-2-(3-(pyridin-2-yl)propoxy)pyridine,
Figure imgf000044_0007
112. 5-(4-methoxyphenyl)-2-(3-(pyridin-2-yl)propoxy)pyridine,
Figure imgf000044_0008
113. N-(3-(trifluoromethoxy)phenyl)-5-(4-(trifluoromethyl)phenyl)pyridin-2-amine,
Figure imgf000045_0001
114. 3-(6-(4-(pyridin-2-yl)piperazin-l-yl)pyridin-3-yl)benzaldehyde,
Figure imgf000045_0002
115. 5 -(2-fluorophenyl)-2-(pyridin-2-ylmethoxy)pyridine,
Figure imgf000045_0003
116. 2-(3-(5-(3-formylphenyl)pyridin-2-ylamino)phenoxy)-N,N-dimethylacetamide,
Figure imgf000045_0004
117. Nl -(5 -(2-fluorophenyl)pyridin-2-yl)-N3 ,N3 -dimethylbenzene- 1 ,3 -diamine,
Figure imgf000045_0005
118. 5 -(benzo [d] [ 1 ,3 ] dioxol-5 -yl)-N-(3 -(trifluoromethyl)benzyl)pyridin-2-amine,
Figure imgf000045_0006
119. N-(3-(6-(p-tolylamino)pyridin-3-yl)phenyl)acetamide,
Figure imgf000045_0007
120. N-(3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)phenyl)acetamide,
Figure imgf000045_0008
121. 5 -phenyl-N-(3 -(trifluoromethyl)phenyl)pyridin-2-amine,
Figure imgf000046_0001
122. N-(4-(6-(3-(trifluoromethyl)phenylamino)pyridin-3-yl)phenyl)acetamide,
Figure imgf000046_0002
123. N-methyl-3-(6-(3-(Trifluoromethyl)phenylamino)pyridin-3-yl)benzamide,
Figure imgf000046_0003
124. 5 -(3 -(dimethylamino)phenyl)-N-(3 -(trifluoromethyl)phenyl)pyridin-2-amine,
Figure imgf000046_0004
125. 5-(naphthalen-2-yl)-N-(3-(trifluoromethyl)phenyl)pyridin-2-amine,
Figure imgf000046_0005
126. N-(3-(6-(phenylamino)pyridin-3-yl)phenyl)acetamide,
Figure imgf000046_0006
127. N-(3 -(6-(methyl(3 -(trifluoromethyl)pheny l)amino)pyridin-3 -yl)phenyl)acetamide,
Figure imgf000046_0007
128. N-(5 -(3 -acetamidophenyl)pyridin-2-yl)-3 -(trifluoromethyl)benzamide,
Figure imgf000046_0008
129. N-(3 -(6-(3 -(trifluoromethyl)phenylamino)pyridin-3 -yl)phenyl)isobutyramide,
Figure imgf000047_0001
130. 2,2,2-trifluoro-N-(3-(6-(3-(trifluoromethyl)phenylamino)pyridin-3- yl)phenyl)acetamide,
Figure imgf000047_0002
131. 6-(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)indolin-2-one,
Figure imgf000047_0003
132. N-(3-(6-(3-(trifluoromethoxy)phenylamino)pyridin-3-yl)phenyl)propionamide,
Figure imgf000047_0004
133. 5 -(2-methylbenzo [d]oxazol-5 -yl)-N-(3 -(trifluoromethoxy)phenyl)pyridin-2-amine,
Figure imgf000047_0005
134. N-(3-(6-(4-(trifluoromethoxy)phenylamino)pyridin-3-yl)phenyl)acetamide,
Figure imgf000047_0006
135. N-(3-(6-(2,2-difluorobenzo[d] [ 1 ,3]dioxol-5-ylamino)pyridin-3-yl)phenyl)acetamide,
Figure imgf000047_0007
136. N-(3-(6-(2,2-difluorobenzo[d] [ 1 ,3]dioxol-5-ylamino)pyridin-3-yl)phenyl)acetamide,
Figure imgf000047_0008
137. N-methyl-N-(3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)phenyl)acetamide,
Figure imgf000048_0001
138. 5 -(2-methylbenzo [d]thiazol-5 -yl)-N-(3 -(trifluoromethoxy)phenyl)pyridin-2-amine,
Figure imgf000048_0002
139. N-(6'-(3-(trifluoromethoxy)phenylamino)-2,3'-bipyridin-4-yl)acetamide,
Figure imgf000048_0003
140. 1 -(3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)phenyl)propan-2-one,
Figure imgf000048_0004
141. N-(5-(3-acetamidophenyl)pyridin-2-yl)-3-(trifluoromethoxy)benzamide,
Figure imgf000048_0005
142. N-(3-(6-(2-(trifluoromethoxy)phenylamino)pyridin-3-yl)phenyl)acetamide,
Figure imgf000048_0006
143. N-(4-(6-(3-(trifluoromethoxy)phenylamino)pyridin-3-yl)phenyl)acetamide,
Figure imgf000048_0007
144. N-(3 -(6-(3 -(trifluoromethoxy)phenylsulfonamido)pyridin-3 -yl)phenyl)acetamide,
Figure imgf000048_0008
145. 3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)benzamide,
Figure imgf000048_0009
146. N-methyl-3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)benzamide,
Figure imgf000049_0001
147. N-(3 -(6-(3 -(trifluoromethylsulfonyl)phenylamino)pyridin-3 -yl)phenyl)acetamide,
Figure imgf000049_0002
148. N-(2-(6-(3-(trifluoromethoxy)phenylamino)pyridin-3-yl)phenyl)acetamide,
Figure imgf000049_0003
149. N-(3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)phenyl)methanesulfonamide,
Figure imgf000049_0004
150. 1 -methyl-3 -(3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)phenyl)urea,
Figure imgf000049_0005
151. N-(3 -(2-(3 -(trifluoromethoxy)phenylamino)pyrimidin-5 -yl)phenyl)acetamide,
Figure imgf000049_0006
152. N-(3 -(5 -(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)phenyl)acetamide,
Figure imgf000049_0007
or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
[00102] Also provided herein is the use of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in the preparation of an agent for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. In one embodiment, provided herein is the use of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in the preparation of an agent for the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy. In one embodiment, provided herein is the use of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in the preparation of an agent for the treatment or prophylaxis of Duchenne muscular dystrophy.
C. Synthesis of the Compounds
[00103] In one embodiment, provided herein is a method of making a compound of formula (I). The compounds of formula (I) can be synthesized from commercially available starting materials using the following methods.
[00104] In one embodiment, compounds of formula (I) may be prepared by reacting a compound of formula (II):
Figure imgf000050_0001
(H) wherein Y, L1, R1, and R3 are as defined herein elsewhere, and X1 is a monovalent radical which may act as a leaving group, such as, e.g., halo, such as, bromo; with a compound of formula (III):
OH R-B
NOH
(HI) wherein R2 is as defined herein elsewhere; or a compound of formula (IV):
Figure imgf000050_0002
(IV) wherein R2 is as defined herein elsewhere.
[00105] In one embodiment, the reaction with a compound of formula (III) or formula (IV) may take place in the presence of l,l-bis(diphenylphosphino)ferrocene palladium (II) chloride complex in dichloromethane, and in the presence of a base, such as, e.g., potassium carbonate.
[00106] In one embodiment, compounds of formulae (III) and (IV) are known and are readily available or may be prepared by methods known to those of skill in the art.
[00107] In one embodiment, compounds of formula (II) in which L1 is -NR4- may be prepared by reacting a compound of formula (V):
Figure imgf000051_0001
(V) wherein Y and R3 are as defined herein elsewhere, X1 is as defined for formula (II), and X2 is a leaving group, such as, e.g., halo, such as, chloro; with a compound of formula (VI):
RJ-NR4H (VI) wherein R1 and R4 are as defined herein elsewhere.
[00108] In one embodiment, when Y is C, the reaction may be conducted at elevated temperature, such as, e.g., between 100 and 2000C. In one embodiment, such reaction is carried out in the absence of a solvent. In another embodiment, the reaction may be carried out at lower temperature, such as, e.g., 10-300C, such as, room temperature, under basic conditions, for example, in the presence of a base, such as, e.g., sodium hydride, and in an organic solvent, such as, e.g., Λ/,Λ/-dimethylformamide. In another embodiment, the reaction may be carried out under acidic conditions, such as, e.g., in hydrochloric acid, and in an organic solvent, such as, e.g., a mixture of dioxane and n-butanol. In some embodiments, the reaction under acidic conditions may be conducted at elevated temperature, such as, e.g., between 100 and 2000C.
[00109] In yet another embodiment, when Y is N, the reaction may be carried out in industrial methylated spirits (IMS) at a temperature of from about 120 to about 17O0C and with the use of microwave irradiation.
[00110] In one embodiment, compounds of formulae (V) and (VI) are known and are readily available or may be prepared by methods known to those of skill in the art. [00111] In one embodiment, compounds of formula (II) in which L1 is -NHC(O)- may be prepared by reacting a compound of formula (VII):
R^C(O)OH (VII) wherein R1 is as defined herein elsewhere, with a compound of formula (VIII):
Figure imgf000052_0001
(VIII) wherein Y and R3 is as defined herein elsewhere, and X1 is as defined for formula (II). [00112] In one embodiment, the reaction may be carried out in the presence of a coupling agent, such as, e.g., benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), and a base, such as, e.g., JV,jV-diisopropylethylamine (DIPEA). In one embodiment, the reaction is carried out in an organic solvent, such as, e.g., N,N- dimethy lformamide .
[00113] In one embodiment, compounds of formula (II) in which L1 is -NHSO2- may be prepared from compounds of formula (VIII) as defined herein elsewhere by reacting with compounds of formula (XI):
R^SO2Cl (XI) wherein R1 is as defined herein elsewhere.
[00114] In one embodiment, the reaction may be carried out under basic conditions, such as, e.g., in the presence of triethylamine, in an organic solvent such as, e.g., dichloromethane. [00115] Compounds of formulae (VII), (VIII), and (XI) are known and are readily available or may be prepared by methods known to those of skill in the art. [00116] In one embodiment, compounds of formula (I) may also be prepared by reacting a compound of formula (IX)
Figure imgf000052_0002
(IX) wherein R1, L1, R3, and Y are as defined herein elsewhere, and R12 is H or Ci-C6 alkyl, or the two R12 groups together with the B and O atoms form a heterocyclyl group, such as, e.g., a 5- or 6-membered heterocyclyl, which may be substituted with methyl groups, for example forming a tetramethyl dioxaborolanyl group; with a compound of formula (X):
R2-Br (X) wherein R2 is as defined herein elsewhere.
[00117] In one embodiment, the reaction may be carried out in the presence of a catalytic agent, such as tetrakis(triphenylphosphine) palladium, and in a solvent, such as, e.g., DMF. [00118] In one embodiment, compounds of formula (X) are known and are readily available or may be prepared by methods known to those of skill in the art.
[00119] In one embodiment, compounds of formula (IX) may be prepared by reacting a compound of formula (II) as defined herein with bis(pinacolato)diboron in the presence of, for example, dichlorobis(triphenylphosphine) palladium (II).
[00120] In one embodiment, compounds of formula (I) in which L1 is a bond, R1 is H, and
R3 is -L3-Rπ may be prepared from compounds of formula (XII):
(\ VR2
X3 (XII) wherein Y, L2 and R2 are as defined herein elsewhere, and X3 is a leaving group, such as, e.g., halo, such as, bromo, by methods analogous to those described for the preparation of other compounds of formula (I).
[00121] In one embodiment, compounds of formula (I) in which L1 is a bond, R1 is H, and R3 is -NH-R11 may be prepared by reacting a compound of formula (XII) as defined herein with a compound of formula (XIII):
R1 ^NH2 (XIII)
[00122] In one embodiment, the reaction may be carried out in the presence of a palladium compound, such as, e.g., palladium acetate, and a chelating agent, such as, e.g., Xantphos™, at elevated temperature, such as, e.g., 120 to 17O0C, and in an organic solvent, such as, e.g., dioxane.
[00123] In one embodiment, compounds of formula (XII) may be prepared from compounds of formula (XIV):
if V
X3
(XIV) wherein Y is defined herein elsewhere, X3 is as defined herein for formula (XII), and X4 is a leaving group, such as, e.g., halo, such as bromo; by the reaction with a compound of formula (III) or formula (IV) as defined herein.
[00124] In one embodiment, the reaction of a compound of formula (XIV) with a compound of formula (III) may take place in the presence of a palladium complex, and a base, such as, e.g., potassium carbonate, in an aqueous solvent. [00125] In the syntheses described herein, suitable protecting groups may be used, as understood by one of ordinary skills in the art. One skilled in the art would also be able to choose the appropriate protecting groups and the conditions to introduce and remove such protecting groups. Information concerning protecting groups is available, for example, in Theodora W. Greene and Peter G. M. Wuts, "Protecting Groups in Organic Synthesis", 4th Edition, Wiley Interscience, 2006.
D. Pharmaceutical Compositions
[00126] In one embodiment, the compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, is administered in the form of a pharmaceutical composition. In one embodiment, the compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia, is administered in the form of a pharmaceutical composition. In one embodiment, the compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in the treatment or prophylaxis of Duchenne muscular dystrophy, is administered in the form of a pharmaceutical composition.
[00127] Provided herein is a pharmaceutical composition comprising a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, and at least one pharmaceutically acceptable excipient or carrier. In one embodiment, provided herein is a pharmaceutical composition comprising a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, and a pharmaceutically acceptable excipient. [00128] In one embodiment, the pharmaceutical composition comprises less than about 80% w/w, less than about 50% w/w, less than about 20% w/w, or between about 0.1 and about 20% w/w, of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in admixture with at least one pharmaceutically acceptable excipient, diluent, or carrier.
[00129] In one embodiment, provided herein is a process for the production of a pharmaceutical composition provided herein, which comprises mixing the ingredients. [00130] In one embodiment, examples of pharmaceutical formulations or compositions, and suitable diluents or carriers, include, but are not limited to, the following: for intravenous injection or infusion — purified water or saline solution; for inhalation compositions — coarse lactose; for tablets, capsules, and dragees — microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin; and for suppositories — natural or hardened oils or waxes.
[00131] In one embodiment, the compound provided herein is used in aqueous solution, e.g., for intravenous infusion, the pharmaceutical composition containing the compound provided herein may further comprise one or more excipients. In certain embodiments, the excipients include, but are not limited to, chelating or sequestering agents, antioxidants, tonicity adjusting agents, pH-modifying agents, and buffering agents. [00132] In one embodiment, solutions containing a compound of formula (I) may, if desired, be evaporated, e.g., by freeze drying or spray drying, to give a solid composition, which may be reconstituted prior to use.
[00133] In one embodiment, the compound provided herein is not used in a solution. In one embodiment, the compound of formula (I) is in a form having a mass median diameter of from about 0.01 to about 10 μm. In certain embodiments, the pharmaceutical composition comprising the compound of formula (I) may further contain one or more preserving, stabilizing, and/or wetting agents, solubilisers, e.g., a water soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water soluble glycol such as propylene glycol, sweetening and/or coloring agents, and/or flavorings. In one embodiment, the compositions may be formulated in sustained release form.
[00134] In one embodiment, the pharmaceutical composition comprises a compound of formula (I) in between about 0.01% and about 99.9% w/w, relative to the entire preparation. In certain embodiments, the pharmaceutical composition comprises a compound of formula (I) in between about 0.1% and about 50% w/w, relative to the entire preparation. [00135] In one embodiment, provided herein is a pharmaceutical composition comprising a compound of formula (I), and at least one pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser.
[00136] In one embodiment, the pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabiliser is non-toxic and does not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be oral or by injection, such as cutaneous, subcutaneous, or intravenous injection. [00137] In one embodiment, the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers. The pharmaceutical compositions provided herein that are formulated for oral administration may be in tablet, capsule, powder, or liquid form. A tablet may comprise a solid carrier or an adjuvant. Liquid pharmaceutical compositions may comprise a liquid carrier, such as water, petroleum, animal or vegetable oils, or mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol may be included. A capsule may comprise a solid carrier such as gelatin. [00138] In another embodiment, the pharmaceutical compositions are provided in a dosage form for parenteral administration, and one or more pharmaceutically acceptable excipients or carriers. Where pharmaceutical compositions may be formulated for intravenous, cutaneous or subcutaneous injection, the active ingredient will be in the form of a parenterally acceptable aqueous solution, which is pyrogen-free and has a suitable pH, isotonicity, and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles, such as Sodium Chloride injection, Ringer's injection, or Lactated Ringer's injection. Preservatives, stabilisers, buffers, antioxidants, and/or other additives may be included as required.
[00139] In yet another embodiment, the pharmaceutical compositions are provided in a dosage form for topical administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.
[00140] In one embodiment, the pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (See, e.g., Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd Edition, Rathbone et al, Eds., Marcel Dekker, Inc.: New York, NY, 2008). [00141] In one embodiment, the pharmaceutical compositions provided herein can be provided in a unit-dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete a unit suitable for administration to a human and animal subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of a unit- dosage form include an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or gallons.
[00142] In one embodiment, the pharmaceutical compositions provided herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
[00143] In one embodiment, the pharmaceutical compositions provided herein further comprise one or more therapeutic agents for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. In one embodiment, the pharmaceutical compositions provided herein further comprise one or more therapeutic agents for the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy. In one embodiment, the pharmaceutical compositions provided herein further comprise one or more therapeutic agents for the treatment or prophylaxis of Duchenne muscular dystrophy.
[00144] In another embodiment, provided herein is the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. In one embodiment, provided herein is the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy. In one embodiment, provided herein is the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prophylaxis of Duchenne muscular dystrophy. In certain embodiments, the medicament is in tablet, capsule, powder, or liquid form. In certain embodiments, the medicament is formulated as described herein.
1. Oral Administration
[00145] The pharmaceutical compositions provided herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye -migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide. [00146] Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH- 103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The amount of a binder or filler in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein. [00147] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of a diluent in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
[00148] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation- exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross- linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; micro crystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof. The amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
[00149] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant. [00150] Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB- O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.
[00151] It should be understood that many carriers and excipients may serve several functions, even within the same formulation.
[00152] The pharmaceutical compositions provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets. [00153] The tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
[00154] The pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
[00155] The pharmaceutical compositions provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in- water or water-in- oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
[00156] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly- alkylene glycol, including, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates. [00157] The pharmaceutical compositions provided herein for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Patent No. 6,350,458. [00158] The pharmaceutical compositions provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non- effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide. [00159] Coloring and flavoring agents can be used in all of the dosage forms provided herein.
[00160] The pharmaceutical compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
2. Parenteral Administration
[00161] The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
[00162] The pharmaceutical compositions provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (See, Remington: The Science and Practice of Pharmacy, supra). [00163] The pharmaceutical compositions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
[00164] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N- methyl-2-pyrrolidone, NN-dimethylacetamide, and dimethyl sulfoxide. [00165] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propylparabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β- cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-β-cyclodextrin
(CAPTISOL®, CyDex, Lenexa, KS).
[00166] When the pharmaceutical compositions provided herein are formulated for multiple dosage administration, the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
[00167] In one embodiment, the pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use.
In yet another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile suspensions. In yet another embodiment, the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile emulsions.
[00168] The pharmaceutical compositions provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
[00169] The pharmaceutical compositions provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
[00170] Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
[00171] Suitable outer polymeric membranes include but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
3. Topical Administration
[00172] The pharmaceutical compositions provided herein can be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
[00173] The pharmaceutical compositions provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches. The topical formulation of the pharmaceutical compositions provided herein can also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.
[00174] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases. [00175] The pharmaceutical compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp., Emeryville, CA), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, OR).
[00176] The pharmaceutical compositions provided herein can be provided in the forms of ointments, creams, and gels. Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in- water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (See, Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollient but generally require addition of antioxidants and preservatives. [00177] Suitable cream base can be oil-in-water or water-in-oil. Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
[00178] Gels are semisolid, suspension-type systems. Single -phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
[00179] The pharmaceutical compositions provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.
[00180] Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid;. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g. [00181] The pharmaceutical compositions provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants. [00182] The pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2- tetrafluoroethane or 1,1, 1,2,3, 3,3-heptafluoropropane. The pharmaceutical compositions can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder can comprise a bioadhesive agent, including chitosan or cyclodextrin.
[00183] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein; a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
[00184] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. [00185] Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as /- leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.
[00186] The pharmaceutical compositions provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.
4. Modified Release
[00187] The pharmaceutical compositions provided herein can be formulated as a modified release dosage form. As used herein, the term "modified release" refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. The pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s).
[00188] Examples of modified release include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500.
(a) Matrix Controlled Release Devices
[00189] The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated using a matrix controlled release device known to those skilled in the art (See, Takada et αl. in "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz Ed., Wiley, 1999). [00190] In certain embodiments, the pharmaceutical compositions provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins. [00191] Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid- glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methyl methacrylate, ethyl methacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride .
[00192] In certain embodiments, the pharmaceutical compositions provided herein are formulated with a non-erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered. Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate -methyl methacrylate copolymers, ethylene- vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, and silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides. [00193] In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
[00194] The pharmaceutical compositions provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.
(b) Osmotic Controlled Release Devices
[00195] The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS). In general, such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semi-permeable membrane with at least one delivery port, which encapsulates the core. The semi-permeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
[00196] In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device. One class of osmotic agents is water- swellable hydrophilic polymers, which are also referred to as "osmopolymers" and "hydrogels." Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.
[00197] The other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffϊnose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.
[00198] Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form. For example, amorphous sugars, such as MANNOGEM EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
[00199] The core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
[00200] Materials useful in forming the semi-permeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water- permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in forming the coating, include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly- (methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes. [00201] Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Patent No. 5,798,119. Such hydrophobic but water- vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
[00202] The delivery port(s) on the semi-permeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220.
[00203] The total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semi-permeable membrane, the composition of the core, and the number, size, and position of the delivery ports. [00204] The pharmaceutical compositions in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
[00205] The osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (See, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 55, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).
[00206] In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, U.S. Patent No. 5,612,059 and WO 2002/17918. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
[00207] In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers.
(c) Multiparticulate Controlled Release Devices
[00208] The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm in diameter. Such multiparticulates can be made by the processes known to those skilled in the art, including wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, e.g., Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989. [00209] Other excipients or carriers as described herein can be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be further processed as a capsule or a tablet.
(d) Targeted Delivery
[00210] The pharmaceutical compositions provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Patent Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.
E. Methods of Use [00211] In one embodiment, provided herein are compounds that upregulate endogenous utrophin, and therefore, are useful in the treatment or prophylaxis of muscular dystrophy, including DMD, and other similar conditions.
[00212] In one embodiment, provided herein is a compound of formula (I) for use in medicine, for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
[00213] In one embodiment, provided herein is a method for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. In one embodiment, the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
[00214] In one embodiment, provided herein is a method for the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy. In one embodiment, the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
[00215] In one embodiment, provided herein is a method for the treatment or prophylaxis of Duchenne muscular dystrophy. In one embodiment, the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof. [00216] In one embodiment, the dose of the compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, is determined with consideration of age, body weight, general health condition, diet, administration time, administration method, clearance rate, combination of drugs, the level of disease for which the patient is under treatment for, and other factors. In one embodiment, the dose varies depending on the target disease, condition, subject of administration, administration method, and the like.
[00217] In one embodiment, the pharmaceutical composition comprising a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, is administered orally as a therapeutic agent for the treatment or prophylaxis of Duchenne muscular dystrophy in a patient suffering from such a disease. In one embodiment, from about 0.01 mg to about 1O g of the compound is administered. In another embodiment, from about 0.1 mg to about 100 mg of the compound is administered. In one embodiment, the compound is administered in a single dose per day. In another embodiment, the compound is administered in 2 or 3 portions per day. [00218] In one embodiment, provided herein is a method of treating, preventing, and/or managing a disorder or symptoms related to Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
[00219] In one embodiment, provided herein is a method of treating, preventing, and/or managing a disorder or symptoms related to Duchenne muscular dystrophy or Becker muscular dystrophy, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
[00220] In one embodiment, provided herein is a method of treating, preventing, and/or managing Duchenne muscular dystrophy. In another embodiment, provided herein is a method of treating, preventing, and/or managing Becker muscular dystrophy. In another embodiment, provided herein is a method of treating, preventing, and/or managing cachexia. [00221] In one embodiment, provided herein is the use of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in the manufacturing of a medicament for the treatment, prevention, and/or management of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. In one embodiment, provided herein is the use of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in the manufacturing of a medicament for the treatment, prevention, and/or management of Duchenne muscular dystrophy or Becker muscular dystrophy. In one embodiment, provided herein is the use of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in the manufacturing of a medicament for the treatment, prevention, and/or management of Duchenne muscular dystrophy. In another embodiment, provided herein is the use of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in the manufacturing of a medicament for the treatment, prevention, and/or management of Becker muscular dystrophy. In another embodiment, provided herein is the use of a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in the manufacturing of a medicament for the treatment, prevention, and/or management of cachexia. [00222] In one embodiment, the method comprises administering to a subject (e.g., a human) a therapeutically or prophylactically effective amount of a composition of a compound of formula (I). In one embodiment, the subject is a human. In another embodiment, the subject is a mammal. In yet another embodiment, the subject is a non- human primate, a farm animal, such as cattle, a sport animal, or a pet such as a horse, dog, or cat.
[00223] In some embodiments, compound activity can be assessed by functional assays described herein elsewhere. In certain embodiments, the efficacious concentration of the compounds provided herein is less than about 0.1 nM, less than about 1 nM, less than about 10 nM, less than about 100 nM, less than about 1 μM, less than about 10 μM, less than about 100 μM, or less than about 1 mM. In other embodiments, compounds' activity may be assessed in various art-recognized animal models as described herein elsewhere. [00224] In some embodiments, the compounds provided herein are active in at least one model, which can be used to measure the activity of the compounds and estimate their efficacy in treating Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. For example, when the model is for Duchenne muscular dystrophy, the compounds are active in, for example, the mdx mouse model, when compared to the effect of a vehicle. In some embodiments, the compounds provided herein are active in a dose-dependent manner. [00225] In one embodiment, depending on the disorder, disease, or condition to be treated, and the subject's condition, the compounds or pharmaceutical compositions provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration, and can be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration. Also provided is administration of the compounds or pharmaceutical compositions provided herein in a depot formulation, in which the active ingredient is released over a predefined time period.
[00226] In one embodiment, in the treatment, prevention, and/or management of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level generally is ranging from about 0.001 to about 1000 mg per kg subject body weight per day (mg/kg per day), from about 0.001 to about 300 mg/kg per day, from about 0.001 to about 100 mg/kg per day, from about 0.01 to about 75 mg/kg per day, from about 0.1 to about 50 mg/kg per day, from about 0.5 to about 25 mg/kg per day, from about 1 to about 20 mg/kg per day, from about 0.01 to about 1000 mg/kg per day, from about 0.1 to about 1000 mg/kg per day, from about 1 to about 1000 mg/kg per day, from about 10 to about 1000 mg/kg per day, from about 100 to about 1000 mg/kg per day, or from about 100 to about 300 mg/kg per day, which can be administered in single or multiple doses per day. Within this range, the dosage can be ranging from about 0.005 to about 0.05, from about 0.05 to about 0.5, from about 0.5 to about 5.0, from about 1 to about 15, from about 1 to about 20, from about 1 to about 50, from about 5 to about 50, from about 10 to about 100, from about 20 to about 200, from about 30 to about 300, or from about 50 to about 500 mg/kg per day. [00227] In one embodiment, in the treatment, prevention, and/or management of one or more symptoms of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia, an appropriate dosage level is less than about 0.001 mg/kg per day, less than about 0.01 mg/kg per day, less than about 0.1 mg/kg per day, less than about 0.5 mg/kg per day, less than about 1 mg/kg per day, less than about 5 mg/kg per day, less than about 10 mg/kg per day, less than about 15 mg/kg per day, less than about 20 mg/kg per day, less than about 25 mg/kg per day, less than about 50 mg/kg per day, less than about 75 mg/kg per day, less than about 100 mg/kg per day, less than about 200 mg/kg per day, less than about 500 mg/kg per day, less than about 1 g/kg per day, less than about 3 g/kg per day, less than about 5 g/kg per day, or less than about 10 g/kg per day.
[00228] In one embodiment, for oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets containing from about 1.0 to about 1,000 mg of the active ingredient, in one embodiment, about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, or about 1,000 mg, of the active ingredient, for the symptomatic adjustment of the dosage to the patient to be treated. In one embodiment, the pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day. [00229] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy, which may be determined by a physician treating the particular patient. [00230] In one embodiment, the compounds provided herein, e.g., a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can be combined or used in combination with other agents or therapies useful in the treatment, prevention, and/or management of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia. Suitable other therapeutic agents include, but are not limited to, corticosteroids, such as, e.g., prednisone and deflazacort. In certain embodiments, other therapies that may be used in combination with the compounds provided herein include, but are not limited to, physical therapy, gene therapy, and/or orthopedic appliances, such as, e.g., braces and wheelchairs.
[00231] In one embodiment, such other agents or drugs, can be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with the compounds provided herein, or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof. When a compound provided herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound provided herein can be utilized, but is not required. Accordingly, the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound provided herein.
[00232] In one embodiment, the weight ratio of a compound provided herein to the second active ingredient can be varied, and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound provided herein is combined with a corticosteroid, the weight ratio of the compound provided herein to the corticosteroid can range from about 1 ,000: 1 to about 1 : 1 ,000, from about 200: 1 to about 1 :200, from about 100:1 to about 1 :100, from about 10:1 to about 1 :10, from about 5:1 to about 1 :5, or from about 2:1 to about 1 :2. In one embodiment, combinations of a compound provided herein and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
[00233] In one embodiment, the compounds provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Patent Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. [00234] In one embodiment, provided herein are also kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a compound provided herein.
[00235] In certain embodiments, the kit includes a container comprising a dosage form of the compound provided herein, or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, in a container comprising one or more other therapeutic agent(s) described herein.
[00236] In one embodiment, kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle-less injectors drip bags, patches, and inhalers.
[00237] In one embodiment, kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to, aqueous vehicles, including but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
EXAMPLES
[00238] Certain embodiments are illustrated by the following non-limiting examples. [00239] HPLC-UV-MS was performed on a Gilson 321 HPLC with detection performed by a Gilson 170 DAD and a Finnigan AQA mass spectrometer operating in electrospray ionization mode. The HPLC column used is a Phenomenex Gemini Cl 8 150x4.6 mm. Preparative HPLC was performed on a Gilson 321 with detection performed by a Gilson 170 DAD. Fractions were collected using a Gilson 215 fraction collector or a Dionex Ultimate 3000 system. The preparative HPLC column used is a Phenomenex Gemini Cl 8 15 Ox 10mm and the mobile phase is acetonitrile/water. [00240] 1H NMR spectra were recorded on a Bruker instrument operating at 300 MHz. NMR spectra were obtained in CDCI3 or DMSO-dβ solutions (reported in ppm), using deuterated chloroform (7.25 ppm) or DMSO-dβ (2.50 ppm) as the reference standard. When peak multiplicities were reported, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets). Coupling constants, when given, are reported in Hertz (Hz). [00241] Column chromatography was performed either by flash chromatography (40-65 μm silica gel) or using an automated purification system (SP 1™ Purification System from Biotage® or an ISCO Companion). Reactions in the microwave were done in an Initiator 8™ (Biotage®) or in an Explorer 48 (CEM).
[00242] The abbreviations used are: DCM (dichloromethane), DIPEA (N,N- diisopropylethylamine), DMF (N,N-dimethylformamide), DMSO (dimethylsulfoxide), EtOAc (ethyl acetate), HATU (O-(7-azabenzotriazol-lyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HCl (hydrochloric acid), MgSO4 (magnesium sulfate), NaOH (sodium hydroxide), Na2CO3 (sodium carbonate), NaHCO3 (sodium bicarbonate), NH4Cl (ammonium chloride), PyBOP ((benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate), BOP (benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), THF (tetrahydrofuran).
Example 1
Synthesis ofN-(3-(6-(p-Tolylamino)pyridin-3-yl)phenyl)acetamide (Compound 119)
5-Bromo-N-p-tolylpyridine-2-amine
[00243] 5-Bromo-2-chloropyridine (1.79g, 9.3mmol) and/?-toluidine (1.0Og, 9.3mmol) were stirred together neat in a sealed tube at 1700C for six hours. The mixture was cooled, diluted with methanol, partitioned between EtOAc and sat. NaOH(aq) solution, the organic phase washed with H2O (2x), the aqueous phase extracted with EtOAc (Ix) and the combined organic phases dried over MgSO4 and concentrated. The residue was purified by column chromatography eluting using a gradient (EtO Ac/petroleum ether 1 :4 v/v) to afford 1.71mg (72%) of the title compound. LCMS RT= 10.73min, MH+= 263.3. 1H NMR (d6-DMSO): 9.08 (IH, s), 8.17 (IH, d, J2.6), 7.68 (IH, dd, J2.6, 8.9), 7.48 (2H, d, J 8.5), 7.07 (2H, d, J 8.1), 6.76 (IH, d, J 8.9), 2.23 (3H, s).
N-(3-(6-(p-Tolylamino)pyridin-3-yl)phenyl)acetamide [00244] A solution of 5-bromo-Λ/-/?-tolylpyridine-2-amine (0.8Og, 3.1mmol), 3- acetamidophenylboronic acid (1.1 Ig, 6.2mmol), 1,1 -Bis(diphenylphosphino)ferrocene palladium(II) chloride, complex with DCM (0.06g, O.βmmol), and potassium carbonate (1.61g, 15.5mmol) dissolved in DME (15mL) and H2O (ImL) were heated using microwave irradiation at 1300C for 10 minutes. The reaction mixture was partitioned between EtOAc and sat. NH4Cl(aq) solution, the organic phase washed with H2O (2x), the aqueous phase extracted with EtOAc (Ix) and the combined organic phases dried over MgSO4 and concentrated. The residue was purified by column chromatography eluting using a gradient (EtOAc/hexanes 1 :3 v/v to EtOAc/hexanes 4:1 v/v) to afford 61mg (62%) of the title compound. LCMS RT= 4.57min, MH+= 318.2. 1U NMR (d6-DMSO): 10.01 (IH, s), 9.06 (IH, s), 8.39 (IH, d, J2.3), 7.83 (IH, s), 7.78 (IH, dd, J2.1, 9.7), 7.58 (2H, d, J 8.4), 7.51 (IH, d, J 7.9), 7.33 (2H, m), 7.09 (2H, d, J 7.9), 6.89 (IH, d, J 11.3), 2.25 (3H, s), 2.07 (3H, s).
[00245] The following compounds were prepared according to the same general method using appropriate starting materials.
N- β -(6-(3 -(Trifluoromethyl)phenylamino)pyridin-3 -yl)phenyl)acetamide (Compound 74) [00246] The title compound was prepared according to the general protocol to afford 172mg (16%). LCMS RT= 6.34min, MH+= 372.3. 1H NMR (d6-DMSO): 10.03 (IH, s), 9.59 (IH, s), 8.48 (IH, d, J3.2), 8.26 (IH, s), 7.94 (IH, d, J 13.4), 7.86 (2H, m), 7.49 (2H, m), 7.38 (IH, d, J6.0), 7.31 (IH, m), 7.21 (IH, d, J7.5), 6.97 (IH, d, J 10.4), 2.07 (3H, s).
Λ/-(3-(6-(3-(Trifluoromethoxy)phenylamino)pyridin-3-yl)phenyl)acetamide (Compound 120) [00247] The title compound was prepared according to the general protocol to afford 330mg (26%). LCMS RT= 6.26min, MH+= 388.3. 1H NMR (d6-DMSO): 10.02 (IH, s), 9.54 (IH, s), 8.47 (IH, d, J2.3), 8.00 (IH, s), 7.87 (2H, m), 7.60 (IH, dd, J 1.2, 8.3), 7.52 (IH, dt, J 1.7, 7.7), 7.35 (3H, m), 6.96 (IH, d, J 8.3), 6.85 (IH, dt, J 1.1, 8.3), 2.07 (3H, s).
A/-(3-(6-(2-(Pyridin-2-yl)ethylamino)pyridin-3-yl)phenyl)acetamide (Compound 103) [00248] The title compound was prepared according to the general protocol to afford 61mg (5%). LCMS RT= 3.92min, MH+= 333.2. 1H NMR (d6-DMSO): 9.98 (IH, s), 8.52 (IH, dd, J0.8, 4.8), 8.24 (IH, d, J2.3), 7.76 (IH, br t), 7.72 (IH, td, J 1.8, 7.7), 7.64 (IH, dd, J2.5, 8.8), 7.48 (IH, d, J 1.9), 7.32 (2H, t, J7.8), 7.24 (2H, br t, J7.5), 6.88 (IH, br), 6.58 (IH, d, J 8.7), 3.65 (2H, t, J7.1), 3.02 (2H, t, J 7.4), 2.05 (3H, s).
N-Q -(6-(Phenylamino)pyridin-3 -vDphenvDacetamide (Compound 126) [00249] The title compound was prepared according to the general protocol to afford 110mg (9%). LCMS RT= 4.55min, MH+= 304.2. 1H NMR (d6-DMSO): 10.02 (IH, s), 9.18 (IH, s), 8.41 (IH, d, J2.3), 7.84 (lH, br t), 7.80 (IH, dd, J2.6, 8.7), 8.5 (2H, dd, J l.l, 8.7), 7.52 (IH, d, J 8.1), 7.36 (IH, t, J 7.7), 7.28 (2H, t, J 7.4), 6.92 (2H, m), 2.07 (3H, s).
5 -Phenyl-Λ/-(3 -(trifluoromethyl)phenyl)pyridin-2-amine (Compound 121) [00250] LCMS RT= 7.71min, MH+ 315.2. 1H NMR (d6-DMSO): 9.57 (IH, s), 8.57 (IH, d, J2.4), 8.28 (IH, s), 7.98-7.91 (2H, m), 7.70-7.67 (2H, m), 7.53-7.43 (3H, m), 7.36-7.31 (IH, m), 7.21 (IH, d, J7.7), 6.97 (IH, d, J8.7).
N-(4-(6-(3 -(Trifluoromethyl)phenylamino)pyridin-3 -vDphenvDacetamide (Compound 122) [00251] LCMS RT= 6.01min, MH+ 372.1. 1H NMR (d6-DMSO): 10.01 (IH, s), 9.53 (IH, s), 8.54 (IH, d, J2.46), 8.27 (IH, s), 7.95-7.90 (2H, m), 7.65 (2H, d, J8.88), 7.60 (2H, d, J 8.88), 7.49 (IH, t, J 8.03), 7.20 (IH, ά, J 1.11), 6.94 (IH, d, J 8.70), 2.06 (3H, s).
Λ/-Methyl-3-(6-(3-(trifluoromethyl)phenylamino)pyridin-3-vDbenzamide (Compound 123) [00252] LCMS RT= 6.09min, MH+ 372.1. 1U NMR (d6-DMSO): 9.62 (IH, s), 8.65 (IH, d, J2.4), 8.55 (IH, bd, J4.5), 8.36 (IH, s), 8.13 (IH, s), 8.03 (IH, dd, J 8.67 2.6), 7.90-7.78 (3H, m), 7.56-7.48 (2H, m), 7.22 (IH, d, J7.8), 6.99 (IH, d, J 8.7), 2.82 (3H, d, J4.5).
5 -(3 -(Dimethylamino)phenvD-Λ/-(3 -(trifluoromethvDphenyl)pyridin-2-amine (Compound
124}
[00253] LCMS RT= 7.19min, MH+ 358.2. 1H NMR (d6-DMSO): 9.54 (IH, s), 8.55 (IH, d, J2.4), 8.31 (IH, br s), 7.96-7.89 (2H, m), 7.52-7.46 (IH, m), 7.27-7.19 (2H, m), 6.96-6.91
(3H, m), 6.72-6.69 (IH, m), 2.96 (6H, s).
5-(Naphthalen-2-yD-Λ/-(3-(trifluoromethyDphenyDpyridin-2-amine (Compound 125) [00254] LCMS RT= 8.74min, MH+ 365.1. 1H NMR (d6-DMSO): 9.63 (IH, s), 8.74 (IH, d, J2.4), 8.34 (IH, s), 8.24 (IH, s), 8.12 (IH, dd, J 8.7, 2.6), 8.02-7.86 (5H, m), 7.57-7.48 (3H, m), 7.22 (IH, d, J 7.6), 7.01 (IH, d, J 8.7). N-(3 -(6-(3 -(Trifluoromethyl)phenylamino)pyridin-3 -yl)phenyl)isobutyramide (Compound
129}
[00255] The title compound was prepared according to the general protocol to afford
106mg (28%). LCMS RT= 4.05min, MH+ 400.1. 1H NMR (d6-DMSO): 9.90 (IH, s), 9.58
(IH, s), 8.49 (IH, d, J2.3), 8.27 (IH, s), 7.89 (3H, m), 7.55 (IH, m), 7.49 (IH, dd, J 7.9),
7.34 (2H, m), 7.21 (IH, A, J IT), 6.97 (IH, d, J 8.4), 2.61 (IH, septet, J 6.8), 1.12 (6H, d, J
6.8).
2,2,2-Trifluoro-Λ/-(3-(6-(3-(trifluoromethyl)phenylamino)pyridin-3-yl)phenyl)acetamide (Compound 130)
[00256] The title compound was prepared according to the general protocol to afford 33mg (8%). LCMS RT= 2.70min, MH+ 426.0. 1H NMR (d6-DMSO): 11.33 (IH, s), 9.62 (IH, s), 8.54 (IH, d, J2.3), 8.28 (IH, s), 7.93 (3H, m), 7.63 (IH, dt, J 1.9, 7.9), 7.52 (3H, m), 7.22 (IH, d, J7.8), 6.98 (IH, d, J8.7).
Example 2 - Preparation of A/-(3-(6-(Methyl(3-(trifluoromethyl)phenyl)amino) pyridin-3- yDphenyPacetamide (Compound 127)
Step 1 - Preparation of 5-Bromo-A/-methyl-N-(3-(trifluoromethyl)phenyl) pyridin-2-amine [00257] To a solution of LHMDS (0.79g 4.7mmol) in dry DMSO was added dropwise a solution of 5-bromo-Λ/-/?-tolylpyridine-2-amine (0.5Og, 1.6mmol) 3 in dry DMSO. The solution was stirred at room temperature for 3 hours before methyl iodide (0.25g, 1.7mmol) was added slowly. The solution was stirred at room temperature overnight. The solution was poured carefully into water, and diluted with DCM. The organic layer was then washed with IM NaOH solution (2x) and water (2x) before being dried (MgSO4) and concentrated. The residue was purified by column chromatography eluting using a gradient (EtOAc/hexanes 1 :9 v/v) to afford 330mg (63%) of the title compound. LCMS RT= 10.8 lmin, MH+ 332.5. 1U NMR (d6-DMSO): 8.17 (IH, dd, J0.4, 2.5), 7.61 (IH, dd, J2.6, 9.0), 7.58 (IH, m), 7.55 (2H, m), 7.48 (IH, m), 6.59 (IH, dd, J 0.4, 9.0), 3.34 (3H, s).
Step 2 - Preparation of A/-(3-(6-(Methyl(3-(trifluoromethyl)phenyl)amino) pyridin-3- yl)phenyl)acetamide (Compound 127) [00258] The title compound was prepared according to the general protocol set out in Example 1 to afford 64mg (16%). LCMS RT= 5.53min, MH+ 386.1. 1U NMR (d6-DMSO): 10.02 (IH, s), 8.43 (IH, d, J2.2), 7.83 (IH, br t), 7.80 (IH, dd, J2.5, 8.9), 7.67 (IH, br), 7.65 (2H, m), 7.54 (2H, m), 7.36 (IH, t, J7.8), 7.29 (IH, d, J7.8), 6.84 (IH, d, J 8.8), 3.49 (3H, s), 2.06 (3H, s).
[00259] The general protocol described for Example 1 was modified in order to prepare the following compounds:
Example 3 - Preparation of A/-(2-(6-(3-(Trifluoromethoxy)phenylamino) pyridin-3- vDphenvDacetamide (Compound 148)
[00260] The title compound was prepared using a method similar to that of Example 1. [00261] 5-Bromo-Λ/-(3-(trifluoromethoxy)phenyl)pyridin-2-amine (300mg, 0.90mmol), 2- acetamidophenylboronic acid pinacol ester (258mg, 0.99mmol), Pd(dppf)Cl2.DCM (37mg, 0.045mmol), potassium carbonate (622mg, 4.5mmol), dimethoxyethane (6ml) and water (1.5ml) combined heated at 13O0C, under microwave activation, for 20mins. The reaction mixture was partitioned between EtOAc (150ml) and sat. NH4Cl solution (150ml). The organic layer was washed with sat. brine (150ml), dried (MgSO4) and concentrated in vacuo. The crude product was absorbed onto silica, purified by column chromatography (0-60% EtO Ac/petrol) to give the title compound as an off-white solid (223mg, 64%). LCMS RT= 1.99, MH+= 388.3. 1H NMR (d6-DMSO): 9.51 (IH, s), 9.31 (IH, br s), 8.21 (IH, s), 7.99 (IH, s), 7.65-7.58 (2H, m), 7.48 (IH, d, J 7.6), 7.42-7.24 (4H, m), 6.92 (IH, d, J 8.9), 6.85 (IH, d, J 7.9), 1.92 (3H, s).
[00262] The following compound was made using the same general protocol but with appropriate starting materials and using 4-acetamidophenylboronic acid in place of the equivalent pinacol ester.
Λ/-(4-(6-(3-(Trifluoromethoxy)phenylamino)pyridin-3-yl)phenyl)acetamide (Compound 143) [00263] The title compound was isolated as a pink solid (134mg, 38%). LCMS RT = 2.00, MH+=388.3. 1H NMR (d6-DMSO): 9.99 (IH, s), 9.47 (IH, s), 8.52 (1 H, d, J2.5), 7.99 (IH, br s), 7.92 (IH, dd, J 8.6 & 2.4), 7.69-7.56 (5H, m), 7.33 (IH, t, J8.1), 6.93 (IH, d, J 8.1), 6.83 (IH, d, J 8.1), 2.06 (3H, s). Compounds prepared using procedure described for Example 1 or modified protocols (Methods A-C below):
Figure imgf000085_0001
method A neat, 170°C, 3h
B: NaH, DMF, rt, 18h C: 4M HCI, dioxaπe, n-BuOH 1700C, MW, 30min
Figure imgf000085_0002
Λ/-(3-(6-(4-(Trifluoromethoxy)phenylamino)pyridin-3-yl)phenyl)acetamide (Compound 134) [00264] LCMS RT= 1.91min, MH+= 388.3. 1U NMR (d6-DMSO): 10.01 (IH, s), 9.40 (IH, s), 8.42 (IH, d, J2.3), 7.84-7.80 (4H, m), 7.51 (IH, d, J7.9), 7.39-7.26 (4H, m), 6.94 (IH, d, J 8.6), 2.06 (3H, s).
Λ/-(3-(6-(2,2-Difluorobenzordiri,31dioxol-5-ylamino)pyridin-3-yl)phenyl) acetamide (Compound 135)
[00265] LCMS RT= 1.84min, MH+= 384.3. 1U NMR (d6-DMSO): 10.02 (IH, s), 9.52 (IH, s), 8.40 (IH, s), 8.01 (IH, s), 7.86 (2H, m), 7.51 (IH, d, J7.5), 7.39-7.31 (4H, m), 6.94 (IH, d, J6.1), 2.06 (3H, s). Λ/-(3-(6-(2-(Trifluoromethoxy)phenylamino)pyridin-3-yl)phenyl)acetamide (Compound 142) [00266] 2-Trifluoromethoxyaniline (0.8Og, 5.0mmol) and sodium hydride (60% dispersion in mineral oil, 1.7eq) were stirred in dry DMF at room temperature for 2 hours, and 5-bromo- 2-chloropyridine (1.0Og, 5.0mmol) was added and the mixture stirred at room temperature overnight. Iced water was added slowly to the mixture, and the mixture was extracted with DCM (3x). The DCM was washed with 2M HCl solution (2x), dried (MgSO4), and concentrated. The residue was purified by column chromatography eluting using a gradient (EtOAc/hexanes 1 :9 v/v).
[00267] The general protocol (described in Example 1) was then used to afford 54mg (6%) of the title compound. LCMS RT= 1.86min, MH+= 388.2. 1U NMR (d6-DMSO): 10.01 (IH, s), 8.80 (IH, s), 8.38 (IH, d, J2.4), 8.23 (IH, dd, J 8.2, 1.4), 7.86-7.82 (2H, m), 7.53 (IH, d, J 8.0), 7.39-7.28 (4H, m), 7.12 (IH, d, J 8.6), 7.06 (IH, dd, J7.7, 1.6), 2.04 (3H, s).
N-(3 -(6-(3 -(Trifluoromethylsulfonyl)phenylamino)pyridin-3 -yPphenyl) acetamide (Compound 147)
[00268] The title compound was then prepared according to Method C in 28% yield (97mg). LCMS RT= 2.11min, MH+= 436.2. 1H NMR (d6-DMSO): 10.00 (IH, s), 9.89 (IH, s), 8.69 (IH, s), 8.50 (IH, s), 8.25 (IH, d, J7.9), 7.91 (2H, m), 7.74 (IH, t, J8.0), 7.59 (IH, d, J7.9), 7.53 (IH, d, J7.2), 7.38 (2H, m), 7.01 (IH, d, J8.6), 2.07 (3H, s).
[00269] Other compounds were prepared by analogous methods using appropriate starting materials.
A/-Methyl-3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -vQbenzamide (Compound 146) [00270] The general protocol described for Example 1 was used to afford 171mg of the title compound (49%, stage 2). LCMS RT= 2.05min, MH+= 388.3. 1U NMR (d6-DMSO): 9.40 (IH, s), 8.62 (IH, d, J2.3), 8.39 (IH, s), 8.11 (IH, t, J 1.6), 8.01 (IH, d, J2.6), 7.98 (IH, d, J2.6), 7.82-7.78 (2H, m), 7.60 (IH, dd, J 8.3, 1.3), 7.53 (IH, t, J7.7), 7.38 (IH, t, J 8.2), 6.99 (IH, d, J 8.3), 6.84 (IH, tt, J 8.1, 1.1), 2.84 (3H, d, J4.6).
3-(6-(3-(Trifluoromethoxy)phenylamino)pyridin-3-yl)benzamide (Compound 145)
[00271] The general protocol described for Example 1 was used to afford 41mg of the title compound (12%). LCMS RT= 2.05min, MH+= 388.3. 1H NMR (d6-DMSO): 9.55 (IH, s), 8.63 (IH, d, J2.4), 8.16 (IH, s), 8.04 (2H, m), 8.00 (IH, d, J2.5), 7.83 (2H, dd, J7.8, 1.5), 7.60-7.50 (2H, m), 7.38 (2H, m), 6.97 (IH, d, J 8.8), 6.85 (IH, d, J 7.2).
N-(3 -(6-(3 -(Trifluoromethoxy)phenylamino)pyridin-3 -vOphenyl) methanesulfonamide (Compound 149)
[00272] The general protocol described for Example 1 was used to afford 35mg of the title compound (6%). LCMS RT= 2.13min, MH+= 424.1. 1H NMR (d6-DMSO): 9.84 (IH, s), 9.57 (IH, s), 8.50 (IH, d, J2.4), 8.01 (IH, s), 7.89 (IH, dd, J2.6, 11.3), 7.60 (IH, dd, J 1.2, 8.3), 7.44-7.35 (4H, m), 7.18 (IH, m), 6.97 (IH, d, J 8.7), 6.86 (IH, d, 7.1), 2.98 (3H, s).
Example 4 - Synthesis of A/-(5-(3-acetamidophenyl)pyridin-2-yl)-3-(trifluoromethyl) benzamide (Compound 128) Step 1
N-(5 -Bromopyridin-2-yl)-3 -(trifluoromethyl)benzamide
[00273] To a stirred solution of 5-bromopyridin-2-amine (1.09g, 6.3mmol) and DIPEA (0.68g, 15.8mmol) in dry DMF was added a solution of 3-(trifluoromethyl)benzoic acid (1.0Og, 5.3mmol) and PyBOP (3.28g, 6.3mmol). The solution was stirred at room temperature overnight. The solution was poured carefully into water, and diluted with DCM. The organic layer was washed with IM NaOH solution (2x) and water (2x) before being dried (MgSO4) and concentrated. The residue was purified by column chromatography eluting using EtOAc/hexanes 1 :9 v/v) to afford 1.12g (62%) of the title compound. LCMS RT= 6.69min, MH+ 345.0. 1H NMR (d6-DMSO): 8.81 (IH, s), 8.28 (2H, m), 8.14 (IH, s), 8.05 (IH, d, J7.9), 7.83 (IH, dd, J2.3, 9.0), 7.78 (IH, d, J7.8), 7.59 (IH, t, J7.8).
Step 2
A/-(5-(3-Acetamidophenyl)pyridin-2-yl)-3-(trifluoromethyl)benzamide (Compound 128) [00274] The title compound was prepared according to the general protocol of Example 1 to afford 880mg (32%). LCMS RT= 6.05min, MH+ 400.0. 1U NMR (d6-DMSO): 11.10 (IH, s), 9.91 (IH, s), 8.65 (IH, d, J 1.9), 8.41 (IH, s), 8.34 (IH, d, J 8.0), 8.30 (IH, d, J 8.7), 8.09 (IH, dd, J2.5, 8.6), 7.96 (IH, d, J7.9), 7.92 (IH, m), 7.78 (IH, t, J7.9), 7.61 (IH, m), 7.40 (2H, m), 2.08 (3H, s).
Example 5 - Preparation of A/-(3-(6-(3-(trifluoromethoxy)phenylamino) pyridin-3- yl)phenyl)propionamide (Compound 132) Step l
Λ/-(3-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propionamide [00275] 3-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.0 g, 4.56 mmol), propanoic acid (363 μL, 4.56 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (708 mg, 4.56 mmol) and water (20 mL) were combined and the mixture stirred at O0C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with diethyl ether (80 mL). The aqueous layer was re-extracted with diethyl ether (50 mL) and the organic extracts combined, dried over MgSO4, and concentrated in vacuo to give an orange oil (0.94 g). Column chromatography (0:1 - 1 :2 EtOAc: petroleum ether gradient) gave the title compound as a white solid (231 mg, 18%). LCMS RT = 2.00 min, MH+ 276.4. 1H NMR (d6-DMSO): 9.85 (IH, s), 7.91 (IH, s), 7.71-7.76 (IH, m), 7.26-7.33 (2H, m), 2.30 (2H, q, J 7.6), 1.07 (3H, t, J 7.6).
Step 2
N-(3 -(6-(3 -(Trifluoromethoxy)phenylamino)pyridin-3 -vDphenvDpropionamide (Compound 132}
[00276] 5-Bromo-N-(3-(trifluoromethoxy)phenyl)pyridin-2-amine (202mg, 0.61mmol), N- (3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)propionamide (200mg, 0.73mmol), 1,1' Bis(diphenylphosphino)ferrocene palladium (II) chloride, complex with DCM (99mg, 0.12 mmol), potassium carbonate (418 mg, 3.03 mmol) and DMEZH2O (4:1, 5 mL) were combined and heated with stirring, under microwave activation, at 13O0C for 15 minutes. The reaction mixture was partitioned between EtOAc (250 mL) and water (150 mL). The aqueous layer was re-extracted with EtOAc (100 mL) and the organic extracts combined, dried over MgSO4 and concentrated in vacuo to give a black residue (400 mg). Column chromatography (0:1 - 3:1 EtOAc: petroleum ether gradient) gave the title compound as an off-white solid (64 mg, 26%). LCMS RT = 2.25 min, MH+ 402.3. 1U NMR (d6-DMSO): 10.00 (IH, s), 9.60 (IH, s), 8.53 (IH, d, J2.5), 8.06 (IH, s), 7.91-7.97 (2H, m), 7.58-7.67 (2H, m), 7.36-7.47 (3H, m), 7.02 (IH, d, J 8.7), 6.89-6.92 (IH, m), 2.40 (2H, q, J 7.6), 1.16 (3H, t, J7.6).
Example 6 - Preparation of 6-(6-(3-(trifluoromethoxy)phenylamino)pyridin-3-yl)indolin-2- one (Compound 131)
Step l 5 -Bromo-Λ/-(3 -(trifluoromethoxy)phenyl)pyridin-2-amine
[00277] In two sealed tubes, 3-(trifluoromethoxy)aniline (1.13 mL, 8.45 mmol) and 5- bromo-2-chloropyridine (1.626 g, 8.45 mmol) were combined and heated with stirring at 17O0C for 16 hours. The reaction mixture was partitioned between DCM and water and then the organic layer was washed with sat. aq. NaHCOs, dried over MgSO4, and concentrated in vacuo to give a black oil (2.46 g). Column chromatography (0:1 - 1 :3 EtOAc: petroleum ether gradient) gave the title compound as a brown oil (2.1Og, 75%). LCMS RT = 2.64 min, MH+ 335.0. 1H NMR (d6-DMSO): 9.56 (IH, s), 8.29 (IH, d, J2.5), 7.86 (IH, s), 7.79 (IH, dd, J9.0, 2.7), 7.52-7.55 (IH, m), 7.38 (IH, t, J 8.2), 7.82-7.87 (2H, m).
Step 2
Mixture of 6-(3-(trifluoromethoxy)phenylamino)pyridin-3-ylboronic acid and 5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethoxy)phenyl)pyridin-2-amine [00278] 5-Bromo-N-(3-(trifluoromethoxy)phenyl)pyridin-2-amine (4.Og, 12.01mmol), bis(pinacolato)diboron (3.353g, 13.21mmol), potassium acetate (3.535g, 36.03mmol), dichlorobis(triphenylphosphine)palladium (II) (423mg, 0.6 mmol) and dioxane (20 mL) were combined and heated with stirring, under microwave activation, at 14O0C for 15 minutes. The reaction mixture was partitioned between EtOAc (250 mL) and water (250 mL). The aqueous layer was acidified with IM HClaq (20 mL) and re-extracted with EtOAc (100 mL). The organic extracts were combined, dried over MgSO4, and concentrated in vacuo to give a black oil (7.122 g). Column chromatography (0:1 - 1 :1 EtOAc: petroleum ether gradient) gave a mixture of the title compounds as an orange oil (4.9Ig). LCMS RT = 1.40 min, MH+ 299.2 (6-(3-(trifluoromethoxy)phenylamino)pyridin-3-ylboronic acid); 2.63 min, MH+ 381.4 (5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethoxy)phenyl)pyridin-2- amine).
Step 3
6-(6-(3-(Trifluoromethoxy)phenylamino)pyridin-3-yl)indolin-2-one (6) (Compound 131) [00279] A mixture of 6-(3-(trifluoromethoxy)phenylamino)pyridin-3-ylboronic acid and 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethoxy)phenyl)pyridin-2- amine (1.761 g), 6-bromoindolin-2-one (783 mg, 4.0 mmol), tetrakis(triphenylphosphine)- palladium (428 mg, 0.4 mmol), potassium acetate (1086 mg, 12.0 mmol) and a mixture of DMF, IMS and H2O (2:1 :1, 16 mL) were combined and heated with stirring, under microwave activation, at 15O0C for 20 minutes. The reaction mixture was partitioned between EtOAc (200 niL) and water (200 mL). The aqueous layer was re-extracted with EtOAc (150 mL). The organic extracts were combined, washed with brine, dried over MgSO4, and concentrated in vacuo to give an orange/brown oil (2.43 g). Column chromatography (0:1 - 3:1 EtOAc: petroleum ether gradient) gave the title compound as an off-white powder (291 mg, 19%). LCMS RT = 2.03 min, MH+ 386.3. 1H NMR (d6-DMSO): 10.49 (IH, s), 9.52 (IH, s) 8.48 (IH, d, J2.5), 8.00 (IH, s), 7.89 (IH, dd, J 8.7, 2.5), 7.58- 7.61 (IH, m), 7.38 (IH, t, J 8.2), 7.19-7.29 (2H, m), 7.01 (IH, d, J 1.3), 6.94 (IH, d, J 8.7), 6.83-6.86 (IH, m), 3.51 (2H, s).
[00280] The following compounds were prepared according to the same general method.
5 -(2-Methylbenzo [dloxazol-5 -yl)-N-(3 -(trifluoromethoxy)phenyl)pyridin-2-amine (Compound 133)
[00281] A solution of 6-(3-(trifluoromethoxy)phenylamino)pyridin-3-ylboronic acid (180 mg, 0.57 mmol), 5-bromo-2-methylbenzo[d]oxazole (100 mg, 0.47 mmol), palladium acetate (20 mg, 0.09 mmol), biphenyl-2-yldicyclohexylphosphine (80 mg, 0.23 mmol) and triethylamine (200 μL, 1.42 mmol) in DMF (2 mL) and H2O (2 mL) were heated using microwave irradiation at 1300C for 10 minutes. The reaction mixture was partitioned between EtOAc and water, the organic phase washed with brine (3x) then dried over MgSO4 and concentrated. The residue was purified by column chromatography eluting with ethyl acetate/hexanes 1 :2 v/v to afford 30 mg (17 %) of the title compound. LCMS RT= 2.38 min, MH+ 386.2. 1H NMR (d6-DMSO): 9.52 (IH, s), 8.59 (IH, d, J2.5), 8.04-7.97 (2H, m), 7.93 (IH, d, J 1 J), 7.75-7.70 (IH, m), 7.67-7.57 (2H, m), 7.38 (IH, t, J 8.2), 6.96 (IH, d, J 8.6), 6.88-6.81 (IH, m), 2.63 (3H, s).
iV-(4-(2-Methylbenzo |"d]thiazol-5 -yl)phenyl)-3 -(trifluoromethoxy)aniline (Compound 138)
[00282] A mixture of 6-(3-(trifluoromethoxy)phenylamino)pyridin-3-ylboronic acid and 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethoxy)phenyl) pyridines- amine (762 mg), 5-bromo-2-methylbenzo[d]thiazole (449 mg, 2.0 mmol), tetrakis(triphenylphosphine)palladium (232 mg, 0.2 mmol), potassium acetate (580 mg, 5.9 mmol) and a mixture of DMF, IMS and H2O (2:1 :1, 12 mL) were combined and heated with stirring, under microwave activation, at 15O0C for 20 minutes. The reaction mixture was partitioned between EtOAc (200 mL) and water (150 mL). The aqueous layer was re- extracted with EtOAc (70 mL). The organic extracts were combined, dried over MgSO4, and concentrated in vacuo to give an orange oil (1.6 g). Column chromatography (0:1 - 3:1 EtOAc: petroleum ether gradient) followed by preparative HPLC gave the title compound a white powder (37 mg, 5%). LCMS RT = 2.59 min MH+ 402.2. 1U NMR (d6-DMSO): 9.56 (IH, s), 8.65 (IH, d, J2.6), 8.19 (IH, d, J 1.6), 8.02-8.11 (3H, m), 7.72 (IH, d, J 8.4, 1.8), 7.61 (IH, d, J 8.2, 1.4), 7.39 (IH, t, J 8.4), 6.98 (IH, d, J 8.4), 6.85 (IH, d, J 8.2), 2.83 (3H, s).
1 -(3 -(6-(3 -(Trifluoromethoxy)phenylamino)pyridin-3 -yl)phenyl)propan-2-one (Compound 140)
[00283] A mixture of 6-(3-(trifluoromethoxy)phenylamino)pyridin-3-ylboronic acid and 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethoxy)phenyl) pyridine- amine (602 mg), l-(3-bromophenyl)propan-2-one (328 mg, 1.54 mmol), tetrakis(triphenylphosphine)palladium (174 mg, 0.2 mmol), potassium acetate (453 mg, 4.6 mmol) and a mixture of DMF, IMS and H2O (2:1 :1, 6 mL) were combined and heated with stirring, under microwave activation, at 15O0C for 20 minutes. The reaction mixture was partitioned between EtOAc (200 mL) and water (150 mL). The aqueous layer was re- extracted with EtOAc (70 mL). The organic extracts were combined, dried over MgSO4, and concentrated in vacuo to give an orange oil (0.80 g). Column chromatography (0:1 - 1 :1 EtOAc: petroleum ether gradient) followed additional column chromatography (0:1 - 1 :1 EtOAc: petroleum ether gradient) gave the title compound as clear gum (27 mg, 5%). LCMS RT = 2.36 min MH+ 387.3. 1H NMR (d6-DMSO): 9.54 (IH, s), 8.54 (IH, d, J2.6), 8.03 (IH, s), 7.94 (IH, dd, J8.6, 2.6), 7.54-7.59 (2H, m), 7.50 (IH, s), 7.35-7.42 (2H, m), 7.15 (IH, d, J 7.5), 6.95 (IH, d, J 8.6), 6.84 (IH, d, J 8.6), 3.83 (2H, s), 2.17 (3H, s).
Example 7 - Preparation of jV-(5-(3-acetamidophenyl)pyridin-2-yl)-3-
(trifluoromethoxy)benzamide (Compound 141)
Step l
N-(5 -Bromopyridin-2-yl)-3 -(trifluoromethoxy)benzamide
[00284] This compound was prepared using a similar method to that described for
Example 4. LCMS RT= 2.36min, MH+= 361.1. 1H NMR (d6-DMSO): 11.22 (IH, s), 8.54
(IH, d, J2.5), 8.18 (IH, d, J8.9), 8.09 (IH, dd, J2.5, 8.1), 8.0 (IH, m), 7.80 (IH, s), 7.69-
7.63 (2H, m). Step 2
N-(5 -(3 - AcetamidophenyPpyridin-2-yP-3 -(trifluoromethoxy)benzamide (Compound 141) [00285] 114mg of the title compound was prepared from JV-(5-bromopyridin-2-yl)-3- (trifluoromethoxy)benzamide using the Suzuki-coupling method described for Example 1 (40%). LCMS RT= 2.07min, MH+= 416.1. 1H NMR (d6-DMSO): 11.19 (IH, s), 10.08 (IH, s), 8.66 (IH, d, J2.2), 8.29 (IH, d, J 8.6), 8.11 (2H, m), 8.02 (IH, s), 7.92 (IH, s), 7.71-7.60 (3H, m), 7.43 (2H, m), 2.07 (3H, s).
Example 8 - Preparation of A/-(3-(6-(3-(trifluoromethoxy)phenylsulfonamido) pyridin-3- yDphenyPacetamide (Compound 144)
Step l
N-(5 -Bromopyridin-2-yl)-3 -(trifluoromethoxy)benzenesulfonamide
[00286] 3-(Trifluoromethoxy)benzene-l-sulfonyl chloride (Ig, 3.8mmol), 5-bromopyridin-
2-amine (1.2eq, 0.8g, 4.6mmol) and triethylamine (2eq, 0.77g, 7.6mmol) were stirred together in dry DCM (20ml) at 00C for 5 minutes. The mixture was then warmed to room temperature, and stirred overnight. The mixture was diluted with DCM, washed with 2M
NaOH (x2). The DCM layer was dried (MgSO4) and concentrated. The crude was purified by column chromatography eluting using a gradient (EtOAc/hexanes 1 :9 v/v). LCMS RT=
2.15min, MH+= 397.1. 1H NMR (d6-DMSO): 11.56 (IH, br s), 8.33 (IH, s), 7.92 (2H, m),
7.86 (IH, s), 7.77-7.67 (2H, m), 7.03 (IH, d, J 8.9).
Step 2
[00287] 29mg of the title compound was prepared from JV-(5-bromopyridin-2-yl)-3- (trifluoromethoxy)benzenesulfonamide using the Suzuki-coupling method described for Example 1 (19%). LCMS RT= 1.83min, MH+= 452.4. 1H NMR (d6-DMSO): 12.16 (IH, s, br), 9.88(1H, s), 8.25 (IH, s), 8.01 (IH, dd, J 8.8, 2.5), 7.94 (IH, J7.9), 7.84 (IH, s), 7.80 (IH, m), 7.72 (IH, t, J 8.2), 7.61-7.54 (2H, m), 7.39-7.26 (3H, m), 2.06 (3H, s).
Example 9 - Preparation of l-methyl-3-(3-(6-(3-(trifluoromethoxy) phenylamino)pyridin-3- yDphenyPurea (Compound 150)
Step 1 l-Methyl-3-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-vPphenvPurea
[00288] 2-(3-Isocyanatophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.2g, 0.8mmol) and DIPEA (0.21g, 1.6mmol) was dissolved in dry THF (10ml) under nitrogen. Methylamine (2M in THF, 0.8ml, l.βmmol) was added to the solution dropwise, and the solution was stirred at room temperature for 2 hours. The THF was removed, the resultant crude dissolved in DCM, which was washed with 2M HCl solution (2x). The DCM layer was dried (MgSO4), and concentrated to yield a yellow solid 0.9g (82%). LCMS RT= 1.77min, MH+= 277.3, 553.2. 1H NMR (d6-DMSO): 8.58 (IH, s), 7.79 (IH, d, J2.2), 7.56 (IH, dt, J2.1, 7.5), 7.25 (2H, m), 6.00 (IH, d, J4.7), 2.68 (3H, d, J4.6), 1.34 (12H, s).
Step 2
1 -Methyl-3 -(3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yPphenyPurea (Compound
150)
[00289] The general protocol described in Example 1 was then used to afford 41mg of the title compound (3%). LCMS RT= 1.96min, MH+= 403.2. 1U NMR (d6-DMSO): 9.53 (IH, s), 8.59 (IH, s), 8.57 (IH, d, J2.4), 8.01 (IH, s), 7.87 (IH, dd, J2.5, 8.6), 7.71 (IH, m), 7.60
(IH, dd, J 1.2, 8.3), 7.41-7.27 (3H, m), 7.18 (IH, dt, J 1.5, 7.1), 6.96 (IH, d, J8.7), 6.85 (IH, d, J 8.3), 6.08 (IH, q, J4.6), 2.66 (3H, d, J4.6).
Example 10 - Preparation of A/-(3-(2-(3-(trifluoromethoxy)phenylamino) pyrimidin-5- yDphenyPacetamide (Compound 151)
Step l
5 -Bromo-iV-(3 -(trifluoromethoxy)phenyl)pyrimidin-2-amine
[00290] A mixture of 5-bromo-2-chloropyrimidine (1.0Og, 5.17mmol) and 3-
(trifluoromethoxy)aniline (69OuL, 5.17mmol) in IMS (12mL) was heated, under microwave activation, at 15O0C for 20min. The reaction mixture was partitioned between DCM (15OmL) and sodium bicarbonate (sat, 5OmL) and the two layers were separated. The aqueous layer was extracted further with DCM (2 x 5OmL), the combined layers were washed with brine until pH 7, dried over anhydrous MgSO4 and evaporated to dryness. The resulting solid was purified by column chromatography eluting using a gradient (EtOAc/hexanes 0:1 v/v to
EtOAc/hexanes 1 :4 v/v) to afford 679 mg (40%) of the title compound. LCMS RT= 2.46min,
MH+ 334.0. 1H NMR (d6-DMSO): 10.18 (IH, s), 8.67 (2H, s), 7.87 (IH, br s), 7.69-7.67 (IH, m), 7.41 (IH, t, J 8.3), 6.96-6.93 (IH, m).
Step 2
N-(3 -(2-(3 -(Trifluoromethoxy)phenylamino)pyrimidin-5 -vDphenvDacetamide (Compound
151) [00291] The general protocol described in Example 1 was then used to afford 142mg of the title compound (20%). LCMS RT= 2.15min, MH+= 389.3. 1U NMR (d6-DMSO): 10.15 (IH, s), 10.07 (IH, s), 8.81 (2H, s), 8.01 (IH, s), 7.89 (IH, s), 7.75 (IH, d, J9.2), 7.57 (IH, dt, J2.9, 6.6), 7.45-7.39 (3H, s), 6.93 (IH, d, J7.9), 2.08 (3H, s).
Example 11 - Preparation of Λ/-(6'-(3-(trifluoromethoxy)phenylamino)-2,3'-bipyridin-4- vDacetamide (Compound 139) Step 1
Λ/-(2-Bromopyridin-4-yl)acetamide
[00292] 2-Bromopyridin-4-amine (2.076 g, 12.0 mmol) wad dissolved in acetic anhydride and the solution stirred with heating at 1000C for 16 hours. Excess acetic anhydride was removed in vacuo and the orange residue partitioned between DCM (150 mL) and sat. aq. NaHCO3 (100 mL x 3). The organic extract was dried over MgSO4 and concentrated in vacuo to give an orange oil (1.80 g). Column chromatography (0:1 - 1 :0 EtOAc: petroleum ether gradient) gave the title compound as an orange oil (743 mg, 29%). LCMS RT = 1.36 min MH+ 217.2. 1H NMR (d6-DMSO): 10.53 (IH, s), 8.21 (IH, d, J5.6), 7.89 (IH, d, J 1.8), 7.45 (IH, dd, J5.6, 1.8), 2.10 (3H, s).
Λ/-(6'-(3-(Trifluoromethoxy)phenylamino)-2,3'-bipyridin-4-yl)acetamide (Compound 139) [00293] A mixture of 6-(3-(trifluoromethoxy)phenylamino)pyridin-3-ylboronic acid and 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethoxy)phenyl)pyridin-2- amine (700 mg, 2.14 mmol), N-(2-bromopyridin-4-yl)acetamide (369 mg, 1.72 mmol), tetrakis(triphenylphosphine)palladium (200 mg, 0.2 mmol), potassium acetate (506 mg, 5.2 mmol) and a mixture of DMF, IMS and H2O (2:1 :1, 6 mL) were combined and heated with stirring, under microwave activation, at 15O0C for 20 minutes. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The aqueous layer was re- extracted with EtOAc (50 mL). The organic extracts were combined, dried over MgSO4, and concentrated in vacuo to give an orange oil (1.05 g). Column chromatography (0:1 - 3:1 EtOAc: petroleum ether gradient) followed by recrystallisation from EtOAc gave the title compound as a white powder (35 mg, 5%). LCMS RT = 1.48 min MH+ 389.2. 1H NMR (de-DMSO): 10.40 (IH, s), 9.64 (IH, s), 8.78 (IH, d, J2.4), 8.47 (IH, d, J5.6), 8.17 (IH, dd, J 8.8, 2.5), 8.03 (IH, d, J 1.6), 8.00 (IH, s), 7.61-7.64 (IH, m), 7.37-7 '.47 (2H, m), 6.97 (IH, d, J 8.6), 6.85-6.89 (IH, m), 2.12 (3H, s). Example 12 - Preparation of A/-methyl-A/-(3-(6-(3-(trifluoromethoxy) phenylamino)pyridin- 3-yl)phenyl)acetamide (Compound 137) Step l
Λ/-Methyl-N-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetamide [00294] N-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetamide (1.0 g, 3.83 mmol) was dissolved in anhydrous THF (32 mL). Sodium hydride (306 mg, 7.66 mmol - 60% in mineral oil) was added and the resulting cloudy white mixture stirred at 2O0C for 30 minutes under an N2 atmosphere. Methyl iodide (716 μL, 11.49 mmol) was added dropwise and the mixture stirred at 2O0C for 16 hours. The reaction mixture was partitioned between EtOAc (100 mL). The aqueous layer was acidified with IM HClaq and re-extracted with EtOAc (100 mL). The organic extracts were combined, dried over MgSO4, and concentrated in vacuo to give a pale yellow oil (1.34 g). Column chromatography (0:1 - 1 :3 EtOAc: petroleum ether gradient) gave the title compound as a clear oil (791 mg, 75%). LCMS RT = 1.95 min MH+ 276.4. 1H NMR (d6-DMSO): 7.63 (IH, s), 7.51 (IH, s), 7.46 (2H, m), 3.15 (3H, s), 1.30 (12H, s), 1.07 (3H, s).
Step 2 jV-Methyl-iV-(3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)phenyl)acetamide (Compound 137)
[00295] N-Methyl-N-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetamide (766 mg, 2.78 mmol), 5-bromo-N-(3-(trifluoromethoxy)phenyl)pyridin-2-amine (464 mg, 1.39 mmol), 1,1' Bis(diphenylphosphino)ferrocene palladium (II) chloride (227 mg, 0.28 mmol), potassium carbonate (960 mg, 6.95 mmol) and DMEZH2O (4:1, 15 mL) were combined and heated with stirring, under microwave activation, at 13O0C for 15 minutes. The reaction mixture was partitioned between EtOAc (150 mL) and water (150 mL). The aqueous layer was re-extracted with EtOAc (50 mL) and the organic extracts combined, dried over MgSO4 and concentrated in vacuo to give a black oil (1.20 g). Column chromatography (0:1 - 3:1 EtOAc: petroleum ether gradient) gave the title compound as brown solid (245 mg, 44%). LCMS RT = 2.18 min MH+ 402.2. 1H NMR (d6-DMSO): 9.59 (IH, s), 8.62 (IH, d, J 2.0), 7.99-8.04 (2H, m), 7.65-7.67 (2H, m), 7.48-7.59 (2H, m), 7.38 (IH, t, J 8.2), 7.27-7.30 (IH, m), 7.96 (IH, d, J 8.6), 6.83-6.87 (IH, m) 3.21 (3H, s), 1.85 (3H, s).
Example 13 - Preparation of A/-(3-(5-(3-(trifluoromethoxy)phenylamino)pyridin-3- vDphenvDacetamide (Compound 152) [00296] A mixture of 3,5 -dibromopyridine (2.0Og, 8.44mmol), 3-acetamidophenylboronic acid (1.5 Ig, 8.44mmol), potassium carbonate (1.17g, 8.44mmol) and palladium (tetrakis)triphenylphosphine (294mg, 0.025mmol) in DME/H20 (4OmL, 3:1) was refluxed for 16h. The solvent was removed in vacuo, the resulting yellow solid was partitioned between DCM (30OmL) and brine (15OmL) and the two layers were separated. The aqueous layer was extracted further with DCM (2x10OmL) and the combined extracts were dried over anhydrous MgSO4. Evaporation of the solvent afforded crude iV-(3-(5-bromopyridin-3- yl)phenyl)acetamide in 74% purity (LC). This material (1.2Og, 4.12mmol), 3- (trifluoromethoxy)aniline (66IuL, 4.95mmol), cesium carbonate (3.36g, 10.3mmol), palladium bis-acetate (47mg, 0.21mmol) and Xantphos (238mg, 0.41mmol) were dissolved in dioxane (7.5mL) and the resulting mixture was heated, under microwave activation, at 15O0C for 20mins. The crude mixture was partitioned between EtOAc (10OmL) and brine (10OmL) and the two layers were separated. The aqueous layer was extracted further with EtOAc (10OmL), the combined layers were dried over anhydrous MgSO4 and evaporated to dryness. The resulting solid was purified by column chromatography eluting using a gradient (EtOAc/hexanes 0:1 v/v to EtOAc/hexanes 1 :0 v/v) to afford 590mg (37%) of the title compound. LCMS RT= 1.59min, MH+ 388.2. 1U NMR (d6-DMSO): 10.07 (IH, s), 8.83 (IH, s), 8.39 (IH, d, J2.5), 8.36 (IH, d, J 1.9), 7.91 (IH, s), 7.65 (IH, t, J2.2), 7.60 (IH, d, J 8.0), 7.45-7.33 (3H, m), 7.17 (IH, dd, J 8.2 1.8), 7.02 (IH, s), 6.84 (IH, d, J 8.2), 2.07 (3H, s).
Example 14
[00297] The activity of the compounds of formula (I) for use in the treatment of DMD was evaluated in the following predictive assay.
Luciferase reporter assay (murine H2K cells)
[00298] The cell line used for the screen was an immortalized mdx mouse H2K cell line that had been stably transfected with a plasmid containing ~5kb fragment of the Utrophin A promoter including the first untranslated exon linked to a luciferase reporter gene. [00299] Under conditions of low temperature and interferon containing media, the cells remained as myoblasts. These were plated into 96 well plates and cultured in the presence of compound for three days. The level of luciferase was then determined by cell lysis and reading of the light output from the expressed luciferase gene utilizing a plate luminometer. Luciferase Assay for 96 Well Plates
[00300] The H2K/mdx/Utro A reporter cell line cells were plated out into 96 well plates
(Falcon 353296, white opaque) at a density of approximately 5000 cells/well in 190 μL normal growth medium. The plates were then incubated at 33°C in the presence of 10% CO2 for 24 hours.
[00301] Compounds were dosed by adding 10 μL of diluted compound to each well giving a final concentration of 10 μM (where a different final concentration was required, the amount of compound solution added was amended accordingly). The plates were then incubated for a further 48 hours. Cells were then lysed in situ following the manufacture's protocols (Promega Steady-Glo Luciferase Assay System (E2520)), then counted for
10 seconds using a plate luminometer (Victor 1420).
Compound Storage
[00302] Compounds for screening were stored at -200C as 10 mM stocks in 100% DMSO until required.
Results
[00303] Biological activity was assessed using the luciferase reporter assay in murine H2K cells, and the results were shown in Table 1, for a concentration of the test compound solution of 10 μM, unless otherwise indicated.
Table 1
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
[00304] The results in Table 1 are classified as follows: + Up to 200% relative to control ++ Between 201 % and 300% relative to control +++ Between 301 % and 400% relative to control ++++ Above 401% relative to control
[00305] The results in Table 1 show that all of the exemplified compounds had increased activity in the luciferase reporter assay relative to the control.
[00306] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the disclosure. [00307] The examples set forth above are provided to give those of ordinary skill in the art a description of how to make and use the embodiments disclosed herein, and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the disclosure. [00308] All of the patents, patent applications and publications referred to herein are incorporated herein by reference in their entireties, as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference. Citation or identification of any reference herein is not an admission that such reference is available as prior art to this application.

Claims

WHAT IS CLAIMED:
1. A compound of formula (I):
Figure imgf000104_0001
(I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein
Y is CH or N, wherein CH is optionally substituted;
L1 is a bond, -O-, -NR4-, -S-, -SO-, -SO2-, -NHC(O)NH-, -NHC(O)-, or -NHS(O)2-;
L2 is a bond, -NHC(O)NH-, -NHC(O)-, -0-, -S-, or -NR8-;
R1 is (i) R5; or (ii) Ci-C6 alkyl optionally substituted with one or more halo, R5, OR6, N(R6)2, or C(O)N(R6)2; or when L1 is a bond, R1 may additionally be H;
R2 is (i) Ci-C6 alkyl; or (ii) aryl or heteroaryl, each of which is optionally substituted with one or more halo, R9, OR9, SR9, N(R9)2, C(O)R9, CH2C(O)R9, NHC(O)R9, NR9C(O)R9, C(O)N(R9)2, NHS(O)2R9, NHC(O)NHR9, or OR10;
R3 is H, halo, Ci-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; or when L1 is a bond and R1 is H, R3 may additionally be -L3-Rπ;
L3 is a bond, -0-, -NR4-, -S-, -SO-, -SO2-, -NHC(O)NH-, -NHC(O)-, or -NHS(O)2-;
R4 is H or Ci-C4 alkyl;
R5 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, OR6, N(R6)2, S(O)2R6, R7, OR7, C(O)R7, NHC(O)R7, optionally substituted Ci-C6 alkyl, or optionally substituted 0(Ci-C6 alkyl), wherein the Ci-C6 alkyl and 0(Ci-C6 alkyl) are each independently optionally substituted with one or more OR6, N(R6)2, or C(O)N(R6)2; or when R5 is a partially or fully saturated ring, R5 may additionally be substituted with one or more oxo; each occurrence of R6 is independently H or Ci-C4 alkyl;
R7 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, OH, N(R6)2, optionally substituted Ci-C6 alkyl, or optionally substituted 0(Ci-C6 alkyl), wherein the Ci-C6 alkyl and 0(Ci-C6 alkyl) are each independently optionally substituted with one or more OR6 or N(R6)2; or when R7 is a partially or fully saturated ring, R7 may additionally be substituted with one or more oxo;
R8 is H or Ci-C4 alkyl; each occurrence of R9 is independently H or Ci-C4 alkyl;
R10 is aryl or heteroaryl, each of which is optionally substituted with one or more halo;
R11 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more halo, R > 9y, ^ Or.9
Figure imgf000105_0001
Ry, C(O)Ry, NHC(O)Ry, or C(O)N(Ry)2; and each occurrence Of Ci-C4 alkyl and Ci-C6 alkyl may independently be further substituted with one or more halo.
2. A method for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia, comprising administering the compound of claim 1.
3. Use of the compound of claim 1 , in the manufacture of a medicament for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
4. Use of the compound of claim 1 , in the manufacture of a medicament for the treatment or prophylaxis of Duchenne muscular dystrophy or Becker muscular dystrophy.
5. The compound, method, or use of any one of claims 1 to 4, wherein Y is
N.
6. The compound, method, or use of any one of claims 1 to 4, wherein Y is optionally substituted CH.
7. The compound, method, or use of any one of claims 1 to 6, wherein L1 is a bond, -NHC(O)NH-, -NHC(O)-, -O-, -S-, -NR4-, or -NHS(O)2-.
8. The compound, method, or use of any one of claims 1 to 7, wherein L2 is a bond or -O-.
9. The compound, method, or use of any one of claims 1 to 8, wherein R3 is H.
10. The compound, method, or use of any one of claims 1 to 6, wherein L1 is a bond, R1 is H, L2 is a bond or -O-, and R3 is -L3-Rπ, wherein L3 is a bond, -O-, -S-, -NR4-, -NHC(O)NH-, or -NHC(O)-.
11. The compound, method, or use of any one of claims 1 to 10, wherein the -L2-R2 is on the 5-position of the pyridyl or pyrimidinyl ring.
12. The compound, method, or use of any one of claims 1 to 11, wherein R2 is Ci-C4 alkyl or Ci-C4 haloalkyl.
13. The compound, method, or use of claim 12, wherein R2 is methyl or trifluoromethyl.
14. The compound, method, or use of any one of claims 1 to 11, wherein R2 is aryl or heteroaryl, each of which is optionally substituted.
15. The compound, method, or use of claim 14, wherein R2 is phenyl, naphthalenyl, pyridyl, furyl, thienyl, benzofuranyl, benzodioxolyl, benzoxazolyl, benzothiazolyl, or indolinone, each of which is optionally substituted.
16. The compound, method, or use of claim 15, wherein R2 is optionally substituted with one or more halo, CH3, CF3, C(O)CH3, C(O)H, OCH3, OCF3, SCH3, N(CH3)2, OH, NHC(O)CH3, NHC(O)CF3, NCH3C(O)CH3, NHC(O)-ethyl, NHC(O)- isopropyl, C(O)NHCH3, C(O)NH2, CH2C(O)CH3, NHS(O)2CH3, NHC(O)NHCH3, or phenoxy.
17. The compound, method, or use of any one of claims 1 to 9 and 11 to 16, wherein L1 is -NHC(O)NH- and R1 is cycloalkyl.
18. The compound, method, or use of claim 17, wherein R1 is cyclopentyl or cyclohexyl.
19. The compound, method, or use of any one of claims 1 to 9 and 11 to 16, wherein L1 is -NHC(O)- or -NHS(O)2-, and R1 is optionally substituted aryl or optionally substituted heteroaryl.
20. The compound, method, or use of claim 19, wherein R1 is phenyl, pyrazolyl, oxazolyl, or isoxazolyl, each of which is optionally substituted with one or more Ci-C4 alkyl, CF3, OCF3, or aryl.
21. The compound, method, or use of any one of claims 1 to 9 and 11 to 16, wherein L1 is a bond and R1 is optionally substituted heterocyclyl.
22. The compound, method, or use of claim 21, wherein R1 is piperazinyl, piperidinyl, or morpholinyl, each of which is optionally substituted, and wherein R1 is attached to the L1 bond through a ring nitrogen.
23. The compound, method, or use of claim 22, wherein R1 is optionally substituted with one or more alkyl, aryl, heteroaryl or C(O)-heterocyclyl, wherein the aryl, heteroaryl, and C(O)-heterocyclyl substituents are optionally further substituted with one or more halo, OH, or Ci-C4 alkyl optionally substituted with one or more halo or OH.
24. The compound, method, or use of any one of claims 1 to 9 and 11 to 16, wherein L1 is S and R1 is Ci-C6 alkyl.
25. The compound, method, or use of any one of claims 1 to 9 and 11 to 16, wherein L1 is -O- or -NR4-, wherein R4 is hydrogen or methyl, and R1 is Ci-C6 alkyl, aryl, or heteroaryl, each of which is optionally substituted.
26. The compound, method, or use of claim 25, wherein R1 is alkyl, optionally substituted with one or more F, 0(Ci-C4 alkyl), C(O)N(Ci-C4 alkyl)2, or with aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionally substituted.
27. The compound, method, or use of claim 25, wherein R1 is aryl or heteroaryl, each of which is optionally substituted with one or more halo, OR6, N(R6)2, S(O)2R6, R7, OR7, C(O)R7, NHC(O)R7, Ci-C6 alkyl optionally substituted with one or more fluoro, or 0(Ci-C6 alkyl) optionally substituted with C(O)N(R6)2 or one or more fluoro.
28. The compound, method, or use of claim 27, wherein R1 is phenyl, dihydro-lH-indenyl, pyridyl, benzodioxolyl, or dihydrobenzodioxinyl.
29. The compound, method, or use of any one of claims 1 to 6 and 10 to 16, wherein L3 is -O- or -NR4-, and R11 is aryl or heteroaryl, each of which is optionally substituted with one or more halo, OR9, N(R9)2, C(O)R9, or NHC(O)R9, wherein R9 is H or Ci-C4 alkyl optionally substituted with one or more fluoro.
30. The compound, method, or use of any one of claims 1 to 4, wherein the compound is:
1 -cyclohexyl-3 -(5 -methylpyridin-2-yl)urea,
5-methyl-N-(5-methylpyridin-2-yl)-3-phenylisoxazole-4-carboxamide,
((2S,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)(4-(5-
(trifluoromethyl)pyridin-2-yl)piperazin- 1 -yl)methanone, N-phenethyl-5-(4-(trifluoromethoxy)phenyl)pyridin-2-amine, 4-(2-(5-(benzo[d][l,3]dioxol-5-yl)pyridin-2-yloxy)phenyl)morpholine, 3 -(6-( 1 -phenylethylamino)pyridin-3 -yl)benzaldehyde, 4-(6-(2-(pyridin-4-yl)ethylamino)pyridin-3-yl)benzaldehyde, 2-(6-(2,3-dihydrobenzo[b][l,4]dioxin-6-ylamino)pyridin-3-yl)benzaldehyde, 5 -(4-phenoxyphenyl)-2-(3 -(pyridin-2-yl)propoxy)pyridine, l-(5-(trifluoromethyl)pyridin-2-yl)-4-(5-(3,4,5-trimethoxyphenyl)pyridin-2- yl)piperazine,
3-(6-(2,6-difluorophenylamino)pyridin-3-yl)benzaldehyde, 2-(3-(5-(4-formylphenyl)pyridin-2-ylamino)pheno xy)-N ,N-dimethylacetamide, N 1 -(6'-methoxy-3 ,3 '-bipyridin-6-yl)-N3 ,N3 -dimethylbenzene- 1 ,3 -diamine, N 1 ,N 1 -dimethyl-N3 -(5 -(2-(methylthio)phenyl)pyridin-2-yl)benzene- 1,3- diamine,
5 -(furan-2-yl)-N-(3 -phenoxyphenyl)pyridin-2-amine, N-(2,6-difluorophenyl)-5-(4-(trifluoromethoxy)phenyl)pyridin-2-amine, 3 -(6-(cyclopropylmethylamino)pyridin-3 -yl)benzaldehyde, l-(3-(trifluoromethyl)phenyl)-4-(5-(3,4,5-trimethoxyphenyl)pyridin-2- yl)piperazine,
N-(3-(6-(3,5-dichlorophenylamino)pyridin-3-yl)phenyl)acetamide, l-(3-(6-(3-(dimethylamino)phenylamino)pyridin-3-yl)phenyl)ethanone, 2-(6-(pyridin-3 -ylamino)pyridin-3 -yl)benzaldehyde,
4-(6-(4-(3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)pyridin-3 -yl)benzaldehyde, 3-(6-morpholinopyridin-3-yl)benzaldehyde, N-(2-morpholinoethyl)-3,3'-bipyridin-6-amine, N-(3-(6-(2-morpholinoethylamino)pyridin-3-yl)phenyl)acetamide, N-( 1 -(4-fluorophenyl)ethyl)-5 -p-tolylpyridin-2-amine, 3 -(6-(2-(pyridin-4-yl)ethylamino)pyridin-3 -yl)benzaldehyde, N-(2-(pyridin-2-yl)ethyl)-5-p-tolylpyridin-2-amine, 3 -(6-(pyridin-2-ylmethoxy)pyridin-3 -yl)benzaldehyde, 4-(6-(2,2,2-trifluoroethylamino)pyridin-3-yl)benzaldehyde, 3-(6-(3,4-dichlorophenylamino)pyridin-3-yl)benzaldehyde, 2-(3-phenoxybenzyloxy)-5-(thiophen-2-yl)pyridine, l-(5-(6-(3,4,5-trimethoxyphenylamino)pyridin-3-yl)thiophen-2-yl)ethanone, 3 -(6-(2-morpholinoethoxy)pyridin-3 -yl)benzaldehyde, 3 -(6-(2-(pyridin-2-yl)ethylamino)pyridin-3 -yl)benzaldehyde, 2-(6-(phenethylamino)pyridin-3-yl)benzaldehyde, 2-(3 -phenoxybenzyloxy)-5 -(3 ,4,5 -trimethoxyphenyl)pyridine, l-(3,5-dichloropyridin-4-yl)-4-(5-(3,4,5-trimethoxyphenyl)pyridin-2- yl)piperazine,
2-(6-( 1 -phenylethylamino)pyridin-3 -yl)benzaldehyde, 2-(6-(3 -(trifluoromethyl)phenylamino)pyridin-3 -yl)benzaldehyde, 1 -(2-(5 -p-tolylpyridin-2-yloxy)ethyl)pyrrolidin-2-one, 3-(6-(4-methylpiperazin- 1 -yl)pyridin-3-yl)benzaldehyde, 3-(6-(isopropylthio)pyridin-3-yl)benzaldehyde, 4-(6-(3 -phenoxyphenylamino)pyridin-3 -yl)phenol,
N-(2,6-difluorobenzyl)-5-(2-(methylthio)phenyl)pyridin-2-amine, l-(5-(2-fluorophenyl)pyridin-2-yl)-4-(pyridin-2-yl)piperazine,
N-(3 -(trifluoromethoxy)phenyl)-3 ,3 '-bipyridin-6-amine,
4-(6-(2-morpholinoethylamino)pyridin-3-yl)benzaldehyde,
5-(2-fluorophenyl)-N-(2-(pyridin-2-yl)ethyl)pyridin-2-amine,
4-(2-(5-(2-chlorophenyl)pyridin-2-yloxy)ethyl)morpholine,
3-(6-(3-(pyridin-2-yl)propoxy)pyridin-3-yl)benzaldehyde,
N-(2-(pyridin-2-yl)ethyl)-3,3'-bipyridin-6-amine,
5-(2-methoxyphenyl)-N-(3-(trifluoromethoxy)phenyl)pyridin-2-amine,
N 1 -(5 -(4-methoxyphenyl)pyridin-2-yl)-N3 ,N3 -dimethylbenzene- 1 ,3 -diamine,
3 -(6-(2-methoxyethylamino)pyridin-3 -yl)benzaldehyde,
N-(3,5-dichlorophenyl)-3,3'-bipyridin-6-amine,
1 -(5 -(6-(3 -(dimethylamino)phenylamino)pyridin-3 -yl)thiophen-2-yl)ethanone,
2-(6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)benzaldehyde,
N 1 -(5 -(3 -chlorophenyl)pyridin-2-yl)-N3 ,N3 -dimethylbenzene- 1 ,3 -diamine,
4-(2-(5-p-tolylpyridin-2-yloxy)phenyl)morpholine,
N-(3-(6-(2-phenoxyphenylamino)pyridin-3-yl)phenyl)acetamide,
2-(3 -phenoxybenzyloxy)-5 -phenylpyridine,
2-(6-(4-(5 -(trifluoromethyl)pyridin-2-yl)piperazin- 1 -yl)pyridin-3 - yl)benzaldehyde,
2-(6-(3-(trifluoromethoxy)phenylamino)pyridin-3-yl)benzaldehyde, N 1 -(5 -(3 -methoxyphenyl)pyridin-2-yl)-N3 ,N3 -dimethylbenzene- 1 ,3 -diamine, 2-(6-morpholinopyridin-3-yl)benzaldehyde, 5 -(3 -methoxyphenyl)-2-(pyridin-2-ylmethoxy)pyridine, 1 -(5 -(2-fluorophenyl)pyridin-2-yl)-4-methylpiperazine, l-(5-(6-(2-phenoxyphenylamino)pyridin-3-yl)thiophen-2-yl)ethanone, 5-(2-chlorophenyl)-N-(2,2,2-trifluoroethyl)pyridin-2-amine, N-(3-(trifluoromethyl)phenyl)-5-(4-(trifluoromethyl)phenyl)pyridin-2-amine, N-(3-(6-(2-(pyridin-4-yl)ethylamino)pyridin-3-yl)phenyl)acetamide, 2-(6-(4-(pyridin-2-yl)piperazin-l-yl)pyridin-3-yl)benzaldehyde, N-(3-(6-(3-(trifluoromethyl)phenylamino)pyridin-3-yl)phenyl)acetamide, 5-(benzofuran-2-yl)-N-(2-phenoxybenzyl)pyridin-2-amine, 5-(4-methoxyphenyl)-N-(2-(pyridin-4-yl)ethyl)pyridin-2-amine, N-(3,4-dichlorophenyl)-5-(thiophen-2-yl)pyridin-2-amine, l-(5-(2-chlorophenyl)pyridin-2-yl)-4-(pyridin-2-yl)piperazine,
2-(2-phenoxybenzyloxy)-5-(3,4,5-trimethoxyphenyl)pyridine,
N-(2,3-dihydro-lH-inden-l-yl)-5-phenylpyridin-2-amine,
3 -(6-(2,3 -dihydro- 1 H-inden- 1 -ylamino)pyridin-3 -yl)benzaldehyde,
2-(6-(pyridin-2-ylmethoxy)pyridin-3-yl)benzaldehyde,
4-(6-(isopropylthio)pyridin-3-yl)benzaldehyde,
2-(6-(3,4-dichlorophenylamino)pyridin-3-yl)benzaldehyde,
3-(6-(2,2,2-trifluoroethylamino)pyridin-3-yl)benzaldehyde,
5-(3-(trifluoromethyl)phenyl)-N-(3,4,5-trimethoxyphenyl)pyridin-2-amine,
N-(2,6-difluorobenzyl)-5-p-tolylpyridin-2-amine,
N-(2,3-dihydro- lH-inden- 1 -yl)-5-p-tolylpyridin-2-amine,
2-(6-(2-(pyridin-2-yl)ethylamino)pyridin-3-yl)benzaldehyde,
2-(3-(5-(2-formylphenyl)pyridin-2-ylamino)pheno xy)-N ,N-dimethylacetamide,
4-(6-(4-methylpiperazin- 1 -yl)pyridin-3-yl)benzaldehyde,
5 -(3 -fluorophenyl)-2-(3 -(pyridin-2-yl)propoxy)pyridine,
4-(6-(3 -phenoxyphenylamino)pyridin-3 -yl)benzaldehyde,
4-(2-(5 -(3 -fluorophenyl)pyridin-2-yloxy)ethyl)morpholine,
2-(6-(cyclopropylmethylamino)pyridin-3-yl)benzaldehyde,
3 -(6-(4-(3 -(trifluoromethyl)phenyl)piperazin- 1 -yl)pyridin-3 -yl)benzaldehyde,
2-(6-(2,2,2-trifluoroethylamino)pyridin-3-yl)benzaldehyde,
3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)benzaldehyde,
5-(benzo[d] [ 1 ,3]dioxol-5-yl)-N-(l -(4-fluorophenyl)ethyl)pyridin-2-amine,
4-(5-(2-chlorophenyl)pyridin-2-yl)morpholine,
4-(6-(2-morpholinoethoxy)pyridin-3-yl)benzaldehyde,
N 1 ,N 1 -dimethyl-N3 -(5 -(thiophen-2-yl)pyridin-2-yl)benzene- 1 ,3 -diamine,
N-(3-(6-(2-(pyridin-2-yl)ethylamino)pyridin-3-yl)phenyl)acetamide,
4-(6-(3,5-dichlorophenylamino)pyridin-3-yl)benzaldehyde,
N-(l-phenylethyl)-3,3'-bipyridin-6-amine,
N-(3 -(5 -(3 -acetamidophenyl)pyridin-2-ylamino)phenyl)-3 -methoxybenzamide,
5-(2-methoxyphenyl)-2-(pyridin-2-ylmethoxy)pyridine,
2-(6-(3 -phenoxyphenylamino)pyridin-3 -yl)benzaldehyde,
3 -methoxy-N-(3 -(5 -(2-(methylthio)phenyl)pyridin-2-ylamino)phenyl)benzamide,
5 -(3 -methoxyphenyl)-2-(3 -phenoxybenzyloxy)pyridine, 5-(2-fluorophenyl)-2-(3-(pyridin-2-yl)propoxy)pyridine,
5-(4-methoxyphenyl)-2-(3-(pyridin-2-yl)propoxy)pyridine,
N-(3-(trifluoromethoxy)phenyl)-5-(4-(trifluoromethyl)phenyl)pyridin-2-amine,
3-(6-(4-(pyridin-2-yl)piperazin-l-yl)pyridin-3-yl)benzaldehyde,
5-(2-fluorophenyl)-2-(pyridin-2-ylmethoxy)pyridine,
2-(3 -(5 -(3 -formylphenyl)pyridin-2-ylamino)pheno xy)-N ,N-dimethylacetamide,
N 1 -(5 -(2-fluorophenyl)pyridin-2-yl)-N3 ,N3 -dimethylbenzene- 1 ,3 -diamine,
5 -(benzo [d] [ 1 ,3 ] dioxol-5 -yl)-N-(3 -(trifluoromethyl)benzyl)pyridin-2-amine,
N-(3 -(6-(p-tolylamino)pyridin-3 -yl)phenyl)acetamide,
N-(3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)phenyl)acetamide,
5 -phenyl-N-(3 -(trifluoromethyl)phenyl)pyridin-2-amine,
N-(4-(6-(3-(trifluoromethyl)phenylamino)pyridin-3-yl)phenyl)acetamide,
N-methyl-3-(6-(3-(Trifluoromethyl)phenylamino)pyridin-3-yl)benzamide,
5 -(3 -(dimethylamino)phenyl)-N-(3 -(trifluoromethyl)phenyl)pyridin-2-amine,
5-(naphthalen-2-yl)-N-(3-(trifluoromethyl)phenyl)pyridin-2-amine,
N-(3 -(6-(phenylamino)pyridin-3 -yl)phenyl)acetamide,
N-(3-(6-(methyl(3-(trifluoromethyl)phenyl)amino)pyridin-3- yl)phenyl)acetamide,
N-(5 -(3 -acetamidophenyl)pyridin-2-yl)-3 -(trifluoromethyl)benzamide, N-(3 -(6-(3 -(trifluoromethyl)phenylamino)pyridin-3 -yl)phenyl)isobutyramide, 2,2,2-trifluoro-N-(3-(6-(3-(trifluoromethyl)phenylamino)pyridin-3- yl)phenyl)acetamide,
6-(6-(3-(trifluoromethoxy)phenylamino)pyridin-3-yl)indolin-2-one, N-(3-(6-(3-(trifluoromethoxy)phenylamino)pyridin-3-yl)phenyl)propionamide, 5 -(2-methylbenzo [d]oxazol-5 -yl)-N-(3 -(trifluoromethoxy)phenyl)pyridin-2- amine,
N-(3-(6-(4-(trifluoromethoxy)phenylamino)pyridin-3-yl)phenyl)acetamide, N-(3-(6-(2,2-difluorobenzo[d] [ 1 ,3]dioxol-5-ylamino)pyridin-3- yl)phenyl)acetamide, N-(3-(6-(2,2-difluorobenzo[d] [ 1 ,3]dioxol-5-ylamino)pyridin-3- yl)phenyl)acetamide, N-methyl-N-(3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 - yl)phenyl)acetamide,
- I l l - 5 -(2-methylbenzo [d]thiazol-5 -yl)-N-(3 -(trifluoromethoxy)phenyl)pyridin-2- amine,
N-(6'-(3-(trifluoromethoxy)phenylamino)-2,3'-bipyridin-4-yl)acetamide, 1 -(3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)phenyl)propan-2-one, N-(5-(3-acetamidophenyl)pyridin-2-yl)-3-(trifluoromethoxy)benzamide, N-(3-(6-(2-(trifluoromethoxy)phenylamino)pyridin-3-yl)phenyl)acetamide, N-(4-(6-(3-(trifluoromethoxy)phenylamino)pyridin-3-yl)phenyl)acetamide, N-(3 -(6-(3 -(trifluoromethoxy)phenylsulfonamido)pyridin-3 -yl)phenyl)acetamide, 3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)benzamide, N-methyl-3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)benzamide, N-(3 -(6-(3 -(trifluoromethylsulfonyl)phenylamino)pyridin-3 - yl)phenyl)acetamide,
N-(2-(6-(3-(trifluoromethoxy)phenylamino)pyridin-3-yl)phenyl)acetamide, N-(3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 - yl)phenyl)methanesulfonamide,
1 -methyl-3 -(3 -(6-(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)phenyl)urea, N-(3 -(2-(3 -(trifluoromethoxy)phenylamino)pyrimidin-5 -yl)phenyl)acetamide, or N-(3 -(5 -(3 -(trifluoromethoxy)phenylamino)pyridin-3 -yl)phenyl)acetamide, or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
31. A pharmaceutical composition comprising the compound of any one of claims 1 and 5 to 30, and a pharmaceutically acceptable excipient.
32. A process for the preparation of the pharmaceutical composition of claim 31, wherein the process comprise admixing the ingredients.
33. A process for the preparation of the compound of any one of claims 1 and 5 to 30, comprising:
a) reacting a compound of formula (II):
Figure imgf000113_0001
(H), wherein X1 is a monovalent leaving group, halo, or bromo, with a compound of formula (III):
OH
R-<
OH
(HI), or a compound of formula (IV):
Figure imgf000114_0001
(IV); or
b) reacting a compound of formula (IX):
Figure imgf000114_0002
(IX), wherein R12 is H or Ci-C6 alkyl, or the two R12 groups together with the B and O atoms form a 5 to 6 membered heterocyclyl, optionally substituted with one or more methyl, with a compound of formula (X):
R2-Br (X); or
c) when L1 is a bond, R1 is H, and R3 is -L3-Rπ, reacting a compound of formula (XII):
Figure imgf000114_0003
(XII), wherein X3 is a leaving group, with a compound of formula (XIII):
R1 ^NH2 (XIII).
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US8519134B2 (en) 2009-11-17 2013-08-27 Novartis Ag Aryl-pyridine derivatives as aldosterone synthase inhibitors
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