WO2010020432A8 - Compounds for treatment of duchenne muscular dystrophy - Google Patents

Compounds for treatment of duchenne muscular dystrophy Download PDF

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WO2010020432A8
WO2010020432A8 PCT/EP2009/006099 EP2009006099W WO2010020432A8 WO 2010020432 A8 WO2010020432 A8 WO 2010020432A8 EP 2009006099 W EP2009006099 W EP 2009006099W WO 2010020432 A8 WO2010020432 A8 WO 2010020432A8
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carboxamide
pyrimidine
fluorophenyl
alkyl
optionally substituted
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PCT/EP2009/006099
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French (fr)
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WO2010020432A3 (en
WO2010020432A2 (en
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Graham Michael Wynne
Stephen Wren
Renate Maria Van Well
Frank SCHROËR
Cristina Lecci
Severine Danielle Poignant
Shucong Ma
Francis Wilson
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Biomarin Iga Limited
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • 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
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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    • 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
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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
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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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    • 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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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • compositions comprising the compounds, and methods of use thereof.
  • method for the treatment 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 frame-shift errors downstream, whereas approximately 40% are point mutations or small frame-shift 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 (Bulfield et al., X Chromosome-Linked Muscular Dystrophy ⁇ mdx) in the Mouse, Proc. Natl. Acad. ScL 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., S1: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.
  • kits for the treatment of muscular dystrophy and related conditions including DMD, compositions comprising the compounds, and methods of use thereof.
  • compounds that upregulate endogenous utrophin and are useful in the treatment of muscular dystrophy, including DMD.
  • R 1 , R 2 , R 3 , R 4 , L 2 , L 3 , and L 4 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 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, or Becker muscular dystrophy.
  • 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.
  • a compound of formula (I) or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
  • the method treats, prevents, and/or ameliorates one or more symptoms of Duchenne muscular dystrophy, hi 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.
  • the compounds of formula (I) are used to treat or prevent Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • 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.
  • C 1 -C 6 alkyl refers to an optionally substituted straight or branched saturated hydrocarbon chain having one to six carbon atoms. In one embodiment, the "C 1 -C 6 alkyl” is optionally substituted with one or more halo. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, t- butyl, and n-hexyl.
  • Cio alkyl have similar meanings except that they contain respectively from one to four and from one to ten carbon atoms.
  • C 2 -C 6 alkenyl refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and containing at least one carbon-carbon double bond.
  • the "C 2 -C 6 alkenyl” is optionally substituted by one or more halo. Examples include, but are not limited to, ethenyl,
  • C 2 -C 6 alkynyl refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and containing at least one carbon-carbon triple bond.
  • the "C 2 -C 6 alkynyl” is optionally substituted by one or more halo. Examples include, but are not limited to, ethynyl,
  • C 2 -C 10 alkenyl and “C 2 -Ci O alkynyl” have similar meanings except that they contain from two to ten carbon atoms.
  • Ci-C 6 haloalkyl refers to a Ci-C 6 alkyl group as defined above substituted by one or more halo.
  • alkylene refers to a linear or branched saturated divalent hydrocarbon radical, wherein the alkylene may optionally be substituted as described herein.
  • alkylene encompasses both linear and branched alkylene, unless otherwise specified.
  • the alkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (Ci-C 2 o), 1 to 15 (Ci-Ci 5 ), 1 to 10 (Ci-Cio), 1 to 6 (Ci-C 6 ), or 1 to 5 (Ci-C 5 ) carbon atoms, or branched saturated 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 ), 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 as "lower alkylene.”
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene (including all isomeric forms), n-propylene, 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 linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms [0026]
  • alkenylene refers to a linear or branched divalent hydrocarbon radical, which contains one or more (in one embodiment, one to five) carbon-carbon double bonds. The alkenylene may be optionally substituted as described herein.
  • alkenylene also embraces radicals having "cis” and “trans” configurations, or alternatively, "£" and "Z” configurations.
  • alkenylene encompasses both linear and branched alkenylene, unless otherwise specified.
  • C 2 -C 6 alkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • 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.
  • alkynylene refers to a linear or branched divalent hydrocarbon radical, which contains one or more (in one embodiment, one to five) carbon-carbon triple bonds.
  • the alkynylene may be optionally substituted as described herein.
  • the term “alkynylene” also encompasses both linear and branched alkynylene, unless otherwise specified.
  • 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
  • alkynylene groups include, but are not limited to, ethynylene (-C ⁇ C-) and propargylene (-CH 2 C ⁇ C-).
  • C 2 -C 6 alkynylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • carbocyclic refers to an optionally substituted ring system in which all the ring atoms are carbon atoms. In one embodiment, the carbocyclic is optionally substituted with one or more halo.
  • heterocyclic refers to an optionally substituted ring system in which one or more of the ring atom(s) is a hetero atom selected from N, O and S.
  • aromatic refers to an optionally substituted carbocyclic or heterocyclic ring system which has aromatic character.
  • the aromatic ring has one or two rings and from 5 to 10 ring atoms. In bicyclic systems, one of the rings may have aromatic character.
  • aromatic ring systems include, but are not limited to, phenyl, naphthalene, pyridine, pyrimidine, furan, thiophene, indole, isoindole, benzofuran, benzimidazole, benzimidazoline, benzodioxyl, benzodioxane, quinoline, isoquinoline, tetrahydroisoquinoline, quinazoline, thiazole, benzthiazole, benzoxazole, indazole, and imidazole ring systems.
  • non-aromatic refers to an optionally substituted carbocyclic or heterocyclic ring system which may be fully or partially saturated.
  • the non-aromatic ring is monocyclic and has from 4 to 7 ring atoms.
  • Examples of non-aromatic ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidine, piperazine, mo ⁇ holine, tetrahydrofuran, and pyrrolidine.
  • the carbocyclic or heterocyclic ring systems are optionally substituted with one or more -X 4 -R 7 , wherein:
  • X 4 is a bond, Ci-C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, -NR 10 -, -S-, -O-, -(CR 10 R 10 V, -(CR 10 R 10 ) q O-, -O(CR 10 R 10 ) q -NR 10 C(O)-, -OC(O)NR 10 -, -NR 10 C(O)NR 10 -, -NR 10 C(S)NR 10 -, -NR 10 C(NH)NR 10 -, -NR 10 C(NH)-, -C(O)- -C(S)- -C(O)O-, -C(O)NR 10 -, -C(S)NR 10 -, -SO-, -SO 2 -, -SO 2 NR 10 -, -OCH 2 C(O)NR 10 -, or -P(O)OR 10 -;
  • R 7 is H, Ci-C 6 alkyl, C 3 -C 7 cycloalkyl, C 7 -C 8 aralkyl, C 3 -C 7 heterocyclyl, C 5 -C 7 aryl, or C 5 -C 7 heteroaryl, wherein the alkyl, cycloalkyl, aralkyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with one or more halo, -OH, -0(Ci-C 6 alkyl), or -N(Ci-C 6 alkyl) 2 groups, and wherein the cycloalkyl, aralkyl, heterocyclyl, aryl, and heteroaryl groups are also optionally substituted with Ci-C 6 alkyl; or, when X 4 is a bond, R 7 may also be halo, -NO 2 , or -CN.
  • the carbocyclic or heterocyclic ring systems are optionally substituted with one or more -X 4 -R 7 , wherein:
  • X 4 is a bond, Ci-C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, -NR 10 -, -S-, -0-, -(CR 10 R 1 V, -(CR 10 R 10 ) q O- -0(CR 10 R 1 VNR 10 C(O)- -OC(O)NR 10 -, -NR 10 C(O)NR 10 -, -NR 10 C(S)NR 10 -, -NR 10 C(NH)NR 10 -, -NR 10 C(NH)- -C(O)-, -C(S)- -C(O)NR 10 -, -C(S)NR 10 -, -SO-, -SO 2 -, -SO 2 NR 10 -, -OCH 2 C(O)NR 10 -, or -P(O)OR 10 -; where each R 10 is independently H or optionally substituted Ci-C 6 al
  • the aromatic or non-aromatic ring systems are optionally substituted with one or more -X 4 -R 7 , wherein X 4 and R 7 are defined herein elsewhere.
  • cycloalkyl or “non- aromatic carbocyclic” refer to an optionally substituted cyclic fully saturated hydrocarbon ring radical, which is bridged or non-bridged.
  • the cycloalkyl has from 3 to 20 (C 3 -C 20 ), from 3 to 15 (C 3 -Ci 5 ), from 3 to 10 (C 3 -Ci 0 ), from 3 to 8 (C 3 -C 8 ), or from 3 to 7 (C 3 -C 7 ) ring carbon atoms.
  • cycloalkyl groups 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 is optionally substituted with one or more -X 4 -R 7 , wherein X 4 and R 7 are defined herein elsewhere.
  • aryl or "aromatic carbocyclic” refer to an optionally substituted monocyclic or multicyclic aromatic group that contains at least one aromatic hydrocarbon ring.
  • the aryl has from 6 to 20 (C 6 -C 2O ), from 6 to 15 (C 6 -C ]5 ), or from 6 to 10 (C 6 -C io) ring atoms.
  • aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).
  • the aryl or aromatic carbocyclic is optionally substituted with one or more -X 4 -R 7 , wherein X 4 and R 7 are defined herein elsewhere.
  • 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.
  • heteroaryl or “aromatic heterocyclic” refer to an optionally substituted monocyclic or multicyclic aromatic group 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.
  • each ring of the heteroaryl group 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.
  • 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, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyr
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
  • the heteroaryl or aromatic heterocyclic is optionally substituted with one or more -X 4 -R 7 , wherein X 4 and R 7 are defined herein elsewhere.
  • heterocyclyl refers to an optionally substituted monocyclic or multicyclic non-aromatic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms.
  • the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, 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, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclic radicals include, but are not limited to, azepinyl, 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, 1,4-dithianyl
  • halo or halogen refers to fluoro, chloro, bromo, or iodo.
  • appropriate pharmaceutically and veterinarily acceptable salts include basic addition salts such as sodium, potassium, calcium, aluminum, zinc, magnesium, and other metal salts, as well as choline, diethanolamine, ethanolamine, ethyl diamine, and other known basic addition salts.
  • pharmaceutically or veterinarily acceptable salts may also include acid addition salts of organic acids, such as, e.g., carboxylic acids, including but not limited to, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, lactobionate, pivolate, camphorate, undecanoate, and succinate; organic sulfonic acids, including but not limited to, methanesulfonate, ethanesulfonate, 2-
  • Salts which are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates.
  • prodrug refers to any covalently bonded compounds which release the active parent drug according to formula (I) in vivo.
  • prodrug refers to any covalently bonded compounds which release the active parent drug according to formula (I) in vivo.
  • a chiral center or another form of isomeric center is present in a compound provided herein, all forms of such isomer or isomers, including 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 an diasteromerically enriched mixture, or the racemic mixture may be separated using known techniques and an individual enantiomer may be used alone.
  • 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 term “therapeutically effective amount” are meant to include the amount of a compound that, when administered, is sufficient to prevent 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.
  • 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 ameliorating 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 refers to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
  • 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 (+) an 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.
  • (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
  • sign of optical rotation, (+) and (-) is not related to the absolute configuration of the molecule, R and S.
  • 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. Where the solvent is water, the solvate is a hydrate.
  • R 1 is H, halo, or Cj-C 6 alkyl
  • L 2 is a linker selected from a bond, -O-, -S(O) n -, and -NR 5 -;
  • R 2 is (i) hydrogen; or (ii) Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 3 -C 8 cycloalkyl, each of which is optionally substituted with one or more halo, -OR 5 , -R 6 , or -OR 6 ; or (iii) 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system, each of which is optionally substituted;
  • L 3 is a linker selected from a bond, -(CR 8 R 8 ) m - -NR 8 -, -O-, -S-, -(CR 8 R 8 ) m NR 8 -, -C(O)NR 8 -, -C(S)NR 8 -, -C(NH)NR 8 - -SO 2 NR 8 -, -C(O)-, -
  • R 3 is (i) hydrogen; or (ii) C]-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 3 -C 8 cycloalkyl, each of which is optionally substituted with one or more halo, -OR 5 , -N(R 5 ) 2 , -R 6 , or -OR 6 ; or (iii) 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system, each of which is optionally substituted; or (iv) when L 3 is -NR 8 - or -C(O)NR 8 -, R 3 together with R 8 and the nitrogen atom to which it is attached form an optionally substituted 5-7 membered nitrogen containing heterocyclic ring, which optionally contains one or two further heteroatoms selected from -O-, -NR 11 -, and -S(O) n -, which is
  • R 4 is (i) hydrogen; or (ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 3 -C 8 cycloalkyl, each of which is optionally substituted with one or more halo, -OR 5 , -N(R 5 ) 2 , -R 6 , or -OR 6 ; or (iii) 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system, each of which is optionally substituted; or (iv) when L 4 is -NR 9 - or -C(O)NR 9 -, R 4 together with R 9 and the nitrogen atom to which it is attached form an optionally substituted 5-7 membered nitrogen containing heterocyclic ring, which optionally contains one or two further heteroatoms selected from -0-, -NR 11 -, and -S(O) n -, which 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.
  • 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.
  • R 3 is (i) hydrogen; or (ii) Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 3 -C 8 cycloalkyl, each of which is optionally substituted with one or more halo, -OR 5 , -N(R 5 ) 2 , -R 6 , or -OR 6 ; or (iii) 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system, each of which is optionally substituted; wherein R 5 and R 6 are as defined herein elsewhere.
  • R 11 is hydrogen, optionally substituted Ci-C 6 alkyl, or 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system each of which is optionally substituted.
  • R 1 is hydrogen. In one embodiment, R 1 is halo. In one embodiment, R 1 is fluoro. In one embodiment, R 1 is chloro. In one embodiment, R 1 is Ci- C 6 alkyl. In one embodiment, R 1 is Ci- C 6 alkyl optionally substituted with one or more halo. In one embodiment, R 1 is Ci- C 6 alkyl optionally substituted with one or more fluoro.
  • R 1 is methyl. In one embodiment, R 1 is ethyl. In one embodiment, R 1 is methyl optionally substituted with one or more fluoro. In one embodiment, R 1 is ethyl optionally substituted with one or more fluoro.
  • L 2 is a bond
  • R 2 is hydrogen or Ci-C 6 alkyl. In one embodiment, R 2 is hydrogen. In one embodiment, R 2 is Ci-C 6 alkyl. In one embodiment, R 2 is Ci-C 6 alkyl optionally substituted with one or more halo. In one embodiment, R 2 is Ci-C 6 alkyl optionally substituted with one or more fluoro. In one embodiment, R 2 is methyl, ethyl, propyl, or isopropyl. In one embodiment, R 2 is methyl, ethyl, propyl, or isopropyl, each of which is optionally substituted with one or more fluoro.
  • L 3 is -CONR 8 -, wherein R 8 is as defined herein elsewhere.
  • L 3 is -CONH-. In one embodiment, L 3 is -CONMe-.
  • L 3 is -NR 8 -, wherein R 8 is as defined herein elsewhere.
  • L is -NH-.
  • L is -N(CH 3 )-.
  • L is -N(CH 2 CH 3 )-.
  • L 4 is a bond, -O-, or -NR 9 -, wherein R 9 is as defined herein elsewhere.
  • L 4 is a bond.
  • L 4 is -O-.
  • L 4 is -NR 9 -.
  • R 4 and R 9 together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring as defined herein elsewhere.
  • L 4 is -NH-.
  • L 4 is -N(CH 3 )-.
  • L 4 is -N(CH 2 CH 3 )-.
  • L 4 is -CONR 9 -, wherein R 9 is as defined herein elsewhere.
  • R 4 and R 9 together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring as defined herein elsewhere.
  • L 4 is -CONH-. In one embodiment, L 4 is -CONMe-.
  • R 1 is hydrogen
  • L 2 is a bond
  • R 2 is hydrogen or C]-C 6 alkyl
  • L is -CONR -, wherein R is as defined herein elsewhere, and L is a bond, -O-, or -NR -, wherein R 9 is as defined herein elsewhere.
  • R 1 is hydrogen, L 2 is a bond, R 2 is hydrogen, L 3 is -CONR 8 -, wherein R 8 is as defined herein elsewhere, and L 4 is a bond, -O-, or -NR 9 -, wherein R 9 is as defined herein elsewhere.
  • R 1 is hydrogen, L 2 is a bond, R 2 is Ci-C 6 alkyl, L 3 is -CONR 8 -, wherein R 8 is as defined herein elsewhere, and L 4 is a bond, -O-, or -NR 9 -, wherein R 9 is as defined herein elsewhere.
  • R 1 is hydrogen, L 2 is hydrogen, L 3 is -CONR 8 -, wherein R 8 is as defined herein elsewhere, and L 4 is a bond, -O-, or -NR 9 -, wherein R 9 is as defined herein elsewhere.
  • R 1 is hydrogen, L 2 is hydrogen, L 3 is -CONR 8 -, wherein R 8 is as defined herein elsewhere, and L 4 is
  • R is hydrogen or Ci-C 6 alkyl
  • L is -CONR -, wherein R is as defined herein elsewhere
  • L 4 is a bond.
  • R 1 is hydrogen, L 2 is a bond
  • R 2 is hydrogen or Cj-C 6 alkyl
  • L 3 is -CONR 8 -, wherein R 8 is as defined herein elsewhere
  • L 4 is -O-.
  • R 1 is hydrogen, L 2 is a bond
  • R 2 is hydrogen or Ci-C 6 alkyl
  • L 3 is -CONR 8 -, wherein R 8 is as defined herein elsewhere
  • L 4 is -NR 9 -, wherein R 9 is as defined herein elsewhere.
  • R is hydrogen, L is a bond, R is hydrogen, L 3 is -CONR 8 -, wherein R 8 is as defined herein elsewhere, and L 4 is a bond.
  • R 1 is hydrogen, L 2 is a bond, R 2 is Ci-C 6 alkyl, L 3 is -CONR 8 -, wherein R 8 is
  • R is hydrogen, L is a bond
  • R 2 is hydrogen
  • L 3 is -CONR 8 -, wherein R 8 is as defined herein elsewhere
  • L 4 is -0-.
  • R 1 is hydrogen, L 2 is a bond
  • R 2 is Ci-C 6 alkyl
  • L 3 is -CONR 8 -, wherein R 8 is as defined herein elsewhere
  • L 4 is -0-.
  • R 1 is hydrogen, L 2 is a bond
  • R 2 is hydrogen, L 3 is -CONR 8 -, wherein R 8 is as defined herein elsewhere, and L 4 is -NR 9 -, wherein R 9 is as defined herein elsewhere.
  • R 1 is hydrogen
  • L 2 is a bond
  • R 2 is Ci-C 6 alkyl
  • L 3 is -CONR 8 -, wherein R 8 is as defined herein elsewhere
  • L 4 is -NR 9 -, wherein R 9 is as defined herein elsewhere.
  • Any combinations of R 1 , L 2 , R 2 , L 3 , R 3 , L 4 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , X 4 , m, n, and q are encompassed by this disclosure and specifically provided herein.
  • provided herein is a compound of formula (Ia):
  • R 3 is hydrogen.
  • R 3 is (i) Ci-C 6 alkyl optionally substituted with one or more -OR 5 or -R 6 ; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl or heterocyclyl group, each of which is optionally substituted with one or more halo, -R 7 , -OR 7 , -OCH 2 C(O)NR 10 R 7 , or -SO 2 R 7 ; or (iii) a 9-10 membered heteroaryl or heterocyclyl group, each of which is optionally substituted with one or more halo, -R 7 , or -OR 7 ; or (iv) R 3 and R 8 together with the nitrogen atom to which they are attached form a piperizine, which is optionally substituted with R 11 at the second nitrogen atom; wherein R 5 , R 6 , R 7 , R 10 , and R 11 are as defined herein elsewhere.
  • R 3 is (i) Ci-C 6 alkyl optionally substituted with one or more -OR 5 or -R 6 ; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl or heterocyclyl group, each of which is optionally substituted with one or more halo, -R 7 , -OR 7 -OCH 2 C(O)NR 10 R 7 , or -SO 2 R 7 ; wherein R 5 , R , R , and R 10 are as defined herein elsewhere.
  • R 3 is (i) Ci-C 6 alkyl optionally substituted with one or more -OR 5 or -R 6 ; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl or heterocyclyl group, each of which is optionally substituted with one or more halo, -R 7 , -OR 7 , or -OCH 2 C(O)NR 10 R 7 ; wherein R 5 , R 6 , R 7 , and R 10 are as defined herein elsewhere.
  • R 3 is (i) Ci-C 6 alkyl optionally substituted with one or more -0(Ci-C 4 alkyl), C 3 -C 7 cycloalkyl, C 3 -C 7 heterocyclyl; C 5 -C 6 aryl, or C 5 -C 6 heteroaryl; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more halo, -OH, Cj-C 4 alkyl, -0(Ci-C 4 alkyl), -SO 2 (Ci-C 4 alkyl), -OCH 2 C(O)N(C]-C 4 alkyl) 2 , C 3 -C 7 cycloalkyl, or C 3 -C 7 heterocyclyl; wherein the alkyl groups are optionally substituted with C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl
  • R 3 is (i) C 1 -C 6 alkyl optionally substituted with one or more methoxy, benzyloxy, cyclopropyl, phenyl, thienyl, or pyridyl; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more fluoro, -OH, methyl, methoxy, benzyloxy, or methane sulfonyl.
  • R 3 is optionally substituted Ci alkyi.
  • R J is unsubstituted Ci alkyl.
  • R 3 is Ci alkyl, substituted with phenyl, thienyl, pyridinyl, cyclopropyl, or -OMe. In one embodiment, R 3 is optionally substituted C 2 alkyl. In one embodiment, R 3 is unsubstituted C 2 alkyl. In one embodiment, R 3 is C 2 alkyl, substituted with phenyl, thienyl, pyridinyl, cyclopropyl, or -OMe. In one embodiment, R 3 is optionally substituted C 3 alkyl. In one embodiment, R 3 is optionally substituted C 4 alkyl. In one embodiment, R 3 is unsubstituted C 4 alkyl.
  • R 3 is optionally substituted C 5 alkyl. In one embodiment, R 3 is optionally substituted C 6 alkyl. [0083] In one embodiment, R 3 is cyclohexyl, phenyl, or pyridinyl, each of which is optionally substituted with one or more halo, -R 7 , -OR 7 , -OCH 2 C(O)NR 10 R 7 , or -SO 2 R 7 . In one embodiment, R 3 is cyclohexyl, phenyl, or pyridinyl, each of which is optionally substituted with one or more halo, -R 7 , -OR 7 , or -OCH 2 C(O)NR 10 R 7 .
  • R is optionally substituted phenyl. In one embodiment, R is unsubstituted phenyl. In one embodiment, R 3 is phenyl substituted with one or more halo,
  • Ci-C 4 alkyl 5-7 membered heterocyclyl, -0(Ci-C 4 alkyl), -0(C 7 -C 8 aralkyl),
  • R 3 is phenyl substituted with one or more fluoro, chloro, methyl, ethyl, propyl, /-propyl, t-butyl, /-butyl, CF 3 , 4- methylpiperazin-1-yl, -OCH 3 , -OCH 2 Ph, -OCH 2 C(O)N(CH 3 ) 2 , Or -SO 2 Me.
  • R 3 is optionally substituted cyclohexyl. In one embodiment,
  • R 3 is unsubstituted cyclohexyl. In one embodiment, R 3 is cyclohexyl substituted with one or more -OH.
  • R 3 is optionally substituted pyridinyl. In one embodiment, R 3 is unsubstituted pyridinyl.
  • R 3 is benzo[cQ[l,3]dioxolyl. In one embodiment, R 3 is 2,3- dihydrobenzo [b] [ 1 ,4] dioxinyl .
  • R 3 and R 8 together with the nitrogen atom to which they are attached form a piperizine ring, which is optionally substituted with an optionally substituted
  • R 3 and R 8 together with the nitrogen atom to which they are attached form a piperizine ring, which is optionally substituted at the second nitrogen atom with diethylaminoethyl.
  • R 3 examples include, but are not limited to, (i) phenyl and pyridyl, each of which is unsubstituted or substituted with one or more fluoro, methyl, t-butyl, 4- methylpiperazin-1-yl, benzyloxy, or methoxy; and (ii) R and R together form a piperazine ring substituted with diethylaminoethyl; and (iii) 2-methoxyethyl, cyclopropylmethyl, thienylmethyl, and cyclohexyl.
  • the aryl groups are optionally substituted with one or more halo, C]-C 6 alkyl, Ci-C 6 alkoxy, benzyloxy, C 3 -C 7 heterocyclyl, optionally substituted with methyl or ethyl.
  • R 3 is phenyl substituted with one or more fluoro. In one embodiment, R 3 is /? ⁇ ra-fluoro-phenyl.
  • R 8 is hydrogen, methyl, or ethyl. In one embodiment, R 8 is hydrogen. In one embodiment, R 8 is methyl. In one embodiment, R 8 is ethyl. [0092] In one embodiment, L 4 is a bond.
  • L 4 is -NR 9 -. In one embodiment, L 4 is -NH-. In one embodiment, L 4 is -N(CH 3 )-. In one embodiment, L 4 is -N(CH 2 CH 3 )-.
  • R 4 is hydrogen
  • R 4 is (i) Cj-C 6 alkyl, optionally substituted with one or more
  • R 4 is (i) C]-C 6 alkyl, optionally substituted with one or more
  • R 5 , R 6 , R 7 , and R 10 are as defined herein elsewhere.
  • R 4 is (i) C 1 -C 6 alkyl, optionally substituted with one or more
  • R 10 are as defined herein elsewhere.
  • R 4 and R 9 together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring, which is optionally substituted with one or more R 7 , wherein R 7 is as defined herein elsewhere.
  • R 4 and R 9 together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring, which is optionally substituted with one or more -X 4 -R 7 , wherein X 4 and R 7 are as defined herein elsewhere.
  • R 4 and R 9 together with the nitrogen atom to which they are attached form a piperizine ring, wherein the second nitrogen atom of the piperizine ring is optionally substituted with R 11 , wherein R 11 are as defined herein elsewhere.
  • R 4 is (i) Ci-C 6 alkyl, which is optionally substituted with one or more -OH, -0(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered carbocyclyl, or 5-6 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl and heterocyclyl groups are optionally substituted with one or more halo, CN, or C 1 -C 4 alkyl; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more halo, -CN, -OH, -0(Ci-C 6 alkyl), C 1 -C 6 alkyl, -SO 2 (C 1 -C 6 alkyl), -NHSO 2 (
  • R 4 is (i) Ci-C 6 alkyl, which is optionally substituted with one or more -OH, -0(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered carbocyclyl, or 5-6 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl and heterocyclyl groups are optionally substituted with one or more halo or CN; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more halo, -OH, -0(Cj-C 6 alkyl), Ci-C 6 alkyl, -SO 2 (C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -NHC(O)
  • R 4 is (i) C]-C 6 alkyl, which is optionally substituted with one or more -OH, -0(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 , 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered carbocyclyl, or 5-6 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl and heterocyclyl groups are optionally substituted with one or more halo or CN; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more halo, -OH, -0(Ci-C 6 alkyl), Ci-C 6 alkyl, -SO 2 (C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -NHC(
  • R 4 is (i) C 1 -C 6 alkyl, which is optionally substituted with one or more -OH, -0(Cj-C 6 alkyl), -N(Cj-C 6 alkyl) 2 , 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered carbocyclyl, or 5-6 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl and heterocyclyl groups are optionally substituted with one or more halo or CN; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more halo, -OH, -0(Ci-C 6 alkyl), Ci-C 6 alkyl, -SO 2 (C-C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -NHC(O)
  • R 4 is optionally substituted Ci alkyl. In one embodiment, R 4 is unsubstituted Ci alkyl. In one embodiment, R 4 is Ci alkyl, optionally substituted with phenyl, fluorophenyl, thienyl, furanyl, methyl-furanyl, pyridinyl, morpholinyl, -OH, -OMe, or -N(Me) 2 . In one embodiment, R 4 is optionally substituted C 2 alkyl. In one embodiment, R 4 is unsubstituted C 2 alkyl.
  • R 4 is C 2 alkyl, optionally substituted with phenyl, fluorophenyl, thienyl, furanyl, methyl-furanyl, pyridinyl, morpholinyl, -OH, -OMe, or -N(Me) 2 .
  • R 4 is optionally substituted C 3 alkyl.
  • R 4 is unsubstituted C 3 alkyl.
  • R 4 is C 3 alkyl, optionally substituted with one or more -OH.
  • R 4 is optionally substituted C 4 alkyl.
  • R 4 is unsubstituted C 4 alkyl.
  • R 4 is C 4 alkyl optionally substituted with one or more -OH. In one embodiment, R 4 is optionally substituted C 5 alkyl. In one embodiment, R 4 is unsubstituted C 5 alkyl. In one embodiment, R 4 is C 5 alkyl optionally substituted with one or more -OH. In one embodiment, R 4 is optionally substituted C 6 alkyl.
  • R 4 is cyclohexyl, phenyl, thienyl, or pyridinyl, each of which is optionally substituted with one or more halo, -CN, -R 7 , -OR 7 , -SO 2 R 7 , -NR 10 SO 2 R 7 , -NR 10 R 7 , -NR 10 C(O)R 7 , -NR 10 C(O)OR 7 , -C(O)R 7 , -C(O)OR 7 , or -C(O)NR 10 R 7 .
  • R 4 is cyclohexyl, phenyl, thienyl, or pyridinyl, each of which is optionally substituted with one or more halo, -CN, -R 7 , -OR 7 , -SO 2 R 7 , -NR 10 R 7 , -NR 10 C(O)R 7 , -NR 10 C(O)OR 7 , or -C(O)NR 10 R 7 .
  • R 4 is optionally substituted phenyl. In one embodiment, R 4 is unsubstituted phenyl. In one embodiment, R 4 is phenyl substituted with one or more halo, CN, OH, Ci-C 4 alkyl, -0(Ci-C 4 alkyl), -0(C 6 aryl), -NH(C-C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , -NHC(O)O(C-C 4 alkyl), -NHC(O)(C-C 4 alkyl), -NHSO 2 (C 1 -C 4 alkyl), -C(O)OH, -C(O)NH 2 , -C(O)NH(C 1 -C 4 alkyl), -C(O)N(C-C 4 alkyl) 2 , -SO 2 (C-C 4 alkyl), 5-7 membered heterocyclyl, or -
  • R 4 is phenyl substituted with one or more fluoro, chloro, bromo, CN, OH, methyl, ethyl, propyl, /-propyl, CF 3 , -CH 2 CH 2 OH, -OCH 3 , -OPh, -N(Et)(CH 2 CH 2 OH), -NHC(O)OEt, -NHC(O)CH 3 , -NHSO 2 CH 3 , -C(O)OH, -C(O)NH 2 , -C(O)NHCH 3 , -SO 2 CH 3 , or -C( ⁇ Xmorpholinyl).
  • R 4 is optionally substituted cyclohexyl. In one embodiment,
  • R 4 is unsubstituted cyclohexyl.
  • R 4 is cyclohexyl optionally substituted with one or more -OH.
  • R 4 is optionally substituted thienyl. In one embodiment, R 4 is unsubstituted thienyl.
  • R 4 is optionally substituted pyridinyl. In one embodiment, R 4 is unsubstituted pyridinyl. In one embodiment, R 4 is pyridinyl optionally substituted with one or more -OH or -OCH 3 .
  • R 4 is cyclopropyl. In one embodiment, R 4 is benzofuranyl.
  • R 4 is indolinonyl. In one embodiment, R 4 is benzo[cG[l,3]dioxolyl. In one embodiment, R 4 is 2,3-dihydrobenzo[b][l,4]dioxinyl.
  • R 4 and R 9 together with the nitrogen atom to which they are attached form a piperazine, piperidine, or morpholine ring, each of which is optionally substituted with one or more: (a) C 1 -C 6 alkyl, which in turn is optionally substituted with one or more -OH, -0(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(Ci-C 6 alkyl) 2 , or (b) 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl, which in turn is optionally substituted with one or more halo or CN.
  • R 4 and R 9 together with the nitrogen atom to which they are attached form a piperazine ring, wherein the second nitrogen atom of the piperizine ring is optionally substituted with: (a) C 1 -C 6 alkyl, which in turn is optionally substituted with one or more -OH, -0(Ci-C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 , or (b) 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl, which in turn is optionally substituted with one or more halo or CN; or (c) -C(O)-(5-7 membered heterocyclyl).
  • R 4 and R 9 together with the nitrogen atom to which they are attached form a piperazine ring, wherein the second nitrogen atom of the piperizine ring is optionally substituted with: (a) C 1 -C 6 alkyl, which in turn is optionally substituted with one or more -OH, -0(C 1 -C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), or -N(C-C 6 alkyl) 2 , or (b) 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl, which in turn is optionally substituted with one or more halo or CN.
  • R 4 and R 9 together with the nitrogen atom to which they are attached form a piperazine ring, wherein the second nitrogen atom of the piperizine ring is optionally substituted with methyl, ethyl, pyridine, diethylaminoethyl, or -C(O)-morpholinyl.
  • R 4 and R 9 together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, or morpholine ring, each of which is further fused to a phenyl ring, wherein the fused ring system is optionally substituted.
  • R 9 when R 9 is not combined with R 4 to form a heterocyclic ring system, R 9 is hydrogen, methyl, or ethyl. In one embodiment, R 9 is hydrogen. In one embodiment, R 9 is methyl. In one embodiment, R 9 is ethyl.
  • L 4 is a bond
  • R 4 is phenyl, furanyl, or indolyl, each of which is optionally substituted.
  • L 4 is a bond
  • R 4 is phenyl, furanyl, or indolyl, each of which is optionally substituted with one or more halo, CN, -C(O)NH(Ci-C 4 alkyl),
  • compounds of formula (I) include, but are not limited to, the following: 1. N-(4-rerr-butylphenyl)-6-(4-hydroxycyclohexylamino)pyrimidine-4-carboxamide
  • a compound of formula (T), 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 (T), 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 (Ia) in which L 4 is -O- or -NR 9 - may be prepared by the reaction of a compound of formula (II):
  • the reaction may be carried out at raised temperature, typically 50-90°C, and in an alcoholic solvent with a suitable boiling point, such as, e.g., isopropyl alcohol.
  • the reaction mixture can be irradiated with microwave radiation, which may shorten the reaction time.
  • the compound of formula (III) may first be reacted with a strong base, typically a source of hydride ions, such as, e.g., sodium hydride.
  • a strong base typically a source of hydride ions, such as, e.g., sodium hydride.
  • reaction with the compound of formula (II) may be conducted at room temperature and in an organic solvent such as, e.g., N.iV-dimethylformamide.
  • compounds of formula (II) in which L is -C(O)NR - can be prepared from a compound of formula (FV):
  • the reaction may be carried out by chlorination of the carboxylic acid to give the acid chloride using an agent such as oxalyl chloride followed by reaction of the acid chloride with the compound of formula (V).
  • An example of such a method is by the reaction of 6-hydroxypyrimidine-4-carboxylic acid with a halogenating agent, typically oxalyl chloride, to give a compound of formula (FV), for example, 6-chloropyrimidine-4-carboxylic acid. This reaction is described in further detail in the examples.
  • a halogenating agent typically oxalyl chloride
  • 6-Hydroxypyrimidine-4-carboxylic acid can be prepared by the reaction of sodium ethyloxalacetate with formamidine acetate. The procedure of this reaction is described in further detail in the examples. Sodium ethyloxalacetate and formamidine acetate are both readily available, for example, from a commercial source.
  • compounds of formula (Ia) may be prepared by the reaction of a compound of formula (VI):
  • R and R are as defined herein elsewhere for formula (I) and (Ia).
  • the reaction may be conducted in the presence of a base, such as, e.g., diisopropylethylamine, and a coupling reagent, such as, e.g., benzotriazole-1-yl-oxy- tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP).
  • a base such as, e.g., diisopropylethylamine
  • a coupling reagent such as, e.g., benzotriazole-1-yl-oxy- tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP).
  • compounds of formula (VI) may be prepared from a corresponding ester of formula (VII):
  • R 12 is Ci-C 6 alkyl or benzyl; using any known method, such as, for example, alkaline hydrolysis, which may be conducted in the presence of a base, such as, e.g., sodium hydroxide.
  • esters of formula (VII) may be prepared from a compound of formula (VIII):
  • reaction may be carried out under similar conditions to those described herein elsewhere for the reaction of a compound of formula (II) with a compound of formula (III).
  • esters of formula (EX) can be prepared from 6- hydroxypyrimidine-4-carboxylic acid, which, in turn, can be prepared by the reaction of sodium ethyloxalacetate with formamidine acetate. The procedures are described in further details in the examples.
  • 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 "Protecting Groups in Organic Synthesis", Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc.
  • the compounds of formula (I), or tautomers, enantiomers, pharmaceutically acceptable salts, hydrates, solvates, complexes, or prodrugs thereof, for use in the treatment of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia is administered in the form of a pharmaceutical composition.
  • the compounds of formula (I), or tautomers, enantiomers, pharmaceutically acceptable salts, hydrates, solvates, complexes, or prodrugs thereof, for use in the treatment of Duchenne muscular dystrophy is administered in the form of a pharmaceutical composition.
  • composition comprising a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, and at lease one pharmaceutically acceptable excipient or carrier.
  • 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 to 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 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, solubilizers, 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.
  • solubilizers 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 e.g., a water soluble cellulose polymer such as hydroxypropyl methylcellulose
  • sweetening and/or coloring agents e.g., a water soluble glycol such as propylene glycol
  • 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. [00151] 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.
  • the pharmaceutical compositions are provided in a dosage form for parenteral administration, and one or more pharmaceutically acceptable excipients or carriers.
  • 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.
  • 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.
  • 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, 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).
  • 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.
  • 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 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 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 of Duchenne muscular dystrophy. [00160] In another embodiment, provided herein is the use of a compound of formula (I) in the manufacture of a medicament for the treatment of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
  • provided herein is the use of a compound of formula (I) in the manufacture of a medicament for the treatment 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 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 chcwable 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; microcrystalline 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 propylparabens, 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. Pat. 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 glycol.
  • 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, N,N-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 propyl-parabens, 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 oc-cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7- ⁇ -cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • cyclodextrins including oc-cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7- ⁇ -cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • 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.
  • 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.
  • 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.
  • 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 acryiic 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. 3. Topical Administration
  • 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 (OAV) 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.
  • 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.
  • 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 l- 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. Pat. 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 al. 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.
  • 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, plasticized
  • 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, raffinose, 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, ed
  • 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. Pat. 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.
  • 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. Pat. 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. See, U.S. Pat. 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.
  • 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, for example, 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. Pat. Nos.
  • 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 in 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 of Duchenne muscular dystrophy in a patient suffering from such a disease.
  • a therapeutic agent for the treatment of Duchenne muscular dystrophy in a patient suffering from such a disease.
  • from about 0.01 mg to about 10 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. [00234] 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 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 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 of Duchenne muscular dystrophy.
  • 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).
  • 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.
  • 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 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 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, or from about 1 to about 20 mg/kg per day, which can be administered in single or multiple doses.
  • 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, or from about 1 to about 50 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,
  • 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, and 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 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, or amelioration 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, 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. Thus, for example, when a compound provided herein is combined with a corticosteroid, the weight ratio of the compound to the corticosteroid can range from about 1,000:1 to about 1: 1,000, about 200:1 to about 1:200, about 100:1 to about 1:100, or about 10:1 to about 1:10. 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. Pat. 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. Examples of such devices include, but are not limited to, syringes, needleless injectors drip bags, patches, and inhalers. [00250] 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.
  • 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,
  • 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.
  • HPLC-UV was performed on a Dionex Ultimate 3000 system.
  • the analytical column used is a Phenomenex Gemini Cl 8 100x4.6 mm, with the preparative column being a Phenomenex Gemini C18 100x30 mm.
  • the mobile phase consisted of 0.1% TFA in water and 95:5 acetonitrile: water.
  • N-Phenyl-6-(phenylamino)pyrimidine-4-carboxamide (Compound 73) [00257] To a solution of 6-(phenylamino)pyrimidine-4-carboxylic acid (65 mg, 0.30 mmol) in dimethylformamide (4 mL), was added aniline (33 ⁇ L, 0.36 mmol), followed by benzotriazol-l-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (187 mg, 0.36 mmol) and ⁇ f,N-diisopropylethylamine (25 ⁇ L, 1.44 mmol).
  • the reaction mixture was partitioned between dichloromethane and saturated NaHCO 3 solution.
  • the aqueous phase was extracted twice with DCM, and the combined organic phases were washed with brine, dried over MgSO 4 and concentrated in vacuo.
  • the crude compound was recrystallized from chloroform, then purified by column chromatography, eluting with ethyl acetate/petroleum ether, 0/1 to 1/0 v/v, to afford 11 mg (8%) of the title compound.
  • Example 9 - Procedure D' Adaptation of General Procedure to Microwave Irradiation
  • 300 mg of 6-chloro-N-(4-fluorophenyl)pyrimidine-4-carboxamide 3 (1.19 mmol, 1 eq) was dissolved in isopropanol (3 mL).
  • the corresponding amine (1.05 eq) was added and the resulting solution was heated at 130°C for 10 minutes under microwave activation.
  • the reaction mixture was cooled down to 0 0 C for 20 minutes and a solid precipitated out.
  • the solid was filtered then washed with isopropanol and ether to give the desired product as a HCl salt. Standard base washing can deliver the free base.
  • N-(4-Ruorophenyl)-6-(3-(methyithio)phenyiamino)pyrimidine-4-carboxamide (0.108 g, 28 mmol) was dissolved in DCM and m-CPBA (70% w/w in water, 0.145 g, 5.9 mmol, 2.1 eq) was added. The mixture was stirred at O 0 C for 2 hours. The mixture was neutralized to pH ⁇ 7 with addition of aqueous NaHCO 3 solution, extracted with DCM (x3), the organic layers combined and dried (MgSO 4 ), and concentrated in vacuo. The crude material was purified by HPLC to afford the title compound as a cream solid (0.054 g, 50%).
  • 6-(Phenylamino)pyrimidine-4-carboxylate 3 (280 mg, 1.5 mmol, 1 eq) was dissolved in isopropanol (12 mL). Aniline (1.05 eq) was added and the resulting solution was reflux ed for 18 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo affording a brown solid. The crude was then diluted with DCM (150 mL), washed with brine (100 mL) and the aqueous layer was extracted further with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulphate and evaporated to dryness.
  • Ethyl 6-(phenylamino)pyrimidine-4-carboxylate 4 (100 mg) was dissolved in a 1 : 1 mixture of THF / water (2 mL) and 0.7 mL of NaOH 1 N (1.5 eq.) was added at room temperature. The reaction mixture was then stirred at room temperature for 18 hours and acidified using 2 N HCl. The white precipitate was then filtered off and washed with ether to give 75 mg of the desired product (76% yield).
  • 6-Amino-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 107) [00340] To 6-chloro-N-(4-fluorophenyl)pyrimidine-4-carboxamide was added 2 eq. of 0.5M ammonia in 1,4-dioxane and the resulting mixture was heated at 130°C for 30 minutes under microwave activation. After cooling to room temperature, the precipitate was removed by filtration and the filtrate concentrated in vacuo. Purification of the residue by column chromatography, eluting with petrol/ethyl acetate, 1/0 to 0/1 v/v, afforded the title compound in 17% yield.
  • N-(4-Fluorophenyl)-6-phenoxypyrimidine-4-carboxamide (Compound 124) [00341] To a solution of sodium hydride (60% dispersion in mineral oil, 71 mg, 1.79 mmol) in DMF (5 mL) was added phenol (0.123 g, 1.31 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then a solution of 6-chloro-N-(4-fluorophenyl)- pyrimidine-4-carboxamide (0.3 g, 1.19 mmol) in DMF (5 mL) was added. The reaction mixture was stirred at room temperature for a further 16 hours, and then partitioned between ethyl acetate and water.
  • 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.

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Abstract

Compounds of formula (I): wherein R1, L2, R2, L3, R3, L4 and R4 are as defined herein, upregulate endogenous utrophin in predictive screens, and thus, 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. GB0815369.4, filed August 22, 2008, the content of which is incorporated by reference herein by its entirety.
FIELD
[0002] Provided herein are compounds for the treatment 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 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 frame-shift errors downstream, whereas approximately 40% are point mutations or small frame-shift 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 (Bulfield et al., X Chromosome-Linked Muscular Dystrophy {mdx) in the Mouse, Proc. Natl. Acad. ScL 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., S1: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] In 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, we 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 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 of muscular dystrophy, including DMD. [0011] In one embodiment, provided herein is a compound of formula (I):
Figure imgf000005_0001
(I) or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof; wherein R1, R2, R3, R4, L2, L3, and L4 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, hi 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, hi one embodiment, the method treats, prevents, and/or ameliorates one or more symptoms of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia, hi 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, hi one embodiment, the method treats, prevents, and/or ameliorates one or more symptoms of Duchenne muscular dystrophy, hi 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 to treat or prevent 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 "C1-C6 alkyl" refers to an optionally substituted straight or branched saturated hydrocarbon chain having one to six carbon atoms. In one embodiment, the "C1-C6 alkyl" is optionally substituted with one or more halo. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, t- butyl, and n-hexyl.
[0020] As used herein, and unless otherwise specified, the terms "Ci-C4 alkyl" and "Ci-
Cio alkyl" have similar meanings except that they contain respectively from one to four and from one to ten carbon atoms.
[0021] As used herein, and unless otherwise specified, the term "C2-C6 alkenyl" refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and containing at least one carbon-carbon double bond. In one embodiment, the "C2-C6 alkenyl" is optionally substituted by one or more halo. Examples include, but are not limited to, ethenyl,
2-propenyl, and 3-hexenyl.
[0022] As used herein, and unless otherwise specified, the term "C2-C6 alkynyl" refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and containing at least one carbon-carbon triple bond. In one embodiment, the "C2-C6 alkynyl" is optionally substituted by one or more halo. Examples include, but are not limited to, ethynyl,
2-propynyl, and 3-hexynyl. [0023] As used herein, and unless otherwise specified, the terms "C2-C10 alkenyl" and "C2-CiO alkynyl" have similar meanings except that they contain from two to ten carbon atoms.
[0024] As used herein, and unless otherwise specified, the term "Ci-C6 haloalkyl" refers to a Ci-C 6 alkyl group as defined above substituted by one or more halo. [0025] As used herein, and unless otherwise specified, the term "alkylene" refers to a linear or branched saturated divalent hydrocarbon radical, wherein the alkylene may optionally be substituted as described herein. The term "alkylene" encompasses both linear and branched alkylene, unless otherwise specified. In certain embodiments, the alkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (Ci-C2o), 1 to 15 (Ci-Ci5), 1 to 10 (Ci-Cio), 1 to 6 (Ci-C6), or 1 to 5 (Ci-C5) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C3-C20), 3 to 15 (C3-Ci5), 3 to 10 (C3-Ci0), 3 to 6 (C3-C6), or 3 to 5 (C3-C5) carbon atoms. As used herein, linear Ci-C6 and branched C3-C6 alkylene groups are also referred as "lower alkylene." Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene (including all isomeric forms), n-propylene, isopropylene, butylene (including all isomeric forms), n-butylene, isobutylene, t-butylene, pentylene (including all isomeric forms), and hexylene (including all isomeric forms). For example, Ci-C6 alkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms [0026] 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 bonds. The alkenylene may be optionally substituted as described herein. Similarly, the term "alkenylene" also embraces radicals having "cis" and "trans" configurations, or alternatively, "£" and "Z" configurations. As used herein, the term "alkenylene" encompasses both linear and branched alkenylene, unless otherwise specified. For example, C2-C6 alkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. 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. [0027] 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 bonds. The alkynylene may be optionally substituted as described herein. The term "alkynylene" also encompasses both linear and branched alkynylene, unless otherwise specified. 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-C2o),
3 to 15 (C3-Ci5), 3 to 10 (C3-Cio), 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-). For example, C2-C6 alkynylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
[0028] As used herein, and unless otherwise specified, the term "carbocyclic" refers to an optionally substituted ring system in which all the ring atoms are carbon atoms. In one embodiment, the carbocyclic is optionally substituted with one or more halo.
[0029] As used herein, and unless otherwise specified, the term "heterocyclic" refers to an optionally substituted ring system in which one or more of the ring atom(s) is a hetero atom selected from N, O and S.
[0030] As used herein, and unless otherwise specified, in the carbocyclic and heterocyclic ring systems, one or more ring CH2 groups may be replaced with a C=O to form a cyclic ketone. In certain embodiment, one or more ring CH2 groups may be replaced with a C=O to form a cyclic amide.
[0031] As used herein, and unless otherwise specified, the term "aromatic" refers to an optionally substituted carbocyclic or heterocyclic ring system which has aromatic character.
In one embodiment, the aromatic ring has one or two rings and from 5 to 10 ring atoms. In bicyclic systems, one of the rings may have aromatic character. Examples of aromatic ring systems include, but are not limited to, phenyl, naphthalene, pyridine, pyrimidine, furan, thiophene, indole, isoindole, benzofuran, benzimidazole, benzimidazoline, benzodioxyl, benzodioxane, quinoline, isoquinoline, tetrahydroisoquinoline, quinazoline, thiazole, benzthiazole, benzoxazole, indazole, and imidazole ring systems.
[0032] 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 is monocyclic and has from 4 to 7 ring atoms. Examples of non-aromatic ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidine, piperazine, moφholine, tetrahydrofuran, and pyrrolidine.
[0033] In one embodiment, the carbocyclic or heterocyclic ring systems are optionally substituted with one or more -X4-R7, wherein:
X4 is a bond, Ci-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NR10-, -S-, -O-, -(CR10R10V, -(CR10R10)qO-, -O(CR10R10)q-NR10C(O)-, -OC(O)NR10-, -NR10C(O)NR10-, -NR10C(S)NR10-, -NR10C(NH)NR10-, -NR10C(NH)-, -C(O)- -C(S)- -C(O)O-, -C(O)NR10-, -C(S)NR10-, -SO-, -SO2-, -SO2NR10-, -OCH2C(O)NR10-, or -P(O)OR10-; where each R10 is independently H or optionally substituted Ci-C6 alkyl; q is O, 1, or 2; and
R7 is H, Ci-C6 alkyl, C3-C7 cycloalkyl, C7-C8 aralkyl, C3-C7 heterocyclyl, C5-C7 aryl, or C5-C7 heteroaryl, wherein the alkyl, cycloalkyl, aralkyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with one or more halo, -OH, -0(Ci-C6 alkyl), or -N(Ci-C6 alkyl)2 groups, and wherein the cycloalkyl, aralkyl, heterocyclyl, aryl, and heteroaryl groups are also optionally substituted with Ci-C6 alkyl; or, when X4 is a bond, R7 may also be halo, -NO2, or -CN.
[0034] In one embodiment, the carbocyclic or heterocyclic ring systems are optionally substituted with one or more -X4-R7, wherein:
X4 is a bond, Ci-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, -NR10-, -S-, -0-, -(CR10R1V, -(CR10R10)qO- -0(CR10R1VNR10C(O)- -OC(O)NR10-, -NR10C(O)NR10-, -NR10C(S)NR10-, -NR10C(NH)NR10-, -NR10C(NH)- -C(O)-, -C(S)- -C(O)NR10-, -C(S)NR10-, -SO-, -SO2-, -SO2NR10-, -OCH2C(O)NR10-, or -P(O)OR10-; where each R10 is independently H or optionally substituted Ci-C6 alkyl; q is O, 1, or 2; and R7 is H, Ci-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, C5-C7 aryl, or C5-C7 heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with one or more halo, -0(Ci-C6 alkyl), or -N(Ci-C6 alkyl)2 groups, and wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are also optionally substituted with Cj-C6 alkyl; or, when X4 is a bond, R7 may also be halo, -NO2, or -CN. [0035] In one embodiment, each R10 is independently H or Ci-C6 alkyl optionally substituted with one or more halo.
[0036] In one embodiment, the aromatic or non-aromatic ring systems are optionally substituted with one or more -X4-R7, wherein X4 and R7 are defined herein elsewhere. [0037] As used herein, and unless otherwise specified, the terms "cycloalkyl" or "non- aromatic carbocyclic" refer to an optionally substituted cyclic fully saturated hydrocarbon ring radical, which is bridged or non-bridged. In certain embodiments, the cycloalkyl has from 3 to 20 (C3-C20), from 3 to 15 (C3-Ci5), from 3 to 10 (C3-Ci0), from 3 to 8 (C3-C8), or from 3 to 7 (C3-C7) ring carbon atoms. Examples of cycloalkyl groups 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 is optionally substituted with one or more -X4-R7, wherein X4 and R7 are defined herein elsewhere.
[0038] As used herein, and unless otherwise specified, the terms "aryl" or "aromatic carbocyclic" refer to an optionally substituted monocyclic or multicyclic aromatic group that contains at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-C2O), from 6 to 15 (C6-C]5), or from 6 to 10 (C6-C io) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, the aryl or aromatic carbocyclic is optionally substituted with one or more -X4-R7, wherein X4 and R7 are defined herein elsewhere.
[0039] 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. [0040] As used herein, and unless otherwise specified, the terms "heteroaryl" or "aromatic heterocyclic" refer to an optionally substituted monocyclic or multicyclic aromatic group 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. In one embodiment, each ring of the heteroaryl group 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. 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, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. 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 or aromatic heterocyclic is optionally substituted with one or more -X4-R7, wherein X4 and R7 are defined herein elsewhere.
[0041] As used herein, and unless otherwise specified, the terms "heterocyclyl," "non- aromatic heterocyclyl," or "non-aromatic heterocyclic" refers to an optionally substituted monocyclic or multicyclic non-aromatic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, 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, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. 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 such heterocyclic radicals include, but are not limited to, azepinyl, 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, thiamoφholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl or heterocyclic is optionally substituted with one or more -X4-R7, wherein X4 and R7 are defined herein elsewhere.
[0042] As used herein, and unless otherwise specified, the terms "halo" or "halogen" refers to fluoro, chloro, bromo, or iodo.
[0043] As used herein, and unless otherwise specified, appropriate pharmaceutically and veterinarily acceptable salts include basic addition salts such as sodium, potassium, calcium, aluminum, zinc, magnesium, and other metal salts, as well as choline, diethanolamine, ethanolamine, ethyl diamine, and other known basic addition salts. [0044] In other embodiments, where appropriate, pharmaceutically or veterinarily acceptable salts may also include acid addition salts of organic acids, such as, e.g., carboxylic acids, including but not limited to, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, lactobionate, pivolate, camphorate, undecanoate, and succinate; organic sulfonic acids, including but not limited to, methanesulfonate, ethanesulfonate, 2-hydroxyethane sulfonate, camphorsulfonate, 2-naphthalenesulfonate, benzenesulfonate, p-chlorobenzenesulfonate and /7-toluenesulfonate; and inorganic acids, including but not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphate, hydrogenphosphate, and dihydrogenphosphate.
[0045] Salts which are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates.
[0046] As used herein, and unless otherwise specified, the term "prodrug" refers to any covalently bonded compounds which release the active parent drug according to formula (I) in vivo. [0047] 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 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 an diasteromerically enriched mixture, or the racemic mixture may be separated using known techniques and an individual enantiomer may be used alone.
[0048] 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.
[0049] 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. [0050] 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.
[0051] As used herein, and unless otherwise specified, the term "therapeutically effective amount" are meant to include the amount of a compound that, when administered, is sufficient to prevent 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.
[0052] 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, 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 P reformulation and Formulation, 2nd Edition, Gibson ed., CRC Press LLC: Boca Raton, FL, 2009.
[0053] 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.
[0054] 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 ameliorating 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.
[0055] As used herein, and unless otherwise specified, the terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
[0056] In certain embodiments, "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. [0057] 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 (+) an 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.
[0058] 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. Where the solvent is water, the solvate is a hydrate.
B. Compounds
[0059] Provided herein is a compound of formula (I):
Figure imgf000016_0001
(I) or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein
R1 is H, halo, or Cj-C6 alkyl;
L2 is a linker selected from a bond, -O-, -S(O)n-, and -NR5-;
R2 is (i) hydrogen; or (ii) Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl, each of which is optionally substituted with one or more halo, -OR5, -R6, or -OR6; or (iii) 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system, each of which is optionally substituted; L3 is a linker selected from a bond, -(CR8R8)m- -NR8-, -O-, -S-, -(CR8R8)mNR8-, -C(O)NR8-, -C(S)NR8-, -C(NH)NR8- -SO2NR8-, -C(O)-, -C(S)-, -SO-, -SO2-, -CR8=CR8-, -C≡C-, -NR8C(O)NR8-, -NR8C(S)NR8-, -NR8C(NH)NR8-, and -NR8C(O)O-;
R3 is (i) hydrogen; or (ii) C]-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl, each of which is optionally substituted with one or more halo, -OR5, -N(R5)2, -R6, or -OR6; or (iii) 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system, each of which is optionally substituted; or (iv) when L3 is -NR8- or -C(O)NR8-, R3 together with R8 and the nitrogen atom to which it is attached form an optionally substituted 5-7 membered nitrogen containing heterocyclic ring, which optionally contains one or two further heteroatoms selected from -O-, -NR11-, and -S(O)n-, which is optionally fused to a further 5-7 membered aromatic or non aromatic carbocyclic or heterocyclic ring each of which is optionally substituted;
L4 is a linker selected from a bond, -(CR9R9)m- -NR9-, -0-, -S-, -(CR9R9)mNR9-, -C(O)NR9-, -C(S)NR9-, -C(NH)NR9-, -SO2NR9-, -C(O)-, -C(S)-, -SO-, -SO2-, -CR9=CR9-, -C≡C-, -NR9C(O)NR9-, -NR9C(S)NR9-, -NR5C(NH)NR5-, and -NR5C(O)O-;
R4 is (i) hydrogen; or (ii) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl, each of which is optionally substituted with one or more halo, -OR5, -N(R5)2, -R6, or -OR6; or (iii) 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system, each of which is optionally substituted; or (iv) when L4 is -NR9- or -C(O)NR9-, R4 together with R9 and the nitrogen atom to which it is attached form an optionally substituted 5-7 membered nitrogen containing heterocyclic ring, which optionally contains one or two further heteroatoms selected from -0-, -NR11-, and -S(O)n-, which is optionally fused to a further 5-7 membered aromatic or non aromatic carbocyclic or heterocyclic ring each of which is optionally substituted; or (v) when L4 is -NR9-, R4 and the nitrogen atom to which it is attached join with R1 to form an optionally substituted 5-7 membered nitrogen containing heterocyclic ring, which optionally contains one or two further heteroatoms selected from -0-, -NR11-, and -S(O)n-, which is optionally fused to a further 5-7 membered aromatic or non aromatic carbocyclic or heterocyclic ring each of which is optionally substituted; each R5 is independently H or C1-C6 alkyl optionally substituted by one or more halo; each R6 is independently 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system, each of which is optionally substituted; each R8 is independently H or Ci-C6 alkyl optionally substituted by one or more halo; each R9 is independently H or Ci-C6 alkyl optionally substituted by one or more halo; each R11 is independently hydrogen, optionally substituted Ci-C6 alkyl, or 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system each of which is optionally substituted; or R11 is -C(O)-(5-7 membered heterocyclyl); each m is independently 1 or 2; and each n is independently 0, 1, or 2; for use in the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia.
[0060] 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.
[0061] 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. [0062] In certain embodiments, provided herein is a compound of formula (I), or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
[0063] In one embodiment, R3 is (i) hydrogen; or (ii) Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl, each of which is optionally substituted with one or more halo, -OR5, -N(R5)2, -R6, or -OR6; or (iii) 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system, each of which is optionally substituted; wherein R5 and R6 are as defined herein elsewhere.
[0064] In one embodiment, R11 is hydrogen, optionally substituted Ci-C6 alkyl, or 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system each of which is optionally substituted. [0065] In one embodiment, R1 is hydrogen. In one embodiment, R1 is halo. In one embodiment, R1 is fluoro. In one embodiment, R1 is chloro. In one embodiment, R1 is Ci- C6 alkyl. 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 fluoro.
In one embodiment, R1 is methyl. In one embodiment, R1 is ethyl. In one embodiment, R1 is methyl optionally substituted with one or more fluoro. In one embodiment, R1 is ethyl optionally substituted with one or more fluoro.
[0066] In one embodiment, L2 is a bond.
[0067] In one embodiment, R2 is hydrogen or Ci-C6 alkyl. In one embodiment, R2 is hydrogen. In one embodiment, R2 is Ci-C6 alkyl. In one embodiment, R2 is Ci-C6 alkyl optionally substituted with one or more halo. In one embodiment, R2 is Ci-C6 alkyl optionally substituted with one or more fluoro. In one embodiment, R2 is methyl, ethyl, propyl, or isopropyl. In one embodiment, R2 is methyl, ethyl, propyl, or isopropyl, each of which is optionally substituted with one or more fluoro.
[0068] In one embodiment, L3 is -CONR8-, wherein R8 is as defined herein elsewhere.
In one embodiment, L3 is -CONH-. In one embodiment, L3 is -CONMe-.
[0069] In one embodiment, L3 is -NR8-, wherein R8 is as defined herein elsewhere. In one embodiment, L is -NH-. In one embodiment, L is -N(CH3)-. In one embodiment, L is -N(CH2CH3)-.
[0070] In one embodiment, L4 is a bond, -O-, or -NR9-, wherein R9 is as defined herein elsewhere. In one embodiment, L4 is a bond. In one embodiment, L4 is -O-. In one embodiment, L4 is -NR9-. In one embodiment, R4 and R9 together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring as defined herein elsewhere. In one embodiment, L4 is -NH-. In one embodiment, L4 is -N(CH3)-. In one embodiment, L4 is -N(CH2CH3)-.
[0071] In one embodiment, L4 is -CONR9-, wherein R9 is as defined herein elsewhere.
In one embodiment, R4 and R9 together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring as defined herein elsewhere. In one embodiment, L4 is -CONH-. In one embodiment, L4 is -CONMe-.
[0072] In one embodiment, R1 is hydrogen, L2 is a bond, R2 is hydrogen or C]-C6 alkyl,
L is -CONR -, wherein R is as defined herein elsewhere, and L is a bond, -O-, or -NR -, wherein R9 is as defined herein elsewhere.
[0073] In one embodiment, R1 is hydrogen, L2 is a bond, R2 is hydrogen, L3 is -CONR8-, wherein R8 is as defined herein elsewhere, and L4 is a bond, -O-, or -NR9-, wherein R9 is as defined herein elsewhere. In one embodiment, R1 is hydrogen, L2 is a bond, R2 is Ci-C6 alkyl, L3 is -CONR8-, wherein R8 is as defined herein elsewhere, and L4 is a bond, -O-, or -NR9-, wherein R9 is as defined herein elsewhere. In one embodiment, R1 is hydrogen, L2 is
*j 1 fi 8 a bond, R is hydrogen or Ci-C6 alkyl, L is -CONR -, wherein R is as defined herein elsewhere, and L4 is a bond. In one embodiment, R1 is hydrogen, L2 is a bond, R2 is hydrogen or Cj-C6 alkyl, L3 is -CONR8-, wherein R8 is as defined herein elsewhere, and L4 is -O-. In one embodiment, R1 is hydrogen, L2 is a bond, R2 is hydrogen or Ci-C6 alkyl, L3 is -CONR8-, wherein R8 is as defined herein elsewhere, and L4 is -NR9-, wherein R9 is as defined herein elsewhere. In one embodiment, R is hydrogen, L is a bond, R is hydrogen, L3 is -CONR8-, wherein R8 is as defined herein elsewhere, and L4 is a bond. In one embodiment, R1 is hydrogen, L2 is a bond, R2 is Ci-C6 alkyl, L3 is -CONR8-, wherein R8 is
A. 1 *? as defined herein elsewhere, and L is a bond. In one embodiment, R is hydrogen, L is a bond, R2 is hydrogen, L3 is -CONR8-, wherein R8 is as defined herein elsewhere, and L4 is -0-. In one embodiment, R1 is hydrogen, L2 is a bond, R2 is Ci-C6 alkyl, L3 is -CONR8-, wherein R8 is as defined herein elsewhere, and L4 is -0-. In one embodiment, R1 is hydrogen, L2 is a bond, R2 is hydrogen, L3 is -CONR8-, wherein R8 is as defined herein elsewhere, and L4 is -NR9-, wherein R9 is as defined herein elsewhere. In one embodiment, R1 is hydrogen, L2 is a bond, R2 is Ci-C6 alkyl, L3 is -CONR8-, wherein R8 is as defined herein elsewhere, and L4 is -NR9-, wherein R9 is as defined herein elsewhere. [0074] Any combinations of R1, L2, R2, L3, R3, L4, R4, R5, R6, R7, R8, R9, R10, R11, X4, m, n, and q are encompassed by this disclosure and specifically provided herein. [0075] In one embodiment, provided herein is a compound of formula (Ia):
Figure imgf000020_0001
(Ia) or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein R3, R4, and R8 are as defined herein elsewhere; and L4 is a bond, -0-, or -NR9-, wherein R9 is as defined herein elsewhere. [0076] In one embodiment, R3 is hydrogen.
[0077] In one embodiment, R3 is (i) Ci-C6 alkyl optionally substituted with one or more -OR5 or -R6; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl or heterocyclyl group, each of which is optionally substituted with one or more halo, -R7, -OR7, -OCH2C(O)NR10R7, or -SO2R7; or (iii) a 9-10 membered heteroaryl or heterocyclyl group, each of which is optionally substituted with one or more halo, -R7, or -OR7; or (iv) R3 and R8 together with the nitrogen atom to which they are attached form a piperizine, which is optionally substituted with R11 at the second nitrogen atom; wherein R5, R6, R7, R10, and R11 are as defined herein elsewhere.
[0078] In one embodiment, R3 is (i) Ci-C6 alkyl optionally substituted with one or more -OR5 or -R6; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl or heterocyclyl group, each of which is optionally substituted with one or more halo, -R7, -OR7 -OCH2C(O)NR10R7, or -SO2R7; wherein R5, R , R , and R10 are as defined herein elsewhere. [0079] In one embodiment, R3 is (i) Ci-C6 alkyl optionally substituted with one or more -OR5 or -R6; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl or heterocyclyl group, each of which is optionally substituted with one or more halo, -R7, -OR7, or -OCH2C(O)NR10R7; wherein R5, R6, R7, and R10 are as defined herein elsewhere.
[0080] In one embodiment, R3 is (i) Ci-C6 alkyl optionally substituted with one or more -0(Ci-C4 alkyl), C3-C7 cycloalkyl, C3-C7 heterocyclyl; C5-C6 aryl, or C5-C6 heteroaryl; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more halo, -OH, Cj-C4 alkyl, -0(Ci-C4 alkyl), -SO2(Ci-C4 alkyl), -OCH2C(O)N(C]-C4 alkyl)2, C3-C7 cycloalkyl, or C3-C7 heterocyclyl; wherein the alkyl groups are optionally substituted with C3-C7 cycloalkyl, C3-C7 heterocyclyl, C5-C6 aryl, or C5-C6 heteroaryl; wherein the cycloalkyl or heterocyclyl groups are optionally substituted with one or more halo, methyl, or ethyl.
[0081] In one embodiment, R3 is (i) C1-C6 alkyl optionally substituted with one or more methoxy, benzyloxy, cyclopropyl, phenyl, thienyl, or pyridyl; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more fluoro, -OH, methyl, methoxy, benzyloxy, or methane sulfonyl. [00821 In one embodiment, R3 is optionally substituted Ci alkyi. In one embodiment, RJ is unsubstituted Ci alkyl. In one embodiment, R3 is Ci alkyl, substituted with phenyl, thienyl, pyridinyl, cyclopropyl, or -OMe. In one embodiment, R3 is optionally substituted C2 alkyl. In one embodiment, R3 is unsubstituted C2 alkyl. In one embodiment, R3 is C2 alkyl, substituted with phenyl, thienyl, pyridinyl, cyclopropyl, or -OMe. In one embodiment, R3 is optionally substituted C3 alkyl. In one embodiment, R3 is optionally substituted C4 alkyl. In one embodiment, R3 is unsubstituted C4 alkyl. In one embodiment, R3 is optionally substituted C5 alkyl. In one embodiment, R3 is optionally substituted C6 alkyl. [0083] In one embodiment, R3 is cyclohexyl, phenyl, or pyridinyl, each of which is optionally substituted with one or more halo, -R7, -OR7, -OCH2C(O)NR10R7, or -SO2R7. In one embodiment, R3 is cyclohexyl, phenyl, or pyridinyl, each of which is optionally substituted with one or more halo, -R7, -OR7, or -OCH2C(O)NR10R7.
[0084] In one embodiment, R is optionally substituted phenyl. In one embodiment, R is unsubstituted phenyl. In one embodiment, R3 is phenyl substituted with one or more halo,
Ci-C4 alkyl, 5-7 membered heterocyclyl, -0(Ci-C4 alkyl), -0(C7-C8 aralkyl),
-OCH2C(O)N(Ci-C4 alkyl)2, or -SO2(C]-C4 alkyl); wherein the alkyl and aralkyl are in turn optionally substituted with one or more halo, and the heterocyclyl is optionally substituted with one or more halo or Cj-C4 alkyl. In one embodiment, R3 is phenyl substituted with one or more fluoro, chloro, methyl, ethyl, propyl, /-propyl, t-butyl, /-butyl, CF3, 4- methylpiperazin-1-yl, -OCH3, -OCH2Ph, -OCH2C(O)N(CH3)2, Or -SO2Me.
[0085] In one embodiment, R3 is optionally substituted cyclohexyl. In one embodiment,
R3 is unsubstituted cyclohexyl. In one embodiment, R3 is cyclohexyl substituted with one or more -OH.
[0086] In one embodiment, R3 is optionally substituted pyridinyl. In one embodiment, R3 is unsubstituted pyridinyl.
[0087] In one embodiment, R3 is benzo[cQ[l,3]dioxolyl. In one embodiment, R3 is 2,3- dihydrobenzo [b] [ 1 ,4] dioxinyl .
[0088] In one embodiment, R3 and R8 together with the nitrogen atom to which they are attached form a piperizine ring, which is optionally substituted with an optionally substituted
C]-C4 alkyl at the second nitrogen atom. In one embodiment, R3 and R8 together with the nitrogen atom to which they are attached form a piperizine ring, which is optionally substituted at the second nitrogen atom with diethylaminoethyl.
[0089] Examples of R3 include, but are not limited to, (i) phenyl and pyridyl, each of which is unsubstituted or substituted with one or more fluoro, methyl, t-butyl, 4- methylpiperazin-1-yl, benzyloxy, or methoxy; and (ii) R and R together form a piperazine ring substituted with diethylaminoethyl; and (iii) 2-methoxyethyl, cyclopropylmethyl, thienylmethyl, and cyclohexyl. In some embodiments, the aryl groups are optionally substituted with one or more halo, C]-C6 alkyl, Ci-C6 alkoxy, benzyloxy, C3-C7 heterocyclyl, optionally substituted with methyl or ethyl.
[0090] In one embodiment, R3 is phenyl substituted with one or more fluoro. In one embodiment, R3 is /?αra-fluoro-phenyl.
[0091] In one embodiment, R8 is hydrogen, methyl, or ethyl. In one embodiment, R8 is hydrogen. In one embodiment, R8 is methyl. In one embodiment, R8 is ethyl. [0092] In one embodiment, L4 is a bond.
[0093] In one embodiment, L4 is -NR9-. In one embodiment, L4 is -NH-. In one embodiment, L4 is -N(CH3)-. In one embodiment, L4 is -N(CH2CH3)-.
[0094] In one embodiment, R4 is hydrogen.
[0095] In one embodiment, R4 is (i) Cj-C6 alkyl, optionally substituted with one or more
-OR5, -N(R5)2, or -R6; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl or heterocyclyl group, each of which is optionally substituted with one or more halo, -CN, -R7, -OR7,
-SO2R7, -NR10SO2R7, -NR10R7, -NR10C(O)R7, -NR10C(O)OR7, -C(O)R7, -C(O)OR7, or
-C(O)NR10R7; or (iii) a 3-4 membered carbocyclyl; or (iv) a 9-10 membered heteroaryl or heterocyclyl; wherein R5, R6, R7, and R10 are as defined herein elsewhere.
[0096] In one embodiment, R4 is (i) C]-C6 alkyl, optionally substituted with one or more
-OR5, -N(R5)2, or -R6; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl or heterocyclyl group, each of which is optionally substituted with one or more halo, -CN, -R7, -OR7,
-SO2R7, -NR10SO2R7, -NR10R7, -NR10C(O)R7, -NR10C(O)OR7, -C(O)R7, -C(O)OR7, or
-C(O)NR10R7; wherein R5, R6, R7, and R10 are as defined herein elsewhere.
[0097] In one embodiment, R4 is (i) C1-C6 alkyl, optionally substituted with one or more
-OR5, -N(R5)2, or -R6; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl or heterocyclyl group, each of which is optionally substituted with one or more halo, -CN, -R7, -OR7,
-SO2R7,-NR10R7, -NR10C(O)R7, -NR10C(O)OR7, or -C(O)NR10R7; wherein R5, R6, R7, and
R10 are as defined herein elsewhere.
[0098] In other embodiments, R4 and R9 together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring, which is optionally substituted with one or more R7, wherein R7 is as defined herein elsewhere.
[0099] In other embodiments, R4 and R9 together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring, which is optionally substituted with one or more -X4-R7, wherein X4 and R7 are as defined herein elsewhere.
[00100] In other embodiments, R4 and R9 together with the nitrogen atom to which they are attached form a piperizine ring, wherein the second nitrogen atom of the piperizine ring is optionally substituted with R11, wherein R11 are as defined herein elsewhere.
[00101] In one embodiment, R4 is (i) Ci-C6 alkyl, which is optionally substituted with one or more -OH, -0(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered carbocyclyl, or 5-6 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl and heterocyclyl groups are optionally substituted with one or more halo, CN, or C1-C4 alkyl; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more halo, -CN, -OH, -0(Ci-C6 alkyl), C1-C6 alkyl, -SO2(C1-C6 alkyl), -NHSO2(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)(Ci-C6 alkyl), -NHC(O)O(Ci-C6 alkyl), -0(C5-C6 aryl), -0(C5-C6 heteroaryl), -C(O)OH, -C(O)(C3-C7 heterocyclyl), -C(O)NH2, Or -C(O)NH(Ci-C6 alkyl), wherein each of the Ci-C6 alkyl is substituted with one or more -OH or halo.
[00102] In one embodiment, R4 is (i) Ci-C6 alkyl, which is optionally substituted with one or more -OH, -0(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered carbocyclyl, or 5-6 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl and heterocyclyl groups are optionally substituted with one or more halo or CN; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more halo, -OH, -0(Cj-C6 alkyl), Ci-C6 alkyl, -SO2(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)(C1-C6 alkyl), -NHC(O)O(C1-C6 alkyl), -0(C5-C6 aryl), -0(C5-C6 heteroaryl), -C(O)OH, -C(O)NH2, or -C(O)NH(C1-C6 alkyl), wherein each of the Ci-C6 alkyl is substituted with one or more -OH or halo. [00103] In one embodiment, R4 is (i) C]-C6 alkyl, which is optionally substituted with one or more -OH, -0(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered carbocyclyl, or 5-6 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl and heterocyclyl groups are optionally substituted with one or more halo or CN; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more halo, -OH, -0(Ci-C6 alkyl), Ci-C6 alkyl, -SO2(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)(C1-C6 alkyl), -NHC(O)O(C1-C6 alkyl), -0(C5-C6 aryl), -0(C5-C6 heteroaryl), -C(O)OH, -C(O)NH2, or -C(O)NH(C1-C6 alkyl), wherein each of the C1-C6 alkyl is substituted with one or more -OH or chloro. [00104] In one embodiment, R4 is (i) C1-C6 alkyl, which is optionally substituted with one or more -OH, -0(Cj-C6 alkyl), -N(Cj-C6 alkyl)2, 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered carbocyclyl, or 5-6 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl and heterocyclyl groups are optionally substituted with one or more halo or CN; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more halo, -OH, -0(Ci-C6 alkyl), Ci-C6 alkyl, -SO2(C-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)(C1-C6 alkyl), -NHC(O)O(C1-C6 alkyl), -0(C5-C6 aryl), -0(C5-C6 heteroaryl), -C(O)OH, -C(O)NH2, or -C(O)NH(C1-C6 alkyl), wherein each of the C1-C6 alkyl is substituted with one or more -OH or fluoro. [00105] In one embodiment, R4 is optionally substituted Ci alkyl. In one embodiment, R4 is unsubstituted Ci alkyl. In one embodiment, R4 is Ci alkyl, optionally substituted with phenyl, fluorophenyl, thienyl, furanyl, methyl-furanyl, pyridinyl, morpholinyl, -OH, -OMe, or -N(Me)2. In one embodiment, R4 is optionally substituted C2 alkyl. In one embodiment, R4 is unsubstituted C2 alkyl. In one embodiment, R4 is C2 alkyl, optionally substituted with phenyl, fluorophenyl, thienyl, furanyl, methyl-furanyl, pyridinyl, morpholinyl, -OH, -OMe, or -N(Me)2. In one embodiment, R4 is optionally substituted C3 alkyl. In one embodiment, R4 is unsubstituted C3 alkyl. In one embodiment, R4 is C3 alkyl, optionally substituted with one or more -OH. In one embodiment, R4 is optionally substituted C4 alkyl. In one embodiment, R4 is unsubstituted C4 alkyl. In one embodiment, R4 is C4 alkyl optionally substituted with one or more -OH. In one embodiment, R4 is optionally substituted C5 alkyl. In one embodiment, R4 is unsubstituted C5 alkyl. In one embodiment, R4 is C5 alkyl optionally substituted with one or more -OH. In one embodiment, R4 is optionally substituted C6 alkyl.
[00106] In one embodiment, R4 is cyclohexyl, phenyl, thienyl, or pyridinyl, each of which is optionally substituted with one or more halo, -CN, -R7, -OR7, -SO2R7, -NR10SO2R7, -NR10R7, -NR10C(O)R7, -NR10C(O)OR7, -C(O)R7, -C(O)OR7, or -C(O)NR10R7. In one embodiment, R4 is cyclohexyl, phenyl, thienyl, or pyridinyl, each of which is optionally substituted with one or more halo, -CN, -R7, -OR7, -SO2R7, -NR10R7, -NR10C(O)R7, -NR10C(O)OR7, or -C(O)NR10R7.
[00107] In one embodiment, R4 is optionally substituted phenyl. In one embodiment, R4 is unsubstituted phenyl. In one embodiment, R4 is phenyl substituted with one or more halo, CN, OH, Ci-C4 alkyl, -0(Ci-C4 alkyl), -0(C6 aryl), -NH(C-C4 alkyl), -N(C1-C4 alkyl)2, -NHC(O)O(C-C4 alkyl), -NHC(O)(C-C4 alkyl), -NHSO2(C1-C4 alkyl), -C(O)OH, -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C-C4 alkyl)2, -SO2(C-C4 alkyl), 5-7 membered heterocyclyl, or -C(O)(5-7 membered heterocyclyl); wherein the alkyl is in turn optionally substituted with one or more halo or OH, and the aryl and heterocyclyl are optionally substituted with one or more halo, OH, or C1-C4 alkyl. In one embodiment, R4 is phenyl substituted with one or more fluoro, chloro, bromo, CN, OH, methyl, ethyl, propyl, /-propyl, CF3, -CH2CH2OH, -OCH3, -OPh, -N(Et)(CH2CH2OH), -NHC(O)OEt, -NHC(O)CH3, -NHSO2CH3, -C(O)OH, -C(O)NH2, -C(O)NHCH3, -SO2CH3, or -C(θXmorpholinyl). [00108] In one embodiment, R4 is optionally substituted cyclohexyl. In one embodiment,
R4 is unsubstituted cyclohexyl. In one embodiment, R4 is cyclohexyl optionally substituted with one or more -OH.
[00109] In one embodiment, R4 is optionally substituted thienyl. In one embodiment, R4 is unsubstituted thienyl.
[00110] In one embodiment, R4 is optionally substituted pyridinyl. In one embodiment, R4 is unsubstituted pyridinyl. In one embodiment, R4 is pyridinyl optionally substituted with one or more -OH or -OCH3.
[00111] In one embodiment, R4 is cyclopropyl. In one embodiment, R4 is benzofuranyl.
In one embodiment, R4 is indolinonyl. In one embodiment, R4 is benzo[cG[l,3]dioxolyl. In one embodiment, R4 is 2,3-dihydrobenzo[b][l,4]dioxinyl.
[00112] In one embodiment, R4 and R9 together with the nitrogen atom to which they are attached form a piperazine, piperidine, or morpholine ring, each of which is optionally substituted with one or more: (a) C1-C6 alkyl, which in turn is optionally substituted with one or more -OH, -0(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(Ci-C6 alkyl)2, or (b) 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl, which in turn is optionally substituted with one or more halo or CN.
[00113] In one embodiment, R4 and R9 together with the nitrogen atom to which they are attached form a piperazine ring, wherein the second nitrogen atom of the piperizine ring is optionally substituted with: (a) C1-C6 alkyl, which in turn is optionally substituted with one or more -OH, -0(Ci-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2, or (b) 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl, which in turn is optionally substituted with one or more halo or CN; or (c) -C(O)-(5-7 membered heterocyclyl).
[00114] In one embodiment, R4 and R9 together with the nitrogen atom to which they are attached form a piperazine ring, wherein the second nitrogen atom of the piperizine ring is optionally substituted with: (a) C1-C6 alkyl, which in turn is optionally substituted with one or more -OH, -0(C1-C6 alkyl), -NH2, -NH(Ci-C6 alkyl), or -N(C-C6 alkyl)2, or (b) 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl, which in turn is optionally substituted with one or more halo or CN.
[00115] In one embodiment, R4 and R9 together with the nitrogen atom to which they are attached form a piperazine ring, wherein the second nitrogen atom of the piperizine ring is optionally substituted with methyl, ethyl, pyridine, diethylaminoethyl, or -C(O)-morpholinyl. [00116] In one embodiment, R4 and R9 together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, or morpholine ring, each of which is further fused to a phenyl ring, wherein the fused ring system is optionally substituted.
[00117] In some embodiments, when R9 is not combined with R4 to form a heterocyclic ring system, R9 is hydrogen, methyl, or ethyl. In one embodiment, R9 is hydrogen. In one embodiment, R9 is methyl. In one embodiment, R9 is ethyl.
[00118] In one embodiment, L4 is a bond, R4 is phenyl, furanyl, or indolyl, each of which is optionally substituted. In one embodiment, L4 is a bond, R4 is phenyl, furanyl, or indolyl, each of which is optionally substituted with one or more halo, CN, -C(O)NH(Ci-C4 alkyl),
-C(O)N(C1-C4 alkyl)2, Or -NHC(O)(C1-C4 alkyl).
[00119] In one embodiment, provided herein is a compound of formula (Ib):
Figure imgf000027_0001
(Ib) or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein R4 is as defined herein elsewhere; and L4 is a bond, -O-, or -NR -, wherein R9 is as defined herein elsewhere. [00120] In one embodiment, provided herein is a compound of formula (Ic):
Figure imgf000027_0002
(Ic) or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein R4 and R9 are as defined herein elsewhere. [00121] In one embodiment, provided herein is a compound of formula (Id):
Figure imgf000027_0003
(Id) or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein R4 is as defined herein elsewhere.
[00122] In one embodiment, specific examples of compounds of formula (I) include, but are not limited to, the following: 1. N-(4-rerr-butylphenyl)-6-(4-hydroxycyclohexylamino)pyrimidine-4-carboxamide
Figure imgf000028_0001
2. N-(4-tert-butylphenyl)-6-(4-(pyridin-2-yl)piperazin-l-yl)pyrimidine-4-carboxamide
Figure imgf000028_0002
3. 6-(ethylamino)-N-(4-(4-methylpiperazin-l-yl)phenyl)pyrimidine-4-carboxamide
Figure imgf000028_0003
4. 6-(lH-indol-5-yl)-N-(2-methoxyethyl)pyrimidine-4-carboxamide
Figure imgf000028_0004
5. N-benzyl-6-(cyclopropylamino)pyrimidine-4-carboxamide
Figure imgf000028_0005
6. 6-(2-methoxyphenylamino)-yV-phenylpyrimidine-4-carboxamide
Figure imgf000028_0006
7. N-(3-(benzyloxy)phenyl)-6-(piperidin- 1 -yl)pyrimidine-4-carboxamide
Figure imgf000029_0001
8. 6-(dimethylamino)-N-methyl-N-phenylpyrimidine-4-carboxamide
Figure imgf000029_0002
9. (/?)-N-(4-fluorophenyl)-6-(l-hydroxy-3-methylbutan-2-ylamino)pyrimidine-4-carboxamide
Figure imgf000029_0003
10. yV-(4-tert-butylphenyl)-6-(4-(2-hydroxyethyl)phenylamino)pyrimidine-4-carboxamide
Figure imgf000029_0004
11. (6-(cyclohexylamino)pyrimidin-4-yl)(4-(2-(diethylamino)ethyl)piperazin- 1 -yl)methanone
Figure imgf000029_0005
12. 6-((2-(dimethylamino)ethyl)(methyl)amino)-^V-(4-fluorophenyl)pyrimidine-4- carboxamide
Figure imgf000029_0006
13. N-(4-fluorophenyl)-6-(2-methoxyethylamino)pyrimidine-4-carboxamide
Figure imgf000030_0001
14. 6-(3-(methylsulfonyl)phenylamino)-N-phenylpyrimidine-4-carboxamide
Figure imgf000030_0002
15. N-(4-fluorophenyl)-6-(4-hydroxyphenylamino)pyrimidine-4-carboxamide
Figure imgf000030_0003
16. 6-(cyclohexylamino)-N-(cyclopropylmethyl)pyrimidine-4-carboxamide
Figure imgf000030_0004
17. 6-(4-methylpiperazin-l-yl)-N-/?-tolylpyrimidine-4-carboxamide
Figure imgf000030_0005
18, iV-(pyridin-3-yl)-6-(thiopiien-2-ylrnethylamino)pyrimidine-4-carboxamide
Figure imgf000030_0006
19. 6-(3-bromophenylamino)-N-(3,4,5-trimethoxyphenyl)pyrimidine-4-carboxamide
Figure imgf000030_0007
20. 6-(benzylamino)-N-(3-(benzyloxy)phenyl)pyrimidine-4-carboxamide
Figure imgf000031_0001
21. 6-(4-hydroxycyclohexylamino)-N-(4-methoxyphenyl)pyrimidine-4-carboxamide
Figure imgf000031_0002
22. 6-(cyclohexylamino)-N-(2-methoxyethyl)pyrimidine-4-carboxamide
Figure imgf000031_0003
23. (/?)-6-(l-hydroxy-3-methylbutan-2-ylamino)-N-phenylpyrimidine-4-carboxamide
Figure imgf000031_0004
24. 6-(4-(2-(diethylamino)ethyl)piperazin-l-yl)-N-methyl-iV-phenylpyrimidine-4- carboxamide
Figure imgf000031_0005
25. N-(3-(benzyloxy)phenyl)-6-(cyclohexylamino)pyrimidine-4-carboxamide
Figure imgf000031_0006
26. N-(3-(benzyloxy)phenyl)-6-(4-hydroxycyclohexylamino)pyrimidine-4-caτboxamide
Figure imgf000032_0001
27. N-isobutyl-6-(methyl(phenyl)amino)pyrimidine-4-carboxamide
Figure imgf000032_0002
28. 6-(4-hydroxyphenylamino)-iV-(4-methoxyphenyl)pyrimidine-4-carboxamide
Figure imgf000032_0003
29. N-(4-terr-butylphenyl)-6-(4-(2-(diethylamino)ethyl)piperazin- 1 -yl)pyrimidine-4- carboxamide
Figure imgf000032_0004
30. N-(3-(benzyloxy)phenyl)-6-(2-methoxyethylamino)pyrimidine-4-carboxamide
Figure imgf000032_0005
31. 6-(4-hydroxy-2-methylphenylamino)-yV-phenylpyrimidine-4-carboxamide
Figure imgf000032_0006
32. 6-(4-(2-(diethylamino)ethyl)piperazin- 1 -yO-N-phenylpyrimidine^-carboxamide
Figure imgf000033_0001
33. 6-(ethylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000033_0002
34. (/?)-6-(l-hydroxy-3-methylbutan-2-ylamino)-N-(4-methoxyphenyl)pyrimidine-4- carboxamide
Figure imgf000033_0003
35. iV-(4-tert-butylphenyl)-6-(2-methoxyethylamino)pyrimidine-4-carboxamide
Figure imgf000033_0004
36. Λ^-(4-fluorophenyl)-6-(isopropylamino)pyrimidine-4-carboxamide
Figure imgf000033_0005
37. N-(4-hydroxycyclohexyl)-6-(piperidin-l-yl)pyrimidine-4-carboxamide
Figure imgf000033_0006
38. (5)-6-(l-hydroxy-3-methylbutan-2-ylamino)-iV-phenylpyrimidine-4-carboxamide
Figure imgf000034_0001
39. 6-(2-chlorophenylamino)-N-(pyridin-3-yl)pyrimidine-4-carboxamide
Figure imgf000034_0002
40. 6-(isopropylamino)-7V-(4-methoxyphenyl)pyrimidine-4-carboxamide
Figure imgf000034_0003
41. N-(3-(benzyloxy)phenyl)-6-(4-hydroxyphenylamino)pyrimidine-4-carboxamide
Figure imgf000034_0004
42. yV-(4-methoxyphenyl)-6-(2-morpholinoethylamino)pyrimidine-4-carboxamide
Figure imgf000034_0005
43. N-(4-ter?-butylphenyl)-6-phenylpyrimidine-4-carboxamide
Figure imgf000034_0006
44. 6-(4-(ethyl(2-hydroxyethyl)amino)phenylamino)-N-(4-fluorophenyl)pyrimidine-4- carboxamide
HO
Figure imgf000035_0001
45. N-methyl-6-(methylamino)-N-phenylpyrimidine-4-carboxamide
Figure imgf000035_0002
46. 6-(2-morpholinoethylamino)-N-(3,4,5-trimethoxyphenyl)pyrimidine-4-carboxamide
Figure imgf000035_0003
Al . N-(4-methoxyphenyl)-6-morpholinopyrimidine-4-carboxamide
Figure imgf000035_0004
48. N-phenyl-6-(thiophen-2-ylmethylamino)pyrimidine-4-carboxamide
Figure imgf000035_0005
49. (5)-N-(4-fluorophenyl)-6-(l-hydroxy-3-methylbutan-2-ylamino)pyrimidine-4- carboxamide
Figure imgf000035_0006
50. N-(4-te/-r-butylphenyl)-6-(3,4,5-trimethoxyphenylamino)pyrimidine-4-carboxamide
Figure imgf000036_0001
51. N-cyclohexyl-6-(2-methoxyethylamino)pyrimidine-4-carboxamide
Figure imgf000036_0002
52. iV-(4-rert-butylphenyl)-6-(furan-3-yl)pyrimidine-4-carboxamide
Figure imgf000036_0003
53. N-benzyl-6-(dimethylamino)pyrimidine-4-carboxamide
Figure imgf000036_0004
54. 6-(cyclopropylamino)-N-(2-(pyridin-2-yl)ethyl)pyrimidine-4-carboxamide
Figure imgf000036_0005
55. 6-(4-hydroxyphenylamino)-N-phenylpyrimidine-4-carboxamide
Figure imgf000036_0006
56. 6-(4-hydroxyphenylamino)-yV-isobutylpyrimidine-4-carboxamide
Figure imgf000037_0001
57. N-benzyl-6-(piperidin- 1 -yl)pyrimidine-4-carboxamide
Figure imgf000037_0002
58. 6-(ethylamino)-N-(2-(pyridin-2-yl)ethyl)pyrimidine-4-carboxamide
Figure imgf000037_0003
59. 6-(benzyl(methyl)amino)-N-(4-methoxyphenyl)pyrimidine-4-carboxamide
Figure imgf000037_0004
60. N-(3-(benzyloxy)phenyl)-6-(dimethylamino)pyrimidine-4-carboxamide
Figure imgf000037_0005
61. (^)-6-(l-hydroxy-3-methyrbutan-2-ylamino)-N-methyl-N-phenylpyrimidine-4- carboxamide
Figure imgf000037_0006
62. ό-CS-acetamidophenyO-N-phenylpyrimidine^-carboxamide
Figure imgf000037_0007
63. 6-(piperidin-l-yl)-N-(thiophen-2-ylmethyl)pyrimidine-4-carboxamide
Figure imgf000038_0001
64. N-(2-methoxyethyl)-6-(piperidin- 1 -yl)pyrimidine-4-carboxamide
Figure imgf000038_0002
65. N-(3-(benzyloxy)phenyl)-6-(ethylamino)pyrimidine-4-carboxamide
Figure imgf000038_0003
66. N-phenyl-6-(pyridin-3-ylmethylamino)pyrimidine-4-carboxamide
Figure imgf000038_0004
67. (6-(4-phenoxyphenylamino)pyrimidin-4-yl)(4-(pyridin-2-yl)piperazin- 1 -yl)methanone
Figure imgf000038_0005
68. N-(4-tert-butylphenyl)-6-(thiophen-2-ylmethylamino)pyrimidine-4-carboxamide
Figure imgf000038_0006
69. N-(3-(2-(dimethylamino)-2-oxoethoxy)phenyl)-6-(piperidin- 1 -yl)pyrimidine-4- carboxamide
Figure imgf000039_0001
70. N-(4-tert-butylphenyl)-6-(3,4-dimethoxyphenylamino)pyrimidine-4-carboxamide
Figure imgf000039_0002
71. iV-isobutyl-6-(piperidin- 1 -yl)pyrimidine-4-carboxamide
Figure imgf000039_0003
72. (5)-6-(l-hydroxy-3-methylbutan-2-ylamino)-N-(4-methoxyphenyl)pyrimidine-4- carboxamide
Figure imgf000039_0004
73. N-phenyl-6-(phenylamino)pyrimidine-4-carboxamide
Figure imgf000039_0005
74. iV-(4-fluorophenyl)-6-(4-fluorophenylamino)pyrimidine-4-carboxamide
Figure imgf000039_0006
75. Λ^-(4-fluorophenyl)-6-(4-methoxyphenylamino)pyrimidine-4-carboxamide
Figure imgf000040_0001
76. 6-(3-chlorophenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000040_0002
77. N-(4-fluorophenyl)-6-(3-fluorophenylamino)pyrimidine-4-carboxamide
Figure imgf000040_0003
78. N-(4-fluorophenyl)-6-(phenylamino)pyrimidine-4-carboxamide
Figure imgf000040_0004
79. 6-(cyclohexylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000040_0005
80. 6-(4-fluorobenzylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000040_0006
81. 6-(benzofuran-5-ylamino)-yV-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000040_0007
82. 6-(benzylamino)-iV-(4-fluorophenyl)pyrimidine-4-carboxainide
Figure imgf000041_0001
83. N-(4-fluorophenyl)-6-(4-(trifluoromethyl)phenylamino)pyrimidine-4-carboxamide
Figure imgf000041_0002
84. iV-(4-fluorophenyl)-6-(4-chlorophenylamino)pyrimidine-4-carboxamide
Figure imgf000041_0003
85. 6-(4-cyanophenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000041_0004
86. 6-(4-chlorophenylamino)-N-phenylpyrimidine-4-carboxamide
Figure imgf000041_0005
87. N-(4-fluorophenyl)-6-(2-oxoindolin-5-ylamino)pyrimidine-4-carboxamide
Figure imgf000041_0006
88. N-(4-fluorophenyl)-6-(thiophen-3-ylmethylamino)pyrimidine-4-carboxamide
Figure imgf000042_0001
89. N-(4-fluorophenyl)-6-(furan-3-ylmethylamino)pyrimidine-4-carboxamide
Figure imgf000042_0002
90. N-(4-fluorophenyl)-6-(furan-2-ylmethylamino)pyrimidine-4-carboxamide
Figure imgf000042_0003
91. N-(4-fluorophenyl)-6-(thiophen-2-ylmethylamino)pyrimidine-4-carboxamide
Figure imgf000042_0004
92. iV-(4-te/-t-butylphenyl)-6-(phenylamino)pyrimidine-4-carboxamide
Figure imgf000042_0005
93. ethyl 4-(6-(4-fluorophenylcarbamoyl)pyrimidin-4-ylamino)phenylcarbamate
Figure imgf000042_0006
94. N-cyclohexyl-6-(phenylamino)pyrimidine-4-carboxamide
Figure imgf000042_0007
95. 6-(4-acetamidophenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000043_0001
96. Λ^-(4-fluorophenyl)-6-(4-(methylsulfonamido)phenylamino)pyrimidine-4-carboxaniide
Figure imgf000043_0002
97. N-(4-fluorophenyl)-6-(2-hydroxyethylamino)pyrimidine-4-carboxamide
Figure imgf000043_0003
98. N-(4-fluorophenyl)-6-(thiophen-3-ylamino)pyrimidine-4-carboxamide
Figure imgf000043_0004
99. iV-(4-fluorophenyl)-6-(2-methoxyphenylamino)pyrimidine-4-carboxamide
Figure imgf000043_0005
100. 4-(6-(4-fluorophenylcarbamoyl)pyrimidin-4-ylamino)benzoic acid
Figure imgf000043_0006
101. /V-(4-fluorophenyl)-6-(methyl(phenyl)amino)pyrimidine-4-carboxamide
Figure imgf000044_0001
102. 6-(benzo[cQ[l,3]dioxol-5-ylamino)-iV-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000044_0002
103. 6-(4-carbamoylphenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000044_0003
104. yV-(benzo[J][l,3]dioxol-5-yl)-6-(phenylamino)pyrimidine-4-carboxamide
Figure imgf000044_0004
105. /V-(4-fluorophenyl)-6-(3-(methylsulfonyl)phenylamino)pyrimidine-4-carboxamide
Figure imgf000044_0005
106. N-(4-fluorophenyl)-6-(6-hydroxypyridin-3-ylamino)pyrimidine-4-carboxamide
Figure imgf000044_0006
107. 6-amino-N-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000044_0007
108. N-(4-fluorophenyl)-6-(3-hydroxyphenylamino)pyrimidine-4-carboxamide
Figure imgf000045_0001
109. 6-(phenylamino)-N-(4-(trifluoromethyl)phenyl)pyrimidine-4-carboxamide
Figure imgf000045_0002
110. iV-isobutyl-6-(phenylamino)pyrimidine-4-carboxamide
Figure imgf000045_0003
111. 6-(phenylamino)-N-(thiophen-2-ylmethyl)pyrimidine-4-carboxamide
Figure imgf000045_0004
112. //-(3-fluorophenyl)-6-(phenylamino)pyrimidine-4-carboxamide
Figure imgf000045_0005
113. N-(4-chlorophenyl)-6-(phenylamino)pyrimidine-4-carboxamide
Figure imgf000045_0006
114. iV-(4-fluorophenyl)-6-(6-methoxypyridin-3-ylamino)pyrimidine-4-carboxamide
Figure imgf000045_0007
115. 6-(3,5-difluoro-4-hydroxyphenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000046_0001
116. yV-(4-fluorophenyl)-6-(piperidin-l-yl)pyrimidine-4-carboxamide
Figure imgf000046_0002
117. N-(3-(methylsulfonyl)phenyl)-6-(phenylamino)pyrimidine-4-carboxamide
Figure imgf000046_0003
118. yV-(4-fluorophenyl)-6-(4-(methylcarbamoyl)phenylamino)pyrimidine-4-carboxamide
Figure imgf000046_0004
119. yV-(4-fluorophenyl)-6-(3-hydroxypropylamino)pyrimidine-4-carboxamide
Figure imgf000046_0005
120. yV-(4-fluorophenyl)-6-(isobutylamino)pyrimidine-4-carboxamide
Figure imgf000046_0006
121. 7V-(4-fluorophenyl)-6-(4-hydroxy-3-methylphenylamino)pyrimidine-4-carboxamide
Figure imgf000047_0001
122. N-(4-fluorophenyl)-6-morpholinopyrimidine-4-carboxamide
Figure imgf000047_0002
123. 6-(4,4-difluoropiperidin-l-yl)-N-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000047_0003
124. N-(4-fluorophenyl)-6-phenoxypyrimidine-4-carboxamide
Figure imgf000047_0004
125. 6-(phenylamino)-N-(pyridin-3-yl)pyrimidine-4-carboxamide
Figure imgf000047_0005
126. yV-(4-fluorophenyl)-6-(indolin- 1 -yl)pyrimidine-4-carboxamide
Figure imgf000047_0006
127. yV-(4-fluorophenyl)-6-(/7-tolylamino)pyrimidine-4-carboxamide
Figure imgf000048_0001
128. 6-(3,4-dihydroquinolin-l(2H)-yl)-7V-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000048_0002
129. N-(4-fluorophenyl)-6-((rrαn5)-4-hydroxycyclohexylamino)pyrimidine-4-carboxamide
Figure imgf000048_0003
130. iV-(3-fluorophenyl)-6-(3-hydroxyphenylamino)pyrimidine-4-carboxamide
Figure imgf000048_0004
131. N-(4-fluorophenyl)-N-methyl-6-(methyl(phenyl)aniino)pyriniidine-4-carboxamide
Figure imgf000048_0005
132. 6-(2H-benzo[^][l,4]oxazin-4(3H)-yl)-N-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000048_0006
133. iV-(2,3-dihydrobenzo|>] [ 1 ,4]dioxin-6-yl)-6-(4-(moφholine-4-carbonyl)piperazin- 1 - yl)pyrimidine-4-carboxamide
Figure imgf000049_0001
134. N-(4-fluorophenyl)-6-(methyl((2-methylfuran-3-yl)methyl)amino)pyrimidine-4- carboxamide
Figure imgf000049_0002
135. N-(4-fluorophenyl)-6-(4-(morpholine-4-carbonyl)piperazin- 1 -yl)pyrimidine-4- carboxamide
Figure imgf000049_0003
136. Λ^-(4-fluorophenyl)-6-(4-(moφholine-4-carbonyl)phenylamino)pyrimidine-4- carboxamide
Figure imgf000049_0004
137. 6-(ethyl(phenyl)amino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide
Figure imgf000049_0005
138. N-methyl-6-(methyl(phenyl)amino)pyrimidine-4-carboxamide
Figure imgf000050_0001
139. 4-(6-(naphthalen-2-yl)pyrimidin-4-ylamino)phenol
Figure imgf000050_0002
or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
[00123] In one embodiment, specific examples of compounds of formula (I) include, but are not limited to, the following:
N-phenyl-6-(phenylamino)pyrimidine-4-carboxamide (Compound 73)
Figure imgf000050_0003
6-(4-hydroxyphenylamino)-N-phenylpyrimidine-4-carboxamide (Compound 55)
Figure imgf000050_0004
yV-(4-fluorophenyl)-6-(4-hydroxyphenylamino)pyrimidine-4-carboxamide (Compound 15)
Figure imgf000050_0005
//-(4-fluorophenyl)-6-(4-fluorophenylamino)pyrimidine-4-carboxamide (Compound 74)
Figure imgf000050_0006
N-(4-fluorophenyl)-6-(4-methoxyphenylamino)pyrimidine-4-carboxamide (Compound 75)
Figure imgf000051_0001
6-(3-chlorophenylamino)-N-(4-fluorophenyl) pyrimidine-4-carboxamide (Compound 76)
Figure imgf000051_0002
Λf-(4-fluorophenyl)-6-(3-fluorophenylamino) pyrimidine-4-carboxamide (Compound 77)
Figure imgf000051_0003
N-(4-fluorophenyl)-6-(phenylamino)pyrimidine-4-carboxamide (Compound 78)
Figure imgf000051_0004
6-(cyclohexylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 79)
Figure imgf000051_0005
6-(benzofuran-5-ylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 81)
Figure imgf000051_0006
6-(4-fluorobenzylarnino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 80)
Figure imgf000051_0007
6-(benzylamino)-iV-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 82)
Figure imgf000051_0008
6-(4-cyanophenylamino)-7V-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 85)
Figure imgf000052_0001
yV-(4-fluorophenyl)-6-(4-(trifluoromethyl)phenylamino)pyrimidine-4-carboxaniide (Compound 83)
Figure imgf000052_0002
N-(4-fluorophenyl)-6-(4-chlorophenylamino)pyrimidine-4-carboxamide (Compound 84)
Figure imgf000052_0003
/V-(4-fluorophenyl)-6-(2-oxoindolin-5-ylamino)pyrimidine-4-carboxamide (Compound 87)
Figure imgf000052_0004
N-(4-fluorophenyl)-6-(6-hydroxypyridin-3-ylamino)pyrimidine-4-carboxamide (Compound 106)
Figure imgf000052_0005
6-(phenylamino)-iV-(4-(trifluoromethyl)phenyl)pyrimidine-4-carboxamide (Compound 109)
Figure imgf000052_0006
6-(3,5-difluoro-4-hydroxyphenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide
(Compound 115)
Figure imgf000053_0001
6-(phenylamino)-N-(pyridin-3-yl)pyrimidine-4-carboxamide (Compound 125)
Figure imgf000053_0002
6-(3,4-dihydroquinolin- 1 (2H)-yl)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 128)
Figure imgf000053_0003
N-(4-fluorophenyl)-6-(4-(morpholine-4-carbonyl)phenylamino)pyrimidine-4-carboxamide (Compound 136)
Figure imgf000053_0004
6-(4-(ethyl(2-hydroxyethyl)amino)phenylamino)-N-(4-fluorophenyl)pyrimidine-4- carboxamide (Compound 44)
ΗC
Figure imgf000053_0005
6-(ethyl(phenyl)amino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 137)
Figure imgf000054_0001
N-(4-fluorophenyl)-6-(methyl ((2-methylfuran-3-yl)methyl)amino)pyrimidine-4-carboxamide (Compound 134)
Figure imgf000054_0002
N-(3-fluorophenyl)-6-(3-hydroxyphenylamino)pyrimidine-4-carboxamide (Compound 130)
Figure imgf000054_0003
6-(4-chlorophenylamino)-iV-phenylpyrimidine-4-carboxamide (Compound 86)
Figure imgf000054_0004
^V-(4-fluorophenyl)-6-(thiophen-3-ylmethylamino)pyrimidine-4-carboxamide (Compound 88)
Figure imgf000054_0005
^V-(4-fluorophenyl)-6-(furan-3-ylmethylamino)pyrimidine-4-carboxamide (Compound 89)
Figure imgf000054_0006
N-(4-fluorophenyl)-6-(furan-2-ylmethylamino)pyrimidine-4-carboxamide (Compound 90)
Figure imgf000054_0007
N-(4-fluorophenyl)-6-(thiophen-2-ylmethylamino)pyrimidine-4-carboxamide (Compound 91)
Figure imgf000055_0001
yV-(4-fluorophenyl)-6-(2-methoxyphenylamino)pyrimidine-4-carboxamide (Compound 99)
Figure imgf000055_0002
iV-(4-fluorophenyl)-6-(6-methoxypyridin-3-ylamino)pyrimidine-4-carboxamide (Compound 114)
Figure imgf000055_0003
6-(4-acetamidophenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 95)
Figure imgf000055_0004
yV-(4-fluorophenyl)-6-(4-(methylsulfonamido)phenylamino)pyrimidine-4-carboxamide (Compound 96)
Figure imgf000055_0005
yV-(4-fluorophenyl)-6-(2-hydroxyethylamino)pyrimidine-4-carboxamide (Compound 97)
Figure imgf000055_0006
iV-(4-fluorophenyl)-6-(thiophen-3-ylamino)pyrimidine-4-carboxamide (Compound 98)
Figure imgf000055_0007
6-(4-carbamoylphenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 103)
Figure imgf000056_0001
N-(4-fluorophenyl)-6-(methyl(phenyl)amino)pyrimidine-4-carboxamide (Compound 101)
Figure imgf000056_0002
6-(benzo[J][l,3]dioxol-5-ylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 102)
Figure imgf000056_0003
4-(6-(4-fluorophenylcarbamoyl)pyrimidin-4-ylamino)benzoic acid (Compound 100)
Figure imgf000056_0004
6-(phenylamino)-N-(thiophen-2-ylmethyl)pyrimidine-4-carboxamide (Compound 111)
Figure imgf000056_0005
N-(4-fluorophenyl)-6-(4-(methylcarbamoyl)phenylamino)pyrimidine-4-carboxamide (Compound 118)
Figure imgf000056_0006
6-(ethylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 33)
Figure imgf000056_0007
N-(4-fluorophenyl)-6-(3-hydroxyphenylamino)pyrimidine-4-carboxamide (Compound 108)
Figure imgf000057_0001
iV-(4-fluorophenyl)-6-(3-hydroxypropylamino)pyrimidine-4-carboxamide (Compound 119)
Figure imgf000057_0002
N-(4-fluorophenyl)-6-(isobutylamino)pyrimidine-4-carboxamide (Compound 120)
Figure imgf000057_0003
N-(4-fluorophenyl)-6-(p-tolylamino)pyrimidine-4-carboxamide (Compound 127)
Figure imgf000057_0004
N-(4-fluorophenyl)-6-(indolin- 1 -yl)pyrimidine-4-carboxamide (Compound 126)
Figure imgf000057_0005
N-(4-fluorophenyl)-6-((tran_j)-4-hydroxycyclohexylamino)pyrimidine-4-carboxamide (Compound 129)
Figure imgf000057_0006
6-(2H-benzo[b] [ 1 ,4]oxazin-4(3H)-yl)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 132)
Figure imgf000058_0001
yV-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-6-(4-(morpholine-4-carbonyl)piperazin-l- yl)pyrimidine-4-carboxamide (Compound 133)
Figure imgf000058_0002
N-methyl-6-(methyl(phenyl)amino)pyrimidine-4-carboxamide (Compound 138)
Figure imgf000058_0003
yV-(4-tert-butylphenyl)-6-(phenylamino)pyrimidine-4-carboxamide (Compound 92)
Figure imgf000058_0004
ethyl 4-(6-(4-fluorophenylcarbamoyl)pyrimidin-4-ylamino)phenylcarbamate (Compound 93)
Figure imgf000058_0005
iV-cyclohexyl-6-(phenylamino)pyrimidine-4-carboxamide (Compound 94)
Figure imgf000058_0006
Λ^-(4-fluorophenyl)-6-(3-(methylsulfonyl)phenylamino)pyrimidine-4-carboxamide (Compound 105)
Figure imgf000059_0001
N-isobutyl-6-(phenylamino)pyrimidine-4-carboxamide (Compound 110)
Figure imgf000059_0002
/V-(3-(methylsulfonyl)phenyl)-6-(phenylamino)pyrimidine-4-carboxamide (Compound 117)
Figure imgf000059_0003
N-(3-fluorophenyl)-6-(phenylamino)pyrimidine-4-carboxamide (Compound 112)
Figure imgf000059_0004
yV-(4-chlorophenyl)-6-(phenylamino)pyrimidine-4-carboxamide (Compound 113)
Figure imgf000059_0005
N-(4-fluorophenyl)-6-(piperidin-l-yl)pyrimidine-4-carboxamide (Compound 116)
Figure imgf000059_0006
N-(4-fluorophenyl)-6-(4-hydroxy-3-methylphenylamino)pyrimidine-4-carboxamide (Compound 121)
Figure imgf000059_0007
N-(4-fluorophenyl)-6-morpholinopyrimidine-4-carboxamide (Compound 122)
Figure imgf000060_0001
6-(4,4-difluoropiperidin- 1 -yl)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 123)
Figure imgf000060_0002
N-(4-fluorophenyl)-6-(4-(morpholine-4-carbonyl)piperazin-l-yl)pyrimidine-4-carboxamide (Compound 135)
Figure imgf000060_0003
N-(4-fluorophenyl)-6-phenoxypyrimidine-4-carboxamide (Compound 124)
Figure imgf000060_0004
N-(4-fluorophenyl)-iV-methyl-6-(methyl(phenyl)amino)pyrimidine-4-carboxamide (Compound 131)
Figure imgf000060_0005
4-(6-(naphthalen-2-yl)pyrimidin-4-ylamino)phenol (Compound 139)
Figure imgf000060_0006
N-(benzo[d][l ,3]dioxol-5-yl)-6-(phenylamino)pyrimidine-4-carboxamide (Compound 104)
Figure imgf000060_0007
6-amino-Λ^(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 107)
Figure imgf000061_0001
or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
[00124] Also provided herein is the use of a compound of formula (T), 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 (T), 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
[00125] 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.
[00126] In one embodiment, compounds of formula (Ia) in which L4 is -O- or -NR9- may be prepared by the reaction of a compound of formula (II):
X ^^ L3
(H) wherein X is halogen, such as, e.g., chlorine; L3 is as defined herein elsewhere, such as, e.g., a bond or -C(O)NR8-; and R3 and R8 are as defined herein elsewhere for formula (I) and (Ia); with a compound of general formula (HI):
R4-L4-H (πi) wherein R4 is as defined herein elsewhere for formula (I) and (Ia); and L4 is -NR9- or -O-. [00127] In one embodiment, for the production of amine compounds, i.e., L4 is -NR9-, the reaction may be carried out at raised temperature, typically 50-90°C, and in an alcoholic solvent with a suitable boiling point, such as, e.g., isopropyl alcohol. Alternatively, the reaction mixture can be irradiated with microwave radiation, which may shorten the reaction time.
[00128] In one embodiment, when L4 is -O-, the compound of formula (III) may first be reacted with a strong base, typically a source of hydride ions, such as, e.g., sodium hydride.
The reaction with the compound of formula (II) may be conducted at room temperature and in an organic solvent such as, e.g., N.iV-dimethylformamide.
[00129] Compounds of formula (III) are known and are commercially available or can be prepared by methods known to those of skill in the art.
[00130] In one embodiment, compounds of formula (II) in which L is -C(O)NR - can be prepared from a compound of formula (FV):
Figure imgf000062_0001
(IV) wherein X is as defined herein elsewhere for formula (II); by the reaction with a compound of formula (V):
R3-NHR8 (V) wherein R3 and R8 are as defined herein elsewhere for formula (I) and (Ia).
[00131] In one embodiment, the reaction may be carried out by chlorination of the carboxylic acid to give the acid chloride using an agent such as oxalyl chloride followed by reaction of the acid chloride with the compound of formula (V).
[00132] Compounds of formula (IV) are known and may be prepared by known methods.
An example of such a method is by the reaction of 6-hydroxypyrimidine-4-carboxylic acid with a halogenating agent, typically oxalyl chloride, to give a compound of formula (FV), for example, 6-chloropyrimidine-4-carboxylic acid. This reaction is described in further detail in the examples.
[00133] 6-Hydroxypyrimidine-4-carboxylic acid can be prepared by the reaction of sodium ethyloxalacetate with formamidine acetate. The procedure of this reaction is described in further detail in the examples. Sodium ethyloxalacetate and formamidine acetate are both readily available, for example, from a commercial source. [00134] In another embodiment, compounds of formula (Ia) may be prepared by the reaction of a compound of formula (VI):
Figure imgf000063_0001
(VI) wherein L4 is -NR9- or -O-, and R4 and R9 are as defined herein elsewhere for formula (I) and (Ia); with a compound of formula (V):
R3-NHR8 (V).
Wherein R and R are as defined herein elsewhere for formula (I) and (Ia).
[00135] In one embodiment, the reaction may be conducted in the presence of a base, such as, e.g., diisopropylethylamine, and a coupling reagent, such as, e.g., benzotriazole-1-yl-oxy- tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP).
[00136] In one embodiment, compounds of formula (VI) may be prepared from a corresponding ester of formula (VII):
Figure imgf000063_0002
(VII) wherein L4 is -NR9- or -O-; R4 is as defined herein elsewhere for formula (I) and (Ia); and
R12 is Ci-C6 alkyl or benzyl; using any known method, such as, for example, alkaline hydrolysis, which may be conducted in the presence of a base, such as, e.g., sodium hydroxide.
[00137] In one embodiment, esters of formula (VII) may be prepared from a compound of formula (VIII):
Figure imgf000064_0001
(VΠD wherein X is halogen; and R12 is as defined herein elsewhere for formula (VII); by the reaction with a compound of formula (III) as defined herein elsewhere.
[00138] In one embodiment, the reaction may be carried out under similar conditions to those described herein elsewhere for the reaction of a compound of formula (II) with a compound of formula (III).
[00139] Compounds of formula (VIII) are readily available or may be prepared by known methods. In one embodiment, compounds of formula (VIII) is prepared by the reaction of the corresponding hydroxyl compound of formula (IX):
Figure imgf000064_0002
(JX) wherein R12 is as defined herein elsewhere for formula (VII). The procedure for this reaction is described in further details in the examples.
[00140] In one embodiment, esters of formula (EX) can be prepared from 6- hydroxypyrimidine-4-carboxylic acid, which, in turn, can be prepared by the reaction of sodium ethyloxalacetate with formamidine acetate. The procedures are described in further details in the examples.
[00141] 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 "Protecting Groups in Organic Synthesis", Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc.
D. Pharmaceutical Compositions
[00142] In one embodiment, the compounds of formula (I), or tautomers, enantiomers, pharmaceutically acceptable salts, hydrates, solvates, complexes, or prodrugs thereof, for use in the treatment of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia, is administered in the form of a pharmaceutical composition. In one embodiment, the compounds of formula (I), or tautomers, enantiomers, pharmaceutically acceptable salts, hydrates, solvates, complexes, or prodrugs thereof, for use in the treatment of Duchenne muscular dystrophy, is administered in the form of a pharmaceutical composition. [00143] 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 lease one pharmaceutically acceptable excipient or carrier.
[00144] 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 to 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.
[00145] In one embodiment, provided herein is a process for the production of a pharmaceutical composition provided herein, which comprises mixing the ingredients. [00146] 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.
[00147] In one embodiment, the compound provided herein is used in aqueous solution, e.g., for 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.
[00148] 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. [00149] 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, solubilizers, 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.
[00150] 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. [00151] 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.
[00152] 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.
[00153] 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. [00154] 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.
[00155] 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.
[00156] 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, 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).
[00157] 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.
[00158] 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.
[00159] In one embodiment, the pharmaceutical compositions provided herein further comprise one or more therapeutic agents for the treatment 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 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 of Duchenne muscular dystrophy. [00160] In another embodiment, provided herein is the use of a compound of formula (I) in the manufacture of a medicament for the treatment 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 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 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
[00161] 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. [00162] 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. [00163] 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 chcwable 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.
[00164] 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; microcrystalline 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.
[00165] 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-0-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. [00166] 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.
[00167] It should be understood that many carriers and excipients may serve several functions, even within the same formulation.
[00168] 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. [00169] 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.
[00170] 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 propylparabens, 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. Pat. 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.
[00171] 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.
[00172] 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. [00173] 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. Pat. No. 6,350,458. [00174] 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. [00175] Coloring and flavoring agents can be used in all of the dosage forms provided herein.
[00176] 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
[00177] 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.
[00178] 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). [00179] 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.
[00180] 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, N,N-dimethylacetamide, and dimethyl sulfoxide. [00181] 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 propyl-parabens, 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 oc-cyclodextrin, β-cyclodextrin, hydroxypropyl-β- cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).
[00182] 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. [00183] 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.
[00184] 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. [00185] 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.
[00186] 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 acryiic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
[00187] 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
[00188] 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.
[00189] 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.
[00190] 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. [00191] 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).
[00192] 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 (OAV) 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. [00193] 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.
[00194] 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.
[00195] 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.
[00196] 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. [00197] 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. [00198] 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.
[00199] 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.
[00200] 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. [00201] 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 l- 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.
[00202] 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
[00203] 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).
[00204] Examples of modified release include, but are not limited to, those described in U.S. Pat. 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
[00205] 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 al. in "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz Ed., Wiley, 1999).
[00206] 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. [00207] 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.
[00208] 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. [00209] 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.
[00210] 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
[00211] 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).
[00212] 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.
[00213] 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, raffinose, 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.
[00214] 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.
[00215] 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.
[00216] 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. [00217] 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. Pat. 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.
[00218] 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. Pat. Nos. 5,612,059 and 5,698,220.
[00219] 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. [00220] 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.
[00221] 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). [00222] 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. Pat. 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.
[00223] 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
[00224] 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, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989. [00225] 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
[00226] 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. Pat. 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
[00227] 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.
[00228] 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.
[00229] 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 in 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.
[00230] 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 of Duchenne muscular dystrophy in a patient suffering from such a disease. In one embodiment, from about 0.01 mg to about 10 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.
[00231] 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.
[00232] In another 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.
[00233] 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. [00234] 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 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 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 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 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 of cachexia. [00235] 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. [00236] In some embodiment, 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. [00237] 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 vehicle. In some embodiments, the compounds provided herein are active in a dose-dependent manner. [00238] 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.
[00239] In the treatment, prevention, or amelioration 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, or from about 1 to about 20 mg/kg per day, which can be administered in single or multiple doses. 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, or from about 1 to about 50 mg/kg per day. [00240] In one embodiment, in the treatment, prevention, or amelioration 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, or less than about 1 g/kg per day.
[00241] 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, and 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.
[00242] 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.
[00243] In another 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, or amelioration 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, or orthopedic appliances, such as, e.g., braces and wheelchairs. [00244] 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. [00245] 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 to the corticosteroid can range from about 1,000:1 to about 1: 1,000, about 200:1 to about 1:200, about 100:1 to about 1:100, or about 10:1 to about 1:10. 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.
[00246] 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. Pat. 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.
[00247] Provided herein also are 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, .
[00248] 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.
[00249] 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, needleless injectors drip bags, patches, and inhalers. [00250] 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
[00251] Certain embodiments are illustrated by the following non-limiting examples. [00252] 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. HPLC-UV was performed on a Dionex Ultimate 3000 system. The analytical column used is a Phenomenex Gemini Cl 8 100x4.6 mm, with the preparative column being a Phenomenex Gemini C18 100x30 mm. The mobile phase consisted of 0.1% TFA in water and 95:5 acetonitrile: water.
[00253] 1H NMR spectra were recorded on a Bruker instrument operating at 300 MHz. NMR spectra were obtained in CDCl3 or DMSO-Cl6 solutions (reported in ppm), using deuterated chloroform (7.25 ppm) or DMSO-d6 (2.50 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are 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). Column chromatography was performed either by flash chromatography (40-65 μm silica gel) or using an automated purification system (SP1™ Purification System from Biotage®). Reactions in the microwave were done in an Initiator 8™ (Biotage®) or in a Discover S-class machine (supplied by CEM Microwave Technology Ltd). [00254] The abbreviations used are: DCM (dichloromethane), DMSO (dimethylsulfoxide), HATU (O-(7-azabenzotriazol-lyl)-N,N,N',//'-tetramethyluronium hexafluorophosphate), HCl (hydrochloric acid), MgSO4 (magnesium sulfate), NaOH (sodium hydroxide), Na2CO3 (sodium carbonate), NaHCO3 (sodium bicarbonate), STAB (sodium triacetoxyborohydride), THF (tetrahydrofuran), BOP (benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), m-CPBA (meta-chloroperoxybenzoic acid).
Example 1 - Methyl 6-(phenylamino)pyrimidine-4-carboxylate hydrochloride
[00255] To a solution of methyl β-chloropyrimidine^-carboxylate (100 mg, 0.58 mmol) in 2-propanol (1 mL) was added aniline (53 μL, 0.58 mmol), followed by 32% HClaq (100 μL). The mixture was heated with stirring, under microwave activation, at 950C for 15 minutes, and the resulting precipitate filtered off and washed with diethyl ether to give 115 mg (86%) of the title compound. 1H NMR (d6-DMSO): 10.26 (IH, s), 8.75 (IH, s), 7.70 (2H, d, J = 7.5 Hz), 7.36-7.45 (3H, m), 7.11 (IH, t, J = 7.5 Hz), 3.90 (3H, s).
Example 2 - 6-(Phenylamino)pyrimidine-4-carboxylic acid
[00256] Methyl 6-(phenylamino)pyrimidine-4-carboxylate (115 mg, 0.5 mmol) was dissolved in dioxane (0.5 mL), 1 M sodium hydroxide (2 mL) was added, and the mixture stirred at 2O0C for 16 hours. The reaction mixture was neutralized with Amberlite IR 120H resin, and resulting precipitate dissolved by addition of methanol and dichloromethane. Filtration of the solution and concentration of the filtrate in vacuo gave 65 mg (60%) of the title compound. 1H NMR (d6-DMSO): 10.23 (IH, s), 8.74 (IH, s), 7.69 (2H, d, J = 7.7Hz), 7.39 (3H, t, J = 6.6 Hz), 7.11 (IH, t, J = 7.7 Hz).
Example 3 - Synthesis of Compounds of Formula (I)
N-Phenyl-6-(phenylamino)pyrimidine-4-carboxamide, (Compound 73) [00257] To a solution of 6-(phenylamino)pyrimidine-4-carboxylic acid (65 mg, 0.30 mmol) in dimethylformamide (4 mL), was added aniline (33 μL, 0.36 mmol), followed by benzotriazol-l-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (187 mg, 0.36 mmol) and Λf,N-diisopropylethylamine (25 μL, 1.44 mmol). The mixture was stirred at 200C for 64 hours and then partitioned between ethyl acetate and water. The aqueous layer was re- extracted with ethyl acetate and the organic layers combined. The organic extract was washed with water, then brine, and dried over magnesium sulfate before concentrating in vacuo. The crude compound was purified by column chromatography, eluting in 0: 1 to 1 : 1 ethyl acetate:petroleum ether, then recrystallized from ethyl acetate and petroleum ether to give 7 mg (8%) of the title compound. LCMS: RT = 6.59 min, M+H+ 291.0. 1H NMR (CDCl3): 9.86 (IH, s), 8.64 (IH, s), 7.67-7.70 (2H, m), 7.55 (IH, d, J = 1.0 Hz), 7.29-7.37 (6H, m), 7.10 (IH, dt, J = 7.4, 1.0 Hz).
Methyl 6-(4-hydroxyphenylamino)pyrimidine-4-carboxylate
[00258] A solution of methyl ό-chloropyrimidine^-carboxylate (0.15 g, 0.87 mmol), 4- aminophenol (0.095 g, 0.87 mmol) and concentrated hydrochloric acid (0.15 mL) in 2- propanol (1.5 mL) was heated at 95°C for 15 minutes under microwave activation, after 30 seconds pre-stirring. The reaction mixture was cooled to room temperature, filtered and the filter cake washed with diethyl ether to give 106 mg (50%) of the title compound. 1H NMR (dβ-DMSO): 10.52 (IH, br), 8.69 (IH, s), 7.26-7.48 (3H, m), 6.80 (2H, d, J = 8.8Hz), 3.90 (3H, s).
6-(4-Hydroxyphenylamino)pyrimidine-4-carboxylic acid
[00259] A solution of methyl 6-(4-hydroxyphenylamino)pyrimidine-4-carboxylate (0.116 g, 0.47 mmol) and 1 M sodium hydroxide (0.57 mL, 0.57 mmol) in dioxane (2 mL) was stirred at room temperature for 16 hours. The reaction mixture was neutralized with amberlite H+, filtered and concentrated in vacuo to yield 129 mg of the title compound. Quantitative yield was assumed. 1H NMR (d6-DMSO): 9.85 (IH, br s), 9.73 (IH, br s), 9.38 (IH, br s), 8.59 (IH, br s), 7.38 (2H, br m), 7.21 (IH, br s), 6.77 (2H, d, J = 8.0 Hz).
6-(4-Hydroxyρhenylamino)-N-phenyipyrimidine-4-carboxamide, (Compound 55) [00260] Thionyl chloride (0.041 mL, 0.56 mmol) and DMF (1 drop) were added to a solution of 6-(4-hydroxyphenylamino)pyrimidine-4-carboxylic acid (0.109 g, 0.47 mmol) in dichloromethane (4 mL), and the reaction mixture was stirred at room temperature. After 3 hours, aniline (0.051 mL, 0.56 mmol) and triethylamine (0.2 mL, 1.41 mmol) were added and the reaction was heated at 400C for 16 hours. The reaction mixture was partitioned between dichloromethane and saturated NaHCO3 solution. The aqueous phase was extracted twice with DCM, and the combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude compound was recrystallized from chloroform, then purified by column chromatography, eluting with ethyl acetate/petroleum ether, 0/1 to 1/0 v/v, to afford 11 mg (8%) of the title compound. 1H NMR (d6-DMSO): 10.53 (IH, s), 9.75 (IH, s), 9.35 (IH, s), 8.68 (IH, s), 7.88 (2H, d, J = 7.6 Hz), 7.39 (5H, m), 7.13 (IH, t, J = 1 A Hz), 6.78 (2H, d, 7 = 8.9 Hz).
Example 4 - General Route To Compounds of Formula (I)
NaOH N "*N (COCI)2 N ^N
H2N SNH . AcOH + Etθ OEt ^ X)H OH
HO Cl
ONa O H2O EtOAc/DMF (25%) (quantitative)
Figure imgf000093_0001
Et3N, DCM (56%)
1. Procedure A
6-Hydroxypyrimidine-4-carboxylic acid
[00261] In a 1 L round bottom flask, 55 g of sodium ethyloxalacetate (1.05 eq, 0.26 mol) and 26 g of formamidine acetate (1 eq, 0.25 mol) were added to a solution of sodium hydroxide (10 g) in 500 mL of water. The reaction mixture was stirred at room temperature for 16 hours.
[00262] Concentrated HCl was added carefully to the mixture until pH = 1, a fine solid precipitated and the reaction mixture was stirred at 0°C for 1 hour. The solid was filtered then washed with water and ether. The white solid was then left in a vacuum oven heated at
4O0C for 20 hours. Trituration in methanol gave the title compound in 25% yield. 1H NMR
(dβ-DMSO): 12.88 (IH, OH), 8.24 (s, IH), 6.83 (s, IH).
2. Procedure B
6-Chloropyrimidine-4-carboxylic acid
[00263] 30 mL of EtOAc was added to 2 g of 6-hydroxypyrimidine-4-carboxylic acid 1 and oxalyl chloride (3.75 mL, 3 eq, 0.043 mol) was added slowly to the mixture followed by a few drops of DMF (evolution of gas was observed). The reaction mixture was heated at 750C for 3 hours and allowed to cool to room temperature overnight. The solvent was then removed in vacuo affording a black solid in quantitative yield. The solid was kept under nitrogen at 4°C. 1H NMR analysis indicated the presence of a mixture of desired product and the corresponding chloro-pyrimidine carboxy acid chloride (which is not stable at room temperature). 1H NMR (d6-DMSO): 9.28 (s, IH), 8.18 (s, IH) "impurity acid chloride" 8.45 (s, IH), 6.93 (s, IH).
3. Procedure C
6-ChIoro-N-(4-fluorophenyl)pyrimidine-4-carboxamide
[00264] A drop of DMF was added to a stirred solution of 6-chloropyrimidine-4- carboxylic acid 2 (2.51 g, 14.28 mmol, 1 eq) and oxalyl chloride (2.5 niL, 28.5 mmol, 2 eq) in dry DCM (50 mL) at room temperature. Stirring was continued for 2 hours and the evolution of gas was observed. The reaction mixture was cooled down to O0C and triethylamine (7 mL, 50 mmol, 3.5 eq) was added dropwise, followed by 4-fluoroaniline (2.7 mL, 28.5 mmol, 2 eq) and the reaction mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo affording a brown solid which was purified by column chromatography eluting using a gradient (ethyl acetate/petrol ether 0:100 v/v to ethyl acetate/petrol ether 40:60 v/v) affording 2 g of the title compound (56% yield). 1H NMR (dβ-DMSO): 10.99 (IH, s, NH), 9.26 (IH, d, 7 = 1.1Hz), 8.19 (IH, d, J = 1.1Hz), 7.92 (2H, m), 7.22 (2H, m).
4. Procedure D: General procedure for compound 4 (thermal)
[00265] 300 mg of 6-chloro-N-(4-fluorophenyl)pyrimidine-4-carboxamide 3 (1.19 mmol, 1 eq) was dissolved in isopropanol (15 mL). The corresponding amine (1.05 eq) was added and the resulting solution was refluxed for 18 hours. The reaction mixture was cooled to 0°C for 20 minutes. The precipitated solid was filtered, washed with isopropanol and ether to give the desired product (HCl salt). Standard base washing can deliver the free base.
N-(4-Fluorophenyl)-6-(4-hydroxyphenylamino)pyrimidine-4-carboxamide (Compound
15)
[00266] A drop of DMF was added to a stirred solution of 6-chloropyrimidine-4- carboxylic acid 1 (792 mg, 5.40 mmol) and oxalyl chloride (940 μL, 10.81 mmol) in dry DCM (20 mL) at room temperature. Stirring was continued for 2.5 hours and the evolution of gas was observed. Triethylamine (2.6 mL, 18.91 mmol) was added dropwise, followed by 4-fluoroaniline (560 μL, 5.94 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo affording a brown solid, which was dissolved in isopropanol (35 mL). 4-Aminophenol (619 mg, 5.67 mmol) was added and the resulting deep brown solution was refluxed for 18 hours. The reaction mixture was cooled to room temperature and the crude diluted with DCM (150 mL). The organic layer was washed with brine (100 mL) and the aqueous layer was extracted further with dichloromethane (2 x 50 mL). The combined organic layers were dried over anhydrous magnesium sulphate and evaporated to dryness. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 0:1 v/v to ethyl acetate/hexanes 55:45 v/v) to afford 277 mg (16% over 3 steps) of the title compound. LCMS: RT = 1.94 min, M+H+ 325.1. 1H NMR (d6-DMSO): 10.65 (IH, s), 9.73 (IH, s), 9.33 (IH, s), 8.67 (IH, s), 7.94-7.89 (2H, m), 7.40 (2H, br s), 7.34 (IH, br s), 7.23-7.17 (2H, m), 6.78 (2H, d, J = 8.7 Hz).
[00267] A similar procedure was used to prepare the following compounds of formula (I) using appropriate starting materials.
N-(4-Fluorophenyl)-6-(4-fluorophenylamino)pyrimidine-4-carboxamide (Compound 74) [00268] LCMS: RT = 2.54 min, M+H+ 327.1. 1H NMR (d6-DMSO) 10.70 (IH, s), 10.05 (IH, s), 8.77 (IH, s), 7.95-7.91 (2H, m), 7.75-7.70 (2H, m), 7.45 (IH, br d), 7.25-7.18 (4H, m).
N-(4-Fluorophenyl)-6-(4-methoxyphenylamino)pyrimidine-4-carboxamide (Compound
75)
[00269] LCxMS: RT = 2.54 min, M+H+ 327.1. 1H NMR (dβ-DMSO): 10.68 (IH, s), 9.87 (IH, s), 8.71 (IH, s), 7.95-7.90 (2H, m), 7.56 (2H, br d), 7.38 (IH, s), 7.21 (2H, d, J = 8.9 Hz), 6.96 (2H, d, J = 8.9 Hz), 3.75 (3H, s).
6-(3-Chlorophenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound
76)
[00270] This compound was isolated as the corresponding hydrochloride salt. LC: RT = 10.67 min, 100% (UV). 1H NMR (d6-DMSO): 10.76 (IH, s), 10.40 (IH, s), 8.87 (IH, d, J = 0.9Hz), 8.09 (IH, t, J = 2.0 Hz), 7.94 (2H, m), 7.57 (2H, m), 7.39 (IH, t, J = 8.1 Hz), 7.21 (2H, m), 7.13 (1H, m). Example 5 - N-(4-Fluorophenyl)-6-(3-fluorophenylamino) pyrimidine-4-carboxamide (Compound 77)
[00271] 500 mg of crude 6-chloro-N-(4-fluorophenyl)pyrimidine-4-carboxamide 3 was dissolved in isopropanol (20 mL). 3-Fluoroaniline (1.05 eq) was added and the resulting solution was reflux ed for 18 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo affording a brown solid. The crude was then diluted with DCM (150 mL). The organic layer was washed with brine (100 mL) and the aqueous layer was extracted further with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 0:100 v/v to ethyl acetate/hexanes 10:90 v/v) to afford 16 mg of the desired compound. LCMS: RT = 2.65min, M+H+ 327.1. 1H NMR (d6-DMSO): 10.74 (IH, s), 10.27 (IH, s), 8.86 (IH, s), 7.90 (3H, m, J = 6.3 Hz), 7.54 (IH, s), 7.39 (2H, t, J = 5.2 Hz), 7.21 (2H, t, / = 8.8 Hz), 6.88 (IH, q, J = 4.3 Hz).
Example 6 - N-(4-Fluorophenyl)-6-(phenylamino)pyrimidine-4-carboxamide (Compound 78)
[00272] Aniline (0.20 mL, 2.19 mmol) was added dropwise to a stirred suspension of 6- chloro-7V-(4-fluorophenyl)pyrimidine-4-carboxamide (500 mg, 2.09 mmol) in isopropanol (20 mL) and the resulting mixture was refluxed for 16 hours. The reaction mixture was cooled down and the solvent removed in vacuo. The remaining solid was partitioned between DCM (100 mL) and saturated hydrogen carbonate (50 mL) and the two layers were separated. The aqueous layer was extracted further with dichloromethane (2 x 50 mL), the combined extracts were washed with brine until pH ~ 7 and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to afford a yellow solid which was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 0: 1 v/v to ethyl acetate/hexanes 2:3 v/v) followed by trituration with diethyl ether to afford 378 mg (61% yield) of the title compound. LCMS: RT = 2.52 min, M+H+ 309.1. 1H NMR (d6-DMSO) 10.71 (IH, s), 10.04 (IH, s), 8.78 (IH, d, J = 1.0Hz), 7.96-7.91 (2H, m), 7.72 (2H, d, J = 7.8 Hz), 7.50 (IH, d, J = 1.0Hz), 7.40-7.35 (2H, m), 7.24-7.18 (2H, m), 7.11-7.06 (IH, m). [00273] A similar route was used to prepare the following.
6-(Cyclohexylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 79)
[00274] The reaction mixture was cooled down and evaporated to dryness. The residue was partitioned between DCM and brine. The aqueous layer was re-extracted twice with DCM, the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography, eluting with petrol/ethyl acetate, 1/0 to 6/4 v/v, afforded the title compound. LCMS: RT = 2.57min, M+H+ 315.1. 1H NMR (d6-DMSO): 10.58 (IH, br s), 8.54 (IH, s), 7.94-7.87 (2H, m), 7.81 (IH, d, J = 7.7 Hz), 7.24-7.14 (3H, m), 3.88 (IH, br s), 1.95-1.85 (2H, br m), 1.78-1.67 (2H, br m), 1.64-1.54 (IH, br m), 1.42-1.11 (5H, br m).
6-(Benzofuran-5-ylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound
81)
[00275] This compound was isolated as the corresponding hydrochloride salt. LC: RT =
13.79 min, 100% (UV). 1H NMR (d6-DMSO): 10.77 (IH, s), 10.28 (IH, s), 8.78 (IH, d,
J = 0.9Hz), 8.10 (IH, br s), 8.01 (IH, d, J = 2.2 Hz), 7.92 (2H, m, J = 3.6Hz), 7.61 (IH, d, J =
8.8Hz), 7.48 (2H, m), 7.22 (2H, t, J = 8.9Hz), 6.99 ( IH, dd, J = 2.1 & 0.8 Hz).
6-(4-Fluorobenzylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 80) [00276] This compound was isolated as the corresponding hydrochloride salt. LC: RT = 13.21 min, 100% (UV). 1H NMR (d6-DMSO): 10.60 (IH, s), 8.58 (IH, s), 8.41 (IH, t, J5.5 = Hz), 7.90 (2H, m), 7.37 (2H, m), 7.19 (5H, m), 4.58 (2H, s).
6-(Benzylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 82) [00277] This compound was isolated as the corresponding hydrochloride salt. LC: RT = 13.00 min, 100% (UV). 1H NMR (d6-DMSO): 10.61 (IH, s), 8.58 (IH, s), 8.41 (IH, t, J = 5.3Hz), 7.90 (2H, m), 7.27 (8H, m), 4.62 (2H, d, J = 5.3Hz).
6-(4-Cyanophenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 85) [00278] This compound was isolated as the corresponding hydrochloride salt. LC: RT = 14.14 min, 98% (UV). 1H NMR (d6-DMSO): 10.77 (IH, s), 10.71 (IH, s), 8.91 (IH, s), 8.00 (2H, d, J = 8.7 Hz), 7.95-7.91 (2H, m), 7.82 (2H, d, 7 = 8.7 Hz), 7.64 (IH, s), 7.21 (2H, t, 7 = 8.9 Hz).
N-(4-Fluorophenyl)-6-(4-(trifluoromethyl)phenylamino)pyrimidine-4-carboxamide (Compound 83)
[00279] LC: RT = 14.91 min, 100% (UV). 1H NMR (d6-DMSO): 10.76 (IH, s), 10.42 (IH, s), 8.89 (IH, s), 8.00-7.92 (4H, m), 7.73 (2H, d, 7 = 8.7 Hz), 7.59 (IH, d, 7 = 1.1 Hz), 7.22 (2H, t, 7 = 8.9 Hz).
iV-(4-Fluorophenyl)-6-(4-chlorophenyIamino)pyriinidine-4-carboxamide (Compound
84)
[00280] LC: RT = 14.76 min, 99% (UV). 1H NMR (d6-DMSO): 10.74 (IH, s), 10.12
(IH, s), 8.82 (IH, s), 7.93 (2H, m), 7.78 (2H, m), 7.51 (IH, s), 7.43 (2H, m), 7.22 (2H, t, 7 =
8.9Hz).
N-(4-Fluorophenyl)-6-(2-oxoindolin-5-ylamino)pyrimidine-4-carboxamide (Compound
87)
[00281] LC: RT = 12.16 min, 100% (UV). 1H NMR (d6-DMSO): 10.68 (IH, s), 10.37 (IH, s), 9.90 (IH, s), 8.71 (IH, s), 7.95-7.90 (2H, m), 7.63 (IH, br s), 7.40 (2H, br m), 7.20 (2H, t, 7 = 9.0 Hz), 6.82 (IH, d, J = 8.4 Hz), 3.51 (2H, s).
N-(4-Fluorophenyl)-6-(6-hydroxypyridin-3-ylamino)pyrimidine-4-carboxamide (Compound 106)
[00282] LCMS: RT = 1.81 min, M+H+ 326.1. 1H NMR (dβ-DMSO): 11.55 (IH, br s), 10.69 (IH, s), 9.67 (IH, s), 8.71 (IH, s), 7.96-7.88 (3H, br m), 7.53 (IH, dd, J = 9.7 & 2.8 Hz), 7.34 (IH, br s), 7.20 (2H, t, 7 = 8.9 Hz), 6.41 (IH, d, J = 9.7 Hz).
6-(Phenylamino)-N-(4-(trifluoromethyl)phenyl)pyrimidine-4-carboxamide (Compound 109)
[00283] This compound was isolated as the corresponding hydrochloride salt. LCMS: RT = 2.76 min, M+H+ 359.1. 1H NMR (d6-DMSO): 10.99 (IH, s), 10.21 (IH, s), 8.81 (IH, s), 8.14 (2H, d, J = 8.5Hz), 7.74 (4H, d, J = 8.6Hz), 7.54 (IH, s), 7.38 (2H, t, J = 7.9 Hz), 7.09 (IH, t, 7 = 7.3 Hz). 6-(3,5-Difluoro-4-hydroxyphenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 115)
[00284] LCMS: RT = 2.29 min, M+H+ 361.2. 1H NMR (d6-DMSO): 10.72 (IH, s), 10.08 (IH, s), 9.91 (IH, br s), 8.81 (IH, s), 7.95-7.91 (2H, m), 7.47-7.43 (3H, m), 7.21 (2H, t, J = 8.9 Hz).
6-(Phenylamino)-N-(pyridin-3-yl)pyrimidine-4-carboxamide (Compound 125) [00285] LCMS: RT = 1.70 min, M+H+ 292.2. 1H NMR (d6-DMSO): 10.88 (IH, s), 10.06 (IH, s), 9.06 (IH, d, J = 2.1 Hz), 8.80 (IH, d, J = 1.1 Hz), 8.34 (IH, dd, J = 4.5 & 1.5 Hz), 8.33-8.28 (IH, m), 7.72 (2H, d, J = 7.8 Hz), 7.50 (IH, d, J = 1.2 Hz), 7.43-7.35 (3H, m), 7.11-7.07 (IH, m).
6-(3,4-Dihydroquinolin-l(2H)-yl)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 128)
[00286] LCMS: RT = 2.82 min, M+H+ 349.1. 1H NMR (d6-DMSO): 10.72 (IH, s), 8.83 (IH, d, J = 1.1 Hz), 7.92-7.88 (2H, m), 7.67 (IH, d, J = 1.1 Hz), 7.48 (IH, d, J = 7.4 Hz), 7.30-7.13 (5H, m), 3.97 (2H, t, J = 6.4 Hz), 2.75 (2H, t, J = 6.4 Hz), 1.95 (2H, q, J = 6.4 Hz).
N-(4-Fluorophenyl)-6-(4-(morpholine-4-carbonyl)phenylamino)pyrimidine-4- carboxamide (Compound 136)
[00287] LCMS: RT = 1.82 min, M+H+ 422.4. 1H NMR (d6-DMSO): 10.73 (IH, br s), 10.35 (IH, br s), 8.84 (IH, d, / = 1.1 Hz), 7.96-7.91 (2H, m), 7.84 (2H, d, J = 8.6 Hz), 7.57 (IH, d, J = 1.1 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.25-7.19 (2H, m), 3.61 (4H, br m), 3.51 (4H, br m).
6-(4-(Ethyl(2-hydroxyethyl)amino)phenylamino)-N-(4-fluorophenyl)pyrimidine-4- carboxamide (Compound 44)
[00288] LCMS: RT = 1.35 min, M+H+ 396.3. 1H NMR (d6-DMSO): 10.62 (IH, s), 9.63 (IH, br s), 8.64 (IH, s), 7.94-7.89 (2H, m), 7.36-7.30 (3H, br m), 7.22-7.17 (2H, m), 6.69 (2H, d, / = 9.0 Hz), 4.68 (IH, t, J = 5.4 Hz), 3.57-3.51 (2H, m), 3.39-3.33 (4H, m), 1.08 (3H, t, 7 = 6.9 Hz). 6-(Ethyl(phenyl)amino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide
(Compound 137)
[00289] LCMS: RT = 2.51 min, M+H+ 337.2. 1H NMR (dfi-DMSO): 10.64 (IH, s),
8.76 (IH, d, J = 1.1 Hz), 7.88-7.83 (2H, m), 7.61-7.56 (2H, m), 7.50-7.44 (IH, m), 7.40-
7.37 (2H, m), 7.20-7.14 (2H, m), 6.80 (IH, d, J = 1.1 Hz), 4.03 (2H, q, J = 7.1 Hz), 1.17 (3H, t, J = I. I Hz).
Example 7 - N-(4-Fluorophenyl)-6-(methyl ((2-methylfuran-3- yl)methyl)amino)pyrimidine-4-carboxamide (Compound 134)
[00290] 300 mg of 6-chloro-N-(4-fluorophenyl) pyrimidine-4-carboxamide was dissolved in isopropanol (20 mL). The corresponding amine (1.05 eq) was added and the resulting solution was refluxed for 18 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo affording a yellow solid. The crude was then diluted with DCM (50 mL). The organic layer was washed (saturated aqueous NaHCO3 then 1 N HCl) and the aqueous layer was extracted further with DCM (2 x 5OmL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 0: 100 v/v to ethyl acetate/hexanes 30:70 v/v) and recrystallization in methanol to afford 65 mg of the title compound (16% yield). LCMS: RT = 2.54 min, M+H+ 341.2. 1H NMR (d6-DMSO): 10.67 (IH, s), 8.67 (IH, d, J = 1.0 Hz), 7.91 (2H, m), 7.43 (IH, d, J = 1.8 Hz), 7.30 (IH, s), 7.20 (2H, t, J = 6.0 Hz), 6.29 (IH, d, J = 1.8 Hz), 4.66 (2H, s), 3.10 (3H, s), 2.33 (3H, s).
Example 8 - N-(3-Fluorophenyl)-6-(3-hydroxyphenyIamino) pyrimidine-4-carboxamide (Compound 130)
[00291] 500 mg of 6-chloro-N-(3-fluorophenyl)pyrimidine-4-carboxamide was dissolved in isopropanol (20 mL). 3-Fluoroaniline (1.05 eq) was added and the resulting solution was refluxed for 18 hours. The reaction mixture was cooled down and the solvent was removed in vacuo affording a yellow solid. The crude was then diluted with dichloromethane (150 mL). The organic layer was washed (saturated aqueous NaHCO3 then 1 N HCl) and the aqueous layer was extracted further with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 0: 100 v/v to ethyl acetate/hexanes 30:70 v/v) to afford 419 mg of the title compound. (65% yield). LCMS: RT = 2.23 min, M+H+ 325.1. 1H NMR (d6-DMSO): 10.80 (IH, s), 9.94 (IH, s), 9.48 (IH, s), 8.78 (IH, d, J = 0.9 Hz), 7.86 (IH, m), 7.74 (IH, m), 7.49 (IH, d, J = 1.1 Hz), 7.40 (IH, m), 7.25 (IH, s), 7.14 (2H, m), 6.97 (IH, m), 6.49 (IH, m).
Example 9 - Procedure D': Adaptation of General Procedure to Microwave Irradiation [00292] 300 mg of 6-chloro-N-(4-fluorophenyl)pyrimidine-4-carboxamide 3 (1.19 mmol, 1 eq) was dissolved in isopropanol (3 mL). The corresponding amine (1.05 eq) was added and the resulting solution was heated at 130°C for 10 minutes under microwave activation. The reaction mixture was cooled down to 00C for 20 minutes and a solid precipitated out. The solid was filtered then washed with isopropanol and ether to give the desired product as a HCl salt. Standard base washing can deliver the free base.
6-(4-Chlorophenylamino)-N-phenylpyrimidine-4-carboxamide (Compound 86) [00293] This compound was isolated as the corresponding hydrochloride salt. The precipitated HCl salt was collected by filtration and washed with ether to afford the title compound in 62% yield. LC: RT = 14.65 min, 100% (UV). 1H NMR (d6-DMSO): 10.60 (IH, s), 10.19 (IH, s), 8.82 (IH, s), 7.89 (2H, d, J = 8.0 Hz), 7.78 (2H, d, J = 8.8 Hz), 7.51 (IH, d, J = 1.0 Hz), 7.46-7.33 (4H, br m), 7.14 (IH, t, / = 7.4 Hz).
[00294] The following compounds were also prepared by this route using appropriate starting materials:
N-(4-Fluorophenyl)-6-(thiophen-3-ylmethylamino)pyrimidine-4-carboxamide (Compound 88)
[00295] LCMS: RT = 2.49 min, M+H+ 315.0. 1H NMR (d6-DMSO): 10.62 (IH, s), 8.60 (IH, s), 8.33 (IH, br s), 7.95-7.86 (2H, br m), 7.53-7.48 (IH, dd, J = 4.9 & 2.9 Hz), 7.39-7.35 (IH, br m), 7.26-7.14 (3H, br m), 7.10 (IH, dd, J = 4.9 & 1.2 Hz), 4.60 (2H, s).
N-(4-Fluorophenyl)-6-(furan-3-ylmethylamino)pyrimidine-4-carboxamide (Compound
89)
[00296] The title compound was synthesized according to the microwave procedure (using
2.1 eq. amine and heated for 30 minutes). The concentrated reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution (aq.). The organic layer was washed with saturated sodium bicarbonate solution (aq.), dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography, eluting with petrol/ethyl acetate, 1/0 to 3/7 v/v, afforded the title compound in 61% yield. LC: RT = 12.66 min, 98% (UV). 1H NMR (d6-DMSO): 10.62 (IH, s), 8.61 (IH, s), 8.20 (IH, br s), 7.94-7.88 (2H, br m), 7.65-7.61 (2H, br m), 7.25-7.16 (3H, br m), 6.49 (IH, s), 4.43 (2H, s).
N-(4-Fluorophenyl)-6-(furan-2-ylmethylamino)pyrimidine-4-carboxamide (Compound 90)
[00297] The title compound was synthesised according to the microwave procedure (using 2.0 eq. amine and heated for 30 minutes). Purification of the crude residue by column chromatography, eluting with petrol/ethyl acetate, 1/0 to 1/1 v/v, afforded the title compound in 88% yield. LC: RT = 12.79 min, 99% (UV). 1H NMR (d6-DMSO): 10.62 (IH, s), 8.62 (IH, s), 8.34 (IH, br s), 7.94-7.87 (2H, br m), 7.62-7.59 (IH, br m), 7.25-7.15 (3H, br m), 6.42-6.40 (IH, br m), 6.34-6.31 (IH, br m), 4.61 (2H, s).
N-(4-Fluorophenyl)-6-(thiophen-2-ylmethyIamino)pyrimidine-4-carboxamide (Compound 91)
[00298] The title compound was synthesised according to the above procedure (53% yield). LC: RT = 13.11 min (99%). 1H NMR (d6-DMSO): 10.63 (IH, s), 8.64 (IH, s), 8.47 (IH, br s), 7.95-8.87 (2H, br m), 7.40 (IH, dd, J = 5.1 & 1.2 Hz), 7.25-7.15 (3H, br m), 7.08-7.05 (IH, br m), 7.00-6.95 (IH, br m), 4.78 (2H, s).
N-(4-Fiuorophenyi)-6-(2-methoxyphenyiamino)pyrimidine-4-carboxamide (Compound
99)
[00299] The above compound was synthesised according to the above procedure (32% yield). LCMS: RT = 2.53 min, M+H+ 339.4. 1H NMR (d6-DMSO): 10.67 (IH, s), 9.40
(IH, s), 8.69 (IH, s), 7.96-7.84 (3H, br m), 7.50 (IH, br s), 7.25-7.09 (4H, br m), 6.98 (IH, td, J = 7.5 & 1.7 Hz), 3.83 (3H, s). N-(4-πuorophenyl)-6-(6-methoxypyridin-3-ylamino)pyrimidine-4-carboxamide (Compound 114)
[00300] LCMS: RT = 2.30 min, M+H+ 340.1. 1H NMR Cd6-DMSO): 10.72 (IH, s), 10.07 (IH, s), 8.74 (IH, br s), 8.43 (IH, br s), 8.02 (IH, dd, J = 9.3 & 2.5 Hz), 7.96-7.89 (2H, br m), 7.42 (IH, s), 7.21 (2H, t, J = 8.9 Hz), 6.88 (IH, d, J = 8.8 Hz), 3.85 (3H, s).
6-(4-Acetamidophenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 95)
[00301] This compound was isolated as the corresponding hydrochloride salt. The title compound was obtained in 69% yield. LCMS: RT = 2.08 min, M+H+ 366.1. 1H NMR (de-DMSO): 10.72 (IH, s), 10.06 (IH, s), 9.96 (IH, s), 8.75 (IH, s), 7.93 (2H, m), 7.63- 7.56 (4H, m), 7.45 (IH, s), 7.24-7.18 (2H, m), 2.03 (3H, s).
N-(4-Fluorophenyl)-6-(4-(methylsulfonamido)phenylamino)pyrimidine-4-carboxamide (Compound 96)
[00302] This compound was isolated as the corresponding hydrochloride salt. The title compound was obtained in 62% yield. LCMS: RT = 2.15 min, M+H+ 402.1. 1H NMR (d6-DMSO): 10.73 (IH, s), 10.13 (IH, s), 9.63 (IH, s), 8.76 (IH, s), 7.95-7.90 (2H, m), 7.67 (2H, d, J = 8.7 Hz), 7.47 (IH, s), 7.24-7.18 (4H, m), 2.96 (3H, s).
N-(4-Fluorophenyl)-6-(2-hydroxyethylamino)pyrimidine-4-carboxamide (Compound
97)
[00303] This compound was isolated as the corresponding hydrochloride salt. The title compound was obtained in 13% yield. LCMS: RT= 1.77 min, M+H+ 277.1. 1H NMR (d6-DMSO): 10.59 (IH, s), 8.55 (IH, s), 7.98-7.88 (3H, m), 7.22-7.16 (3H, m), 4.80 (IH, t, J = 5.3 Hz), 3.57-3.43 (4H, m).
N-(4-FIuorophenyl)-6-(thiophen-3-ylamino)pyrimidine-4-carboxamide (Compound 98) [00304] The title compound was obtained in 63% yield. LCMS: RT= 2.49 min, M+H+ = 315.0. 1K NMR (dβ-DMSO): 10.63 (2H, s), 8.81 (IH, s), 7.91-7.96 (2H, m), 7.76 (IH, s), 7.52-7.55 (IH, m), 7.44 (IH, s), 7.16-7.24 (3H, m). 6-(4-Carbamoylphenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 103)
[00305] This compound was isolated as the corresponding hydrochloride salt. The title compound was obtained in 47% yield. LCMS: M+H+ = 351.9. 1H NMR Cd6-DMSO): 10.75 (IH, s), 10.31 (IH, s), 8.86 (IH, s), 7.96-7.81 (7H, m), 7.57 (IH, s), 7.28-7.18 (3H, m).
N-(4-Fluorophenyl)-6-(methyl(phenyl)amino)pyrimidine-4-carboxamide (Compound 101)
[00306] The crude hydrochloride salt of the title compound (43% yield) was dissolved in DCM, washed with sodium bicarbonate, water, brine, and then dried over magnesium sulfate and concentrated in vacuo. Subsequent purification by column chromatography, eluting with petrol/ethyl acetate, 1/0 to 4/1, v/v, followed by recrystallization in hot isopropanol gave the title compound. LCMS: RT= 2.57 min, M+H+= 323.1. 1H NMR (d6-DMSO): 10.68 (IH, s), 8.78 (IH, s), 7.89-7.84 (2H, m), 7.59-7.54 (2H, m), 7.45-7.41 (3H, m), 7.21-7.15 (2H, m), 6.96 (IH, d, J = 1.1 Hz), 3.50 (3H, s).
6-(Benzo[d][l,3]dioxol-5-ylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 102)
[00307] This compound was isolated as the corresponding hydrochloride salt. The title compound was obtained in 59% yield. LCMS: RT= 2.45 min, M+H+ = 353.1. 1H NMR (dβ-DMSO): 10.73 (IH, s), 10.05 (IH, s), 8.74 (IH, s), 7.94-7.90 (2H, m), 7.41 (2H, s), 7.24-7.18 (2H, m), 7.03 (IH, d, J = 8.5 Hz), 6.93 (IH, d, J = 8.4 Hz), 6.03 (2H, s).
4-(6-(4-FluorophenylcarbamoyI)pyrimidin-4-ylamino)benzoic acid (Compound 100) [00308] This compound was isolated as the corresponding hydrochloride salt. The title compound was obtained in 49% yield. LCMS: RT = 2.23 min, M+H+ = 353.1. 1H NMR (d6-DMSO): 12.75 (IH, br s), 10.76 (IH, s), 10.39 (IH, s), 8.89 (IH, s), 7.96-7.88 (6H, m), 7.60 (IH, s), 7.22 (2H, t, J = 8.9 Hz).
6-(Phenylamino)-N-(thiophen-2-ylmethyl)pyrimidine-4-carboxamide (Compound 111) [00309] The title compound was obtained in 58% yield. LCMS: RT = 2.3 min, M+H+ = 311.1. 1H NMR (dβ-DMSO): 9.96 (IH, s), 9.39 (IH, t, 7 = 6.3 Hz), 8.69 (IH, d, J = 1.1 Hz), 7.70 (2H, d, J = 8.0 Hz), 7.40-7.33 (4H, m), 7.07 (IH, t, J = 7.5 Hz), 7.01 (IH, dd, J = 3.5 & 1.2 Hz), 6.97-6.94 (IH, m), 4.61 (2H, d, J = 6.3 Hz).
N-(4-Fluorophenyl)-6-(4-(methylcarbamoyl)phenylamino)pyrimidine-4-carboxamide
(Compound 118)
[00310] The title compound was obtained in 26% yield. LCMS: M+H+ = 366.1.
1H NMR (de-DMSO): 10.75 (IH, s), 10.27 (IH, s), 8.86 (IH, s), 8.34 (IH, d, J = 4.6 Hz),
7.96-7.84 (6H, m), 7.56 (IH, d, J = 1.0 Hz), 7.22 (2H, t, J = 9.0 Hz), 2.78 (3H, d, J = 4.5
Hz).
6-(Ethylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 33) [00311] The title compound was obtained in 39% yield. LCMS: RT= 2.05 min, M+H+ =
261.0. 1H NMR (U6-DMSO): 10.59 (IH, s), 8.56 (IH, s), 7.93-7.88 (3H, m), 7.22-7.15 (3H, m), 3.31 (2H), 1.16 (3H, t, J = 7.3 Hz).
N-(4-Fluorophenyl)-6-(3-hydroxyphenylamino)pyrimidine-4-carboxamide (Compound
108)
[00312] The title compound was obtained in 41% yield. LCMS: RT = 2.17 min, M+H+ =
325.2. 1K NMR (d6-DMSO): 10.70 (IH, s), 9.92 (IH, s), 9.47 (IH, s), 8.77 (IH, s), 7.95-
7.91 (2H, m), 7.49 (IH, d, J = 1.1 Hz), 7.25-7.12 (5H, m), 6.51-7.48 (IH, m).
N-(4-Fluorophenyl)-6-(3-hydroxypropylamino)pyrimidine-4-carboxamide (Compound
119)
[00313] The title compound was obtained in 20% yield. LCMS: RT = 1.80 min, M+H+ =
291.1. 1H NMR (d6-DMSO): 10.58 (IH, s), 8.56 (IH, s), 7.93-7.88 (3H, m), 7.22-7.16 (3H, m), 4.51 (IH, m), 3.49-3.40 (4H, m), 1.72-1.67 (2H, m).
N-(4-Fluorophenyl)-6-(isobutylamino)pyrimidine-4-carboxamide (Compound 120) [00314] The title compound was obtained in 29% yield. LCMS: RT = 2.34 min, M+H+ =
289.2. 1H NMR (d6-DMSO): 10.58 (IH, s), 8.55 (IH, s), 7.93-7.88 (3H, m), 7.22-7.16 (3H, m), 3.23-3.01 (2H, m), 1.87-1.83 (IH, m), 0.91 (6H, d, / = 6.7 Hz). N-(4-Fluorophenyl)-6-(p-tolylamino)pyrimidine-4-carboxamide (Compound 127) [00315] The title compound was obtained in 16% yield. LCMS: RT = 2.67, M+H+ = 323.2. 1H NMR (d6-DMSO): 10.67 (IH, s), 9.93 (IH, s), 8.75 (IH, s), 7.95-7.90 (2H, m), 7.58 (2H, d, J = 8.3 Hz), 7.45 (IH, d, J = 1.0 Hz), 7.24-7.17 (4H, m), 2.29 (3H, s).
N-(4-Fluorophenyl)-6-(indolin-l-yl)pyrimidine-4-carboxamide (Compound 126) [00316] The title compound was obtained in 18% yield. LCMS: RT = 2.93, M+H+ = 335.2. 1H NMR (d6-DMSO): 10.77 (IH, s), 8.91 (IH, s), 8.49 (IH, d, J = 7.9 Hz), 7.97- 7.93 (2H, m), 7.40 (IH, s), 7.32-7.19 (4H, m), 7.02 (IH, X, J = 7.7 Hz), 4.20 (2H, t, J = 8.6 Hz), 3.32-3.24 (2H, m).
N-(4-Fluorophenyl)-6-((trans)-4-hydroxycyclohexylamino)pyrimidine-4-carboxamide (Compound 129)
[00317] The title compound was obtained in 5% yield. LCMS: RT = 1.82 min, M+H+ =
331.2. 1H NMR (d6-DMSO): 10.61 (IH, s), 8.60 (IH, s), 7.97-7.92 (2H, m), 7.81 (IH, d, J = 7.6 Hz), 7.27-7.19 (2H, m), 4.63 (IH, d, J = 4.3 Hz), 3.86 (IH, br s), 3.47 (IH, br s), 1.98-1.89 (4H, m), 1.36-1.22 (4H, m).
6-(2H-Benzo[b][l,4]oxazin-4(3H)-yl)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 132)
[00318] The title compound was obtained in 9% yield. LCMS: RT = 2.64 min, M+H+ = 351.1. 1H NMR (d6-DMSO): 10.78 (IH, s), 8.89 (IH, d, J = 1.1 Hz), 7.94-7.89 (2H, m), 7.81 (IH, d, J = 1.1 Hz), 7.57 (IH, dd, J = 7.9 & 1.4 Hz), 7.24-7.10 (3H, m), 7.01-6.94 (2H, m), 4.33^.20 (4H, m).
N-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)-6-(4-(morpholine-4-carbonyl)piperazin-l- yl)pyrimidine-4-carboxamide (Compound 133)
[00319] The title compound was obtained in 51 % yield. LCMS: RT = 1.95 min, M+H+ =
455.3. 1H NMR (d6-DMSO): 10.40 (IH, s), 8.62 (IH, d, J = 1.1 Hz), 7.48 (IH, d, J = 2.5 Hz), 7.36 (IH, d, J = 1.0 Hz), 7.30 (IH, dd, J = 8.8 & 2.5 Hz), 6.80 (IH, d, J = 8.9 Hz), 4.19 (4H, m), 3.71 (4H, m), 3.55 (4H, m), 3.26-3.13 (8H, m). N-Methyl-6-(methyl(phenyl)amino)pyrimidine-4-carboxamide (Compound 138) [00320] The title compound was obtained in 69% yield. LCMS: RT = 1.60 min, M+H+ = 243.2. 1H NMR (d6-DMSO): 8.74 (IH, d, J = 4.6 Hz), 8.67 (IH, d, J = 1.1 Hz), 7.57-7.52 (2H, m), 7.44-7.38 (3H, m), 6.85 (IH, d, J = 1.1 Hz), 3.46 (3H, s), 2.73 (3H, d, J = 4.9 Hz).
N-(4-tert-Butylphenyl)-6-(phenylamino)pyrimidine-4-carboxamide (Compound 92) [00321] This compound was isolated as the corresponding hydrochloride salt. The title compound was obtained in 68% yield. LCMS: RT = 3.10 min, M+H+= 347.2. 1H NMR (d6-DMSO): 10.53 (IH, s), 10.05 (IH, s), 8.78 (IH, s), 7.79 (2H, d, J = 10.2 Hz), 7.72 (2H, d, J = 9.1 Hz), 7.49 (IH, s), 7.40-7.35 (4H, m), 7.09 (IH, t, J = 8.6 Hz), 1.28 (9H, s).
Ethyl 4-(6-(4-fluorophenylcarbamoyl)pyrimidin-4-ylamino)phenylcarbamate (Compound 93)
[00322] This compound was isolated as the corresponding hydrochloride salt. The title compound was obtained in 50% yield. LCMS: RT = 2.35 min, M+H+= 396.1. 1H NMR (d6-DMSO): 10.72 (IH, s), 10.04 (IH, s), 9.61 (IH, s), 8.74 (IH, s), 7.92 (2H, m), 7.59 (2H, d, J = 9.6 Hz), 7.45 (3H, d, J = 12.3 Hz), 7.21 (3H, t, J = 10.4 Hz), 4.12 (2H, q, J = 8.3 Hz), 1.24 (3H, t, 7 = 8.3 Hz).
N-Cyclohexyl-6-(phenylamino)pyrimidine-4-carboxamide (Compound 94)
[00323] This compound was isolated as the corresponding hydrochloride salt. The title compound was obtained in 47% yield. LCMS: RT = 2.35 min, M+H+ = 297.2. 1H NMR (dβ-DMSO): 9.94 (IH, s), 8.68 (IH, s), 8.5 (IH, d, J = 10.2 Hz), 7.70 (2H, d, J = 9.1 Hz), 7.36 (3H, m), 7.07 (IH, t, J = 8.6 Hz), 3.75 (IH, d, J = 9.5 Hz), 1.79-1.11 (1OH, m).
N-Isobutyl-6-(phenylamino)pyrimidine-4-carboxamide (Compound 110)
[00324] This compound was isolated as the corresponding hydrochloride salt. The title compound was prepared in 23% yield. LCMS: RT = 2.30 min, M+H+ = 271.1. 1H NMR (d6-DMSO): 10.02 (IH, s), 8.79 (IH, t, J = 7.0 Hz), 8.70 (IH, s), 7.69 (2H, d, J = 8.9 Hz), 7.39 (IH, s), 7.35 (2H, d, J = 9.8 Hz), 7.07 (IH, t, J = 8.6 Hz), 7.11 (2H, t, J = 7.8 Hz), 1.93- 1.80 (IH, m), 0.87 (6H, d, J = 7.8 Hz). N-(3-Fluorophenyl)-6-(phenylamino)pyrimidine-4-carboxamide (Compound 112)
[00325] The title compound was prepared in 26% yield. LCMS: RT = 2.55 min, M+H+ =
309.1. 1H NMR (d6-DMSO): 10.82 (IH, s), 10.06 (IH, s), 8.79 (IH, s), 7.87 (IH, m, J = 3.2 Hz), 7.27 (3H, m, J = 5.9 Hz), 7.50 (IH, t, J = 1.4 Hz), 7.39 (3H, m), 7.08 (IH, t, J = 7.4 Hz), 6.97 (IH, m, J = 3.1 Hz).
N-(4-Chlorophenyl)-6-(phenylamino)py rimidine-4-carboxamide (Compound 113)
[00326] This compound was isolated as the corresponding hydrochloride salt. The title compound was prepared in 80% yield. LCMS: RT = 2.7min, M+H+ = 325.1. 1H NMR (d6-DMSO): 10.79 (IH, s), 10.16 (IH, s), 8.79 (IH, s), 7.95 (2H, dd, J = 3.0 Hz), 7.27 (2H, d, J = 7.7 Hz), 7.51 (IH, d, J = 1.1 Hz), 7.39 (4H, m), 7.09 (IH, t, J = 7.4Hz).
N-(4-Fluorophenyl)-6-(piperidin-l-yl)pyrimidine-4-carboxamide (Compound 116)
[00327] The title compound was prepared in 16% yield. LCMS: RT = 2.45 min, M+H+ =
301.2. 1H NMR (d6-DMSO): 10.67 (IH, s, NH), 8.62 (IH, d, J = 0.9 Hz), 7.91 (2H, m, J = 2.4 Hz), 7.40 (IH, s), 7.20 (2H, m, J = 4.5 Hz), 3.73 (4H, m), 1.61 (6H, m).
N-(4-Fluorophenyl)-6-(4-hydroxy-3-methylphenylamino)pyrimidine-4-carboxamide (Compound 121)
[00328] The title compound was prepared according in 15% yield. LCMS: RT = 2.22 min, M+H+= 339.2. 1H NMR (d6-DMSO): 10.64 (IH, s), 9.66 (IH, s), 9.22 (IH, s), 8.67 (IH, d, J = 0.9 Hz), 7.91 (2H, m, J = 3.6 Hz), 7.24 (5H, m, J = 11.0 Hz), 6.77 (IH, d, J = 8.5 Hz), 2.25 (3H, s).
N-(4-Fluorophenyl)-6-morpholinopyrimidine-4-carboxamide (Compound 122) [00329] The title compound was prepared according to the general microwave protocol. Three recrystallizations in diethyl ether gave the desired product in 27% yield. LCMS: RT = 2.17 min, M+H+ = 303.2. 1H NMR (d6-DMSO): 10.80 (IH, s), 8.67 (IH, d, J = 1.0 Hz), 7.92 (2H, m, J = 3.6 Hz), 7.40 (IH, d, J = 1.0 Hz), 7.20 (2H, m), 3.69 (8H, m). 6-(4,4-Difluoropiperidin-l-yl)-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 123)
[00330] This compound was isolated as the corresponding hydrochloride salt. The title compound was prepared in 36% yield. LCMS: RT = 2.48 min, M+H+ = 337.2. 1H NMR (d6-DMSO): 10.63 (IH, s), 8.67 (IH, d, J = 1.1 Hz), 7.92 (2H, m, J = 3.6 Hz), 7.52 (IH, d, 7 = 1.1 Hz), 7.21 (2H, q, J = 6.0 Hz), 3.88 (4H, m), 2.05 (4H, m).
N-(4-Fluorophenyl)-6-(4-(morpholine-4-carbonyl)piperazin-l-yl)pyrimidine-4- carboxamide (Compound 135)
[00331] The title compound was prepared in 70% yield. LCMS: RT = 1.72 min, M+H+ = 415.2. 1H NMR (d6-DMSO): 10.68 (IH, s), 8.67 (IH, d, J = 1.0 Hz), 7.92 (2H, m, J = 3.6 Hz), 7.41 (IH, d, J = 1.0 Hz), 7.20 (2H, t, J = 8.9 Hz), 3.75 (4H, s), 3.58 (4H, t, J = 4.6 Hz), 3.29 (4H, t, J = 5.0 Hz), 3.18 (4H, t, J = 4.5 Hz).
N-(4-Fluorophenyl)-6-(3-(methylsulfonyl)phenylamino)pyrimidine-4-carboxamide (Compound 105)
[00332] The above method was used to prepare N-(4-fluorophenyl)-6-(3- (methylthio)phenylamino)pyrimidine-4-carboxamide as an HCl salt (44% yield). LCMS: RT = 2.66 min, M+H+= 255.0. 1H NMR (d6-DMSO): 10.73 (IH, s), 10.07 (IH, s), 8.82 (IH, s), 7.94 (2H, m), 7.75 (IH, s), 7.50 (IH, s), 7.46 (IH, d, J = 9.6 Hz), 7.31 (IH, t, J = 9.2 Hz), 7.21 (2H, t, J = 10.4 Hz), 6.97 (IH, d, J = 9.0 Hz), 3.31 (3H, s).
5. Procedure E
[00333] N-(4-Ruorophenyl)-6-(3-(methyithio)phenyiamino)pyrimidine-4-carboxamide (0.108 g, 28 mmol) was dissolved in DCM and m-CPBA (70% w/w in water, 0.145 g, 5.9 mmol, 2.1 eq) was added. The mixture was stirred at O0C for 2 hours. The mixture was neutralized to pH ~ 7 with addition of aqueous NaHCO3 solution, extracted with DCM (x3), the organic layers combined and dried (MgSO4), and concentrated in vacuo. The crude material was purified by HPLC to afford the title compound as a cream solid (0.054 g, 50%). LCMS: RT = 2.25 min, M+H+ = 387. 1H NMR (d6-DMSO): 10.77 (IH, s), 10.44 (IH, s), 8.89 (IH, s), 8.44 (IH, s), 8.02 (2H, d, J = 7.6 Hz), 7.97-7.92 (IH, m), 7.68-7.60 (2H, m), 7.55 (IH, s), 7.22 (2H, t, J = 8.9 Hz), 3.23 (3H, s). N-(3-(MethylsuIfonyI)phenyl)-6-(phenylamino)pyrimidine-4-carboxaniide (Compound
117)
[00334] The title compound was prepared according to the general microwave procedure and procedure E (oxidation) in 42% yield. LCMS: RT = 2.22 min, M+H+ = 368.9. 1H NMR (dβ-DMSO): 11.02 (IH, s), 10.09 (IH, s), 8.81 (IH, s), 8.62 (IH, s), 8.17 (IH, dt, 7 = 7.6 &
1.8 Hz), 7.73 (2H, d, J = 7.8 Hz), 7.69-7.63 (2H, m), 7.51 (IH, s), 7.38 (2H, t, J = 7.5 Hz),
7.09 (IH, t, J = 7.4 Hz), 3.22 (3H, s).
Example 10 - Alternative Route to Compounds of General Formula (I)
Figure imgf000110_0001
,NH, /-PrOH 750C
Figure imgf000110_0002
Compound 2: Ethyl 6-hydroxypyrimidine-4-carboxylate
[00335] 6-Hydroxypyrimidine-4-carboxylic acid (500 mg, 3.57 mmol, 1 eq) was suspended in 10 mL of ethanol followed by the addition of 0.02 mL of sulfuric acid (0.1 eq). The reaction mixture was then refluxed for 12 hours. The reaction mixture was cooled to room temperature and the solvent concentrated in vacuo. The residue was diluted with ethyl acetate and washed with NaHCO3 aq. and brine twice. The aqueous layers were re-extracted with ethyl acetate twice. Organics layers were combined, dried over Na2SO4 and concentrated in vacuo. No purification was attempted at this stage (crude yield = 33%). LCMS: RT = 1.51 min, M+H+= 169.2. 1H NMR (CDCl3): 8.33 (s, IH), 6.95 (s, IH), 4.35 (2H, q, J = 7.1 Hz), 1.35 (3H, t, J = 7.1Hz).
Compound 3: Ethyl 6-chloropyrimidine-4-carboxylate
[00336] Ethyl acetate (7 mL) was added to 200 mg of ethyl 6-hydroxypyrimidine-4- carboxylate 2 and the reaction mixture placed under an inert atmosphere. Oxalyl chloride (0.31 mL, 3 eq, 3.57 mmol) was added slowly to the mixture followed by a few drops of DMF (the evolution of gas was observed). The reaction mixture was heated at 75°C for 12 hours. The solvent was then removed in vacuo affording a black solid in quantitative yield. LCMS: RT = 1.92min, M+H+ = 187.1. 1H NMR (CDCl3): 9.29 (s, IH), 8.23 (s, IH), 4.45 (2H, q, J = 7.1 Hz), 1.40 (3H, t, J = 7.1Hz).
Compound 4: Ethyl 6-(phenylamino)pyrimidine-4-carboxylate
[00337] 6-(Phenylamino)pyrimidine-4-carboxylate 3 (280 mg, 1.5 mmol, 1 eq) was dissolved in isopropanol (12 mL). Aniline (1.05 eq) was added and the resulting solution was reflux ed for 18 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo affording a brown solid. The crude was then diluted with DCM (150 mL), washed with brine (100 mL) and the aqueous layer was extracted further with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulphate and evaporated to dryness. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 0:100 v/v to ethyl acetate/hexanes 50:50 v/v) to afford 110 mg of the desired compound (49% yield). LCMS: RT = 1.91 min, M+H+ = 244.1. 1H NMR (de-DMSO): 10.00 (IH, s), 8.73 (IH, s), 7.70 (2H, d, J = 7.9 Hz), 7.37 (3H, m, J = 5.0 Hz), 7.36 (IH, t, J = 7.4 Hz), 4.33 (2H, q, J = 7.1 Hz), 1.32 (3H, t, J = 7.1 Hz).
Compound 5: 6-(Phenylamino)pyrimidine-4-carboxylic acid
[00338] Ethyl 6-(phenylamino)pyrimidine-4-carboxylate 4 (100 mg) was dissolved in a 1 : 1 mixture of THF / water (2 mL) and 0.7 mL of NaOH 1 N (1.5 eq.) was added at room temperature. The reaction mixture was then stirred at room temperature for 18 hours and acidified using 2 N HCl. The white precipitate was then filtered off and washed with ether to give 75 mg of the desired product (76% yield). 1H NMR (d6-DMSO): 10.00 (IH, s), 8.70 (IH, s), 7.70 (2H, d, J = 7.9 Hz), 7.37 (3H, m, J = 7.9 Hz), 7.07 (IH, t, J = 7.4 Hz).
N-(Benzo[d][l,3]dioxol-5-yl)-6-(phenylamino)pyrimidine-4-carboxamide (Compound
104)
[00339] 6-(Phenylamino)pyrimidine-4-carboxylic acid (74 mg, 0.35 mmol, 1.0 eq.) was dissolved in DCM, 3,4-(methylendioxy)aniline (1.5 eq, 0.5 mmol) was added dropwise followed by BOP (1.5 eq, 0.5 mmol) and DIPEA (1.5 eq, 0.5 mmol). The reaction mixture was stirred at room temperature for 12 hours. Water was added to the mixture and the two phases were separated. The organic layer was washed with brine (100 mL) and the aqueous layer was extracted further with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness. Purification by recrystallisation in DCM gave 39 mg of the title compound (34% yield). LCMS: RT = 2.45 min, M+H+ = 335.1. 1H NMR (d6-DMSO): 10.60 (IH, s), 10.10 (IH, s), 8.83 (IH, s), 7.79 (2H, d, J = 7.8 Hz), 7.62 (IH, d, J = 2.1 Hz), 7.54 (IH, d, J = 1.0 Hz), 7.45 (3H, m, J = 4.0 Hz), 7.15 (IH, t, J = 7.4 Hz), 6.98 (IH, d, J = 8.4 Hz), 6.10 (2H, s).
Other routes
6-Amino-N-(4-fluorophenyl)pyrimidine-4-carboxamide (Compound 107) [00340] To 6-chloro-N-(4-fluorophenyl)pyrimidine-4-carboxamide was added 2 eq. of 0.5M ammonia in 1,4-dioxane and the resulting mixture was heated at 130°C for 30 minutes under microwave activation. After cooling to room temperature, the precipitate was removed by filtration and the filtrate concentrated in vacuo. Purification of the residue by column chromatography, eluting with petrol/ethyl acetate, 1/0 to 0/1 v/v, afforded the title compound in 17% yield. LCMS: RT = 1.82 min, M+H+ = 233.1. 1H NMR (d6-DMSO): 10.48 (IH, s), 8.39 (IH, br s), 7.83-7.76 (2H, br m), 7.23 (2H, br s), 7.08 (2H, t, J = 8.9 Hz), 7.01 (IH, d, J = 1.2 Hz).
Procedure F
N-(4-Fluorophenyl)-6-phenoxypyrimidine-4-carboxamide (Compound 124) [00341] To a solution of sodium hydride (60% dispersion in mineral oil, 71 mg, 1.79 mmol) in DMF (5 mL) was added phenol (0.123 g, 1.31 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then a solution of 6-chloro-N-(4-fluorophenyl)- pyrimidine-4-carboxamide (0.3 g, 1.19 mmol) in DMF (5 mL) was added. The reaction mixture was stirred at room temperature for a further 16 hours, and then partitioned between ethyl acetate and water. The organic layer was washed twice with water, and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by column chromatography, eluting with ethyl acetate/petroleum ether, 0/1 to 3/7, v/v. Subsequent recrystallization in methanol and trituration in ethyl acetate/petroleum ether afforded 50 mg (14%) of the title compound. LCMS: RT = 2.55 min, M+H+ = 310.4. 1HNMR Cd6-DMSO): 10.89 (IH, s), 8.97 (IH, d, J = 1.0 Hz), 7.96-7.91 (2H, m), 7.59 (IH, d, J = 1.1 Hz), 7.54-7.49 (2H, m), 7.37-7.20 (5H, m).
N-(4-Fluorophenyl)-N-methyl-6-(methyI(phenyl)amino)pyrimidine-4-carboxamide (Compound 131)
[00342] To a solution of N-(4-fluorophenyl)-6-(methyl(phenyl)amino)pyrimidine-4- carboxamide (150 mg, 0.465 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 37 mg, 0.93 mmol). The mixture was stirred at 65°C for 1 hour, then methyl iodide (58 μL, 0.93 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by column chromatography, eluting with ethyl acetate/petroleum ether, 0/1 to 1/0, v/v, to afford 54 mg (35%) of the title compound. LCMS: RT = 1.97 min, M+H+ = 337.1. 1HNMR (d6-DMSO): 8.37 (IH, s), 7.51 (2H, t, J = 7.9 Hz), 7.38 (IH, t, J = 7.3 Hz), 7.16 (6H, m), 6.29 (IH, s), 3.43 (3H, s), 3.35 (3H, s).
4-(6-(Naphthalen-2-yl)pyrimidin-4-ylamino)phenol (Compound 139)
[00343] A solution of 4-chloro-6-(naphthalen-2-yl)pyrimidine (0.24 g, 1 mmol), 4- aminophenol (0.11 g, 1 mmol) and concentrated hydrochloric acid (0.3 mL) in 2-propanol (3 mL) was heated at 95°C for 15 minutes in a microwave, after 30 seconds pre-stirring. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and saturated NaHCO3. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude compound was purified by column chromatography, eluting with ethyl acetate/ petroleum ether, 0/1 to 4/1, v/v, then recrystallized from an ethyl acetate/petroleum ether mixture to afford 38 mg (13%) of the title compound. LCMS: RT = 4.68 min, M+H+ = 314.2. 1H NMR (d6-DMSO): 9.42 (IH, s); 9.27 (IH, br); 8.63 (2H, m); 7.95-8.11 (4H, m); 7.59 (2H, m); 7.43 (2H, m); 7.24 (IH, m); 6.78 (2H, m).
Example 11
[00344] The activity of the compounds of formula (I) for use in the treatment of DMD was evalulated in the following predictive assay.
- I l l - Luciferase reporter assay (murine H2K cells)
[00345] 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. [00346] 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
[00347] 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.
[00348] 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 (Victorl420).
Compound StoraRe
[00349] Compounds for screening were stored at -2O0C as 10 mM stocks in 100% DMSO until required.
Results
[00350] Biological activity was assessed using the luciferase reporter assay in murine H2K cells, and the results are shown in Table 1 , which also lists the concentration of the test compound solution in μM. Table 1
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
[00351] 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
[00352] The results in Table 1 show that all of the exemplified compounds had increased activity in the luciferase reporter assay relative to the control.
[00353] 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. [00354] 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. [00355] 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 in this application is not an admission that such reference is available as prior art to this application.

Claims

WHAT IS CLAIMED:
1. Use of a compound of formula (I):
L2
R1 (I) or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein
R1 is H, halo, or C1-C6 alkyl;
L2 is a linker selected from a bond, -O-, -S(O)n-, and -NR5-;
R2 is (i) hydrogen; or (ii) Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl, each of which is optionally substituted with one or more halo, -OR5, -R6, or -OR6; or (iii) 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system, each of which is optionally substituted;
L3 is a linker selected from a bond, -(CR8R8)m-, -NR8-, -O-, -S-, -(CR8R8)mNR8-, -C(O)NR8-, -C(S)NR8-, -C(NH)NR8-, -SO2NR8-, -C(O)-, -C(S)-, -SO-, -SO2-, -CR8=CR8-, -C≡C-, -NR8C(O)NR8-, -NR8C(S)NR8-, -NR8C(NH)NR8-, and -NR8C(O)O-;
R3 is (i) hydrogen; or (ii) Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl, each of which is optionally substituted with one or more halo, -OR5, -N(R5)2, -R6, or -OR6; or (iii) 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system, each of which is optionally substituted; or (iv) when L3 is -NR8- or -C(O)NR8-, R3 together with R8 and the nitrogen atom to which it is attached form an optionally substituted 5-7 membered nitrogen containing heterocyclic ring, which optionally contains one or two further heteroatoms selected from -O-, -NR11-, and -S(O)n-, which is optionally fused to a further 5-7 membered aromatic or non aromatic carbocyclic or heterocyclic ring each of which is optionally substituted; L4 is a linker selected from a bond, -(CR9R9)m-, -NR9-, -O-, -S-, -(CR9R9)mNR9-, -C(O)NR9-, -C(S)NR9-, -C(NH)NR9-, -SO2NR9-, -C(O)-, -C(S)-, -SO-, -SO2-, -CR9=CR9-, -C≡C- -NR9C(O)NR9-, -NR9C(S)NR9-, -NR5C(NH)NR5-, and -NR5C(O)O-;
R4 is (i) hydrogen; or (ii) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl, each of which is optionally substituted with one or more halo, -OR5, -N(R5)2, -R6, or -OR6; or (iii) 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system, each of which is optionally substituted; or (iv) when L4 is -NR9- or -C(O)NR9-, R4 together with R9 and the nitrogen atom to which it is attached form an optionally substituted 5-7 membered nitrogen containing heterocyclic ring, which optionally contains one or two further heteroatoms selected from -0-, -NR11-, and -S(O)n-, which is optionally fused to a further 5-7 membered aromatic or non aromatic carbocyclic or heterocyclic ring each of which is optionally substituted; or (v) when L4 is -NR9-, R4 and the nitrogen atom to which it is attached join with R1 to form an optionally substituted 5-7 membered nitrogen containing heterocyclic ring, which optionally contains one or two further heteroatoms selected from -O-, -NR11-, and -S(O)n-, which is optionally fused to a further 5-7 membered aromatic or non aromatic carbocyclic or heterocyclic ring each of which is optionally substituted; each R5 is independently H or Ci-C6 alkyl optionally substituted by one or more halo; each R6 is independently 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system, each of which is optionally substituted; each R8 is independently H or Cj-C6 alkyl optionally substituted by one or more halo; each R9 is independently H or Ci-C6 alkyl optionally substituted by one or more halo; each R11 is independently hydrogen, optionally substituted Ci-C6 alkyl, or 5-10 membered mono- or bicyclic aromatic or 3-7 membered non aromatic carbocyclic or heterocyclic ring system each of which is optionally substituted; or R11 is -C(O)- (5-7 membered heterocyclyl); each m is independently 1 or 2; and each n is independently 0, 1, or 2; in the manufacture of a medicament for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
2. The use of claim 1, wherein R1 is hydrogen.
3. The use of any one of claims 1 to 2, wherein L2 is a bond.
4. The use of any one of claims 1 to 3, wherein R2 is hydrogen or C1-C6 alkyl.
5. The use of any one of claims 1 to 4, wherein L3 is -CONR8-.
6. The use of any one of claims 1 to 5, wherein L4 is a bond, -O-, or -NR9-
7. The use of any one of claims 1 to 6, wherein R 2 is hydrogen.
8. The use of claim 7 of the compound having formula (Ia):
Figure imgf000121_0001
(Ia) wherein L4 is a bond, -O-, or -NR9-; or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
9. The use of claim 8, wherein R3 is hydrogen, or (i) C1-C6 alkyl optionally substituted with one or more -OR5 or -R6; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl or heterocyclyl group, each of which is optionally substituted with one or more halo, -R7, -OR7, -OCH2C(O)NR10R7, or -SO2R7; or (iii) a 9-10 membered heteroaryl or heterocyclyl group, each of which is optionally substituted with one or more halo, -R7, or -OR7; wherein each R7 is independently H, halo, -NO2, -CN, C]-C6 alkyl, C3-C7 cycloalkyl, C7-Cg aralkyl, C3-C7 heterocyclyl, C5-C7 aryl, or C5-C7 heteroaryl, wherein the alkyl, cycloalkyl, aralkyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with one or more halo, -OH, -0(Ci-C6 alkyl), or -N(Ci-C6 alkyl)2 groups, and wherein the cycloalkyl, aralkyl, heterocyclyl, aryl, and heteroaryl moieties are also optionally substituted with Ci-C6 alkyl; and each R10 is independently H or optionally substituted Ci-C6 alkyl.
10. The use of claim 9, wherein R3 is (i) Ci-C6 alkyl optionally substituted with one or more -OR5 or -R6; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl or heterocyclyl group, each of which is optionally substituted with one or more halo, -R7, -OR7,-OCH2C(O)NR10R7, Or -SO2R7.
11. The use of claim 10, wherein R3 is (i) Cj-C6 alkyl optionally substituted with one or more -0(Ci-C4 alkyl), C3-C7 cycloalkyl, C3-C7 heterocyclyl; C5-C6 aryl, or C5-C6 heteroaryl; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more halo, -OH, C]-C4 alkyl, -0(Ci-C4 alkyl), -SO2(C1-C4 alkyl), -OCH2C(O)N(C1-C4 alkyl)2, C3-C7 cycloalkyl, or C3-C7 heterocyclyl; wherein the alkyl groups are optionally substituted with C3-C7 cycloalkyl, C3-C7 heterocyclyl, C5-C6 aryl, or C5-C6 heteroaryl; wherein the cycloalkyl or heterocyclyl groups are optionally substituted with one or more halo, methyl, or ethyl.
12. The use of claim 11, wherein R3 is (i) C]-C6 alkyl optionally substituted with one or more methoxy, benzyloxy, cyclopropyl, phenyl, thienyl, or pyridyl; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more fluoro, -OH, methyl, methoxy, benzyloxy, or methane sulfonyl.
13. The use of claim 12, wherein R3 is selected from: (i) phenyl and pyridyl, each of which is unsubstituted or substituted with one or more fluoro, methyl, t-butyl, 4- methylpiperazin-1-yl, benzyloxy, or methoxy; and (ii) 2-methoxyethyl, cyclopropylmethyl, thienylmethyl, and cyclohexyl; wherein the aryl groups are optionally substituted with one or more halo, Ci-C6 alkyl, Ci-C6 alkoxy, benzyloxy, C3- C7 heterocyclyl, optionally substituted with methyl or ethyl.
14. The use of claim 9, wherein R3 is 9-10 membered heteroaryl or heterocyclyl group.
15. The use of claim 14, wherein R3 is benzo[cf][l,3]dioxolyl or 2,3- dihydrobenzo [b] [ 1 ,4] dioxinyl .
16. The use of claim 9, wherein R3 is phenyl substituted with one or more fluoro.
17. The use of claim 16, wherein R3 is pαrø-fluoro phenyl.
18. The use of any one of the claims 8 to 17, wherein R is hydrogen, methyl, or ethyl.
19. The use of claim 8, wherein R3 and R8 together with the nitrogen atom to which t thheeyy aarree aattttaacchhee*d form a piperizine, which is optionally substituted with R11 at the second nitrogen atom.
20. The use of claim 19, wherein R3 and R8 together with the nitrogen atom to which they are attached form a piperizine, which is optionally substituted with an optionally substituted C1-C4 alkyl at the second nitrogen atom.
21. The use of claim 20, wherein R11 is diethylaminoethyl.
22. The use of any one of claims 8 to 21, wherein L4 is -NR9-.
23. The use of claim 22, wherein R9 is hydrogen, methyl, or ethyl.
24. The use of any one of claims 8 to 23, wherein R4 is hydrogen, or (i) Ci- C6 alkyl, optionally substituted with one or more -OR5, -N(R5)2, or -R6; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl or heterocyclyl group, each of which is optionally substituted with one or more halo, -CN, -R7, -OR7, -SO2R7, -NR10SO2R7, -NR10R7, -NR10C(O)R7, -NR10C(O)OR7, -C(O)R7, -C(O)OR7, or -C(O)NR10R7; or (iii) a 3-4 membered carbocyclyl; or (iv) a 9-10 membered heteroaryl or heterocyclyl; wherein each R7 is independently H, halo, -NO2, -CN, Ci-C6 alkyl, C3-C7 cycloalkyl, C7-C8 aralkyl, C3-C7 heterocyclyl, C5-C7 aryl, or C5-C7 heteroaryl, wherein the alkyl, cycloalkyl, aralkyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with one or more halo, -OH, -0(Ci-C6 alkyl), or -N(Ci-C6 alkyl)2 groups, and wherein the cycloalkyl, aralkyl, heterocyclyl, aryl, and heteroaryl moieties are also optionally substituted with Ci-C6 alkyl; and each R10 is independently H or optionally substituted C]-C6 alkyl.
25. The use of claim 24, wherein R4 is (i) Ci-C6 alkyl, optionally substituted with one or more -OR5, -N(R5)2, or -R6; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl or heterocyclyl group, each of which is optionally substituted with one or more halo, -CN, -R7, -OR7, -SO2R7, -NR10SO2R7, -NR10R7, -NR10C(O)R7, -NR10C(O)OR7, -C(O)R7, -C(O)OR7, Or -C(O)NR10R7.
26. The use of claim 25, wherein R4 is (i) C]-C6 alkyl, which is optionally substituted with one or more -OH, -0(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, 5-6 membered aryl, 5-6 membered heteroaryl, 5-6 membered carbocyclyl, or 5-6 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl and heterocyclyl groups are optionally substituted with one or more halo, CN, or Ci-C4 alkyl; or (ii) a 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl group, each of which is optionally substituted with one or more halo, -CN, -OH, -0(Cj-C6 alkyl), C]-C6 alkyl, -SO2(C1-C6 alkyl), -NHSO2(C-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)(C]-C6 alkyl), -NHC(O)O(C1-C6 alkyl), -0(C5-C6 aryl), -0(C5-C6 heteroaryl), -C(O)OH, -C(O)(C3- C7 heterocyclyl), -C(O)NH2, or -C(O)NH(C1-C6 alkyl), wherein each of the C1-C6 alkyl is substituted with one or more -OH or halo.
27. The use of claim 24, wherein R4 is cyclopropyl, benzofuranyl, indolinonyl, benzo[rf][l,3]dioxolyl, or 2,3-dihydrobenzo[b][l,4]dioxinyl.
28. The use of claim 22, wherein R4 and R9 together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring, which is optionally substituted with one or more -R7; wherein each R7 is independently H, halo, -NO2, -CN, C1-C6 alkyl, C3-C7 cycloalkyl, C7-C8 aralkyl, C3-C7 heterocyclyl, C5-C7 aryl, or C5-C7 heteroaryl, wherein the alkyl, cycloalkyl, aralkyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with one or more halo, -OH, -0(Ci-C6 alkyl), or -N(C1-C6 alkyl)2 groups, and wherein the cycloalkyl, aralkyl, heterocyclyl, aryl, and heteroaryl moieties are also optionally substituted with Ci-C6 alkyl.
29. The use of claim 28, wherein R4 and R9 together with the nitrogen atom to which they are attached form a piperazine, piperidine, or morpholine ring, each of which is optionally substituted with one or more: (a) C1-C6 alkyl, which in turn is optionally substituted with one or more -OH, -0(Ci-C6 alkyl), -NH2, -NH(Ci-C6 alkyl), or -N(Cj-C6 alkyl)2, or (b) 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl, which in turn is optionally substituted with one or more halo or CN.
30. The use of claim 22, wherein R4 and R9 together with the nitrogen atom to which they are attached form a piperazine ring, wherein the second nitrogen atom of the piperizine ring is optionally substituted with: (a) C]-C6 alkyl, which in turn is optionally substituted with one or more -OH, -0(Ci-C6 alkyl), -NH2, -NH(Ci-C6 alkyl), or -N(Ci-C6 alkyl)2, or (b) 5-6 membered aryl, heteroaryl, carbocyclyl, or heterocyclyl, which in turn is optionally substituted with one or more halo or CN; or (c) -C(O)-(5-7 membered heterocyclyl).
31. The use of claim 30, wherein R4 and R9 together with the nitrogen atom to which they are attached form a piperazine ring, wherein the second nitrogen atom of the piperizine ring is optionally substituted with methyl, ethyl, pyridine, diethylaminoethyl, or -C(O)-morpholinyl.
32. The use of claim 22, wherein R4 and R9 together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, or morpholine ring, each of which is further fused to a phenyl ring, wherein the fused ring system is optionally substituted.
33. The use of any one of claims 8 to 21, wherein L4 is a bond.
34. The use of claim 33, wherein R4 is phenyl, furanyl, or indolyl, each of which is optionally substituted with one or more halo, CN, -C(O)NH(Ci-C4 alkyl), -C(O)N(C1-C4 alkyl)2, Or -NHC(O)(C1-C4 alkyl).
35. The use of claim 1, wherein the compound is: N-(4-tert-butylphenyl)-6-(4-hydroxycyclohexylamino)pyrimidine-4- carboxamide,
N-(4-tert-butylphenyl)-6-(4-(pyridin-2-yl)piperazin-l-yl)pyrimidine-4- carboxamide,
6-(ethylamino)-N-(4-(4-methylpiperazin-l-yl)phenyl)pyrimidine-4-carboxamide,
6-(lH-indol-5-yl)-N-(2-methoxyethyl)pyrimidine-4-carboxamide,
N-benzyl-6-(cyclopropylamino)pyrimidine-4-carboxamide,
6-(2-methoxyphenylamino)-N-phenylpyrimidine-4-carboxamide,
N-(3-(benzyloxy)phenyl)-6-(piperidin-l-yl)pyrimidine-4-carboxamide,
6-(dimethylamino)-N-methyl-N-phenylpyrimidine-4-carboxamide,
(R)-N-(4-fluorophenyl)-6-(l-hydroxy-3-methylbutan-2-ylamino)pyrimidine-4- carboxamide,
N-(4-tert-butylphenyl)-6-(4-(2-hydroxyethyl)phenylamino)pyrimidine-4- carboxamide,
(6-(cyclohexylamino)pyrimidin-4-yl)(4-(2-(diethylamino)ethyl)piperazin-l- yl)methanone,
6-((2-(dimethylamino)ethyl)(methyl)amino)-N-(4-fluorophenyl)pyrimidine-4- carboxamide,
JN-(4-fluorophenyl)-6-(2-methoxyethylamino)pyrimidine-4-carboxamide,
6-(3-(methylsulfonyl)phenylamino)-N-phenylpyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(4-hydroxyphenylamino)pyrimidine-4-carboxamide,
6-(cyclohexylamino)-N-(cyclopropylmethyl)pyrimidine-4-carboxamide,
6-(4-methylpiperazin- 1 -yl)-N-p-tolylpyrimidine-4-carboxamide,
N-(pyridin-3-yl)-6-(thiophen-2-ylmethylamino)pyrimidine-4-carboxamide,
6-(3-bromophenylamino)-N-(3,4,5-trimethoxyphenyl)pyrimidine-4-carboxamide,
6-(benzylamino)-N-(3-(benzyloxy)phenyl)pyrimidine-4-carboxamide,
6-(4-hydroxycyclohexylamino)-N-(4-methoxyphenyl)pyrimidine-4-carboxamide,
6-(cyclohexylamino)-N-(2-methoxyethyl)pyrimidine-4-carboxamide, (R)-6-(l-hydroxy-3-methylbutan-2-ylamino)-N-phenylpyrimidine-4- carboxamide,
6-(4-(2-(diethylamino)ethyl)piperazin-l-yl)-N-methyl-N-phenylpyrimidine-4- carboxamide,
N-(3-(benzyloxy)phenyl)-6-(cyclohexylamino)pyrimidine-4-carboxamide, N-(3-(benzyloxy)phenyl)-6-(4-hydroxycyclohexylamino)pyrimidine-4- carboxamide,
N-isobutyl-6-(methyl(phenyl)amino)pyrimidine-4-carboxamide,
6-(4-hydroxyphenylamino)-N-(4-methoxyphenyl)pyrimidine-4-carboxamide,
N-(4-tert-butylphenyl)-6-(4-(2-(diethylamino)ethyl)piperazin-l-yl)pyrimidine-4- carboxamide,
N-(3-(benzyloxy)phenyl)-6-(2-methoxyethylamino)pyrimidine-4-carboxamide,
6-(4-hydroxy-2-methylphenylamino)-N-phenylpyrimidine-4-carboxamide,
6-(4-(2-(diethylamino)ethyl)piperazin-l-yl)-N-phenylpyrimidine-4-carboxamide,
6-(ethylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide,
(R)-6-( 1 -hydroxy-3 -methylbutan-2-ylamino)-N-(4-methoxyphenyl)pyrimidine-
4-carboxamide,
N-(4-tert-butylphenyl)-6-(2-methoxyethylamino)pyrimidine-4-carboxamide, N-(4-fluorophenyl)-6-(isopropylamino)pyrimidine-4-carboxamide, N-(4-hydroxycyclohexyl)-6-(piperidin-l-yl)pyrimidine-4-carboxamide, (S)-6-( 1 -hydroxy-3 -methylbutan-2-ylamino)-N-phenylpyrimidine-4- carboxamide,
6-(2-chlorophenylamino)-N-(pyridin-3-yl)pyrimidine-4-carboxamide,
6-(isopropylamino)-N-(4-methoxyphenyl)pyrimidine-4-carboxamide,
N-(3-(benzyloxy)phenyl)-6-(4-hydroxyphenylamino)pyrimidine-4-carboxamide,
N-(4-methoxyphenyl)-6-(2-moφholinoethylamino)pyrimidine-4-carboxamide,
N-(4-tert-butylphenyl)-6-phenylpyrimidine-4-carboxamide,
6-(4-(ethyl(2-hydroxyethyl)amino)phenylamino)-N-(4-fluorophenyl)pyrimidine-
4-carboxamide,
N-methyl-6-(methylamino)-N-phenylpyrimidine-4-carboxamide, 6-(2-morpholinoethylamino)-N-(3,4,5-trimethoxyphenyl)pyrimidine-4- carboxamide,
N-(4-methoxyphenyl)-6-moφholinopyrimidine-4-carboxamide, N-phenyl-6-(thiophen-2-ylmethylamino)pyrimidine-4-caτboxamide, (S)-N-(4-fluorophenyl)-6-( l-hydroxy-3-methylbutan-2-ylamino)pyrimidine-4- carboxamide,
N-(4-tert-butylpheny 1) - 6- (3,4,5 -trimethoxypheny lamino)pyrimidine-4- carboxamide,
N-cyclohexyl-6-(2-methoxyethylamino)pyrimidine-4-carboxamide,
N-(4-tert-butylphenyl)-6-(furan-3-yl)pyrimidine-4-carboxamide,
N-benzyl-6-(dimethylamino)pyrimidine-4-carboxamide,
6-(cyclopropylamino)-N-(2-(pyridin-2-yl)ethyl)pyrimidine-4-carboxamide,
6-(4-hydroxyphenylamino)-N-phenylpyrimidine-4-carboxamide,
6-(4-hydroxyphenylamino)-N-isobutylpyrimidine-4-carboxamide,
N-benzyl-6-(piperidin- 1 -yl)pyrimidine-4-carboxamide,
6-(ethylamino)-N-(2-(pyridin-2-yl)ethyl)pyrimidine-4-carboxamide,
6-(benzyl(methyl)amino)-N-(4-methoxyphenyl)pyrimidine-4-carboxamide,
N-(3-(benzyloxy)phenyl)-6-(dimethylamino)pyrimidine-4-carboxamide,
(R)-6-( 1 -hydroxy-3 -methylbutan-2-ylamino)-N-methyl-N-phenylpyrimidine-4- carboxamide,
6-(3-acetamidophenyl)-N-phenylpyrimidine-4-carboxamide, 6-(piperidin- 1 -yl)-N-(thiophen-2-ylmethyl)pyrimidine-4-carboxamide, N-(2-methoxyethyl)-6-(piperidin- 1 -yl)pyrimidine-4-carboxamide, N-(3-(benzyloxy)phenyl)-6-(ethylamino)pyrimidine-4-carboxamide, N-phenyl-6-(pyridin-3-ylmethylamino)pyrimidine-4-carboxamide, (6-(4-phenoxyphenylamino)pyrimidin-4-yl)(4-(pyridin-2-yl)piperazin-l- yl)methanone,
N-(4-tert-butylphenyl)-6-(thiophen-2-ylmethylamino)pyrimidine-4-carboxamide, N-(3-(2-(dimethylamino)-2-oxoethoxy)phenyl)-6-(piperidin-l-yl)pyrimidine-4- carboxamide,
N-(4-tert-butylphenyl)-6-(3,4-dimethoxyphenylamino)pyrimidine-4- carboxamide,
N-isobutyl-6-(piperidin- 1 -yl)pyrimidine-4-carboxamide,
(S)-6-( l-hydroxy-3-methylbutan-2-ylamino)-N-(4-methoxyphenyl)pyrimidine-
4-carboxamide,
N-phenyl-6-(phenylamino)pyrimidine-4-carboxamide, N-(4-fluorophenyl)-6-(4-fluorophenylamino)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(4-methoxyphenylamino)pyrimidine-4-carboxamide,
6-(3-chlorophenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(3-fluorophenylamino)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(phenylamino)pyrimidine-4-carboxamide,
6-(cyclohexylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide,
6-(4-Ruorobenzylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide,
6-(benzofuran-5-ylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide,
6-(benzylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(4-(trifluoromethyl)phenylamino)pyrimidine-4- carboxamide,
N-(4-fluorophenyl)-6-(4-chlorophenylamino)pyrimidine-4-carboxamide,
6-(4-cyanophenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide,
6-(4-chlorophenylamino)-N-phenylpyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(2-oxoindolin-5-ylamino)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(thiophen-3-ylmethylamino)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(furan-3-ylmethylamino)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(furan-2-ylmethylamino)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(thiophen-2-ylmethylamino)pyrimidine-4-carboxamide,
N-(4-tert-butylphenyl)-6-(phenylamino)pyrimidine-4-carboxamide, ethyl 4-(6-(4-fluorophenylcarbamoyl)pyrimidin-4-ylamino)phenylcarbamate,
N-cyclohexyl-6-(phenylamino)pyrimidine-4-carboxamide,
6-(4-acetamidophenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(4-(methylsulfonamido)phenylamino)pyrimidine-4- carboxamide,
N-(4-fluorophenyl)-6-(4-(methylsulfonamido)phenylamino)pyrimidine-4- carboxamide,
N-(4-fluorophenyl)-6-(thiophen-3-ylamino)pyrimidine-4-carboxamide, N-(4-fluorophenyl)-6-(2-methoxyphenylamino)pyrimidine-4-carboxamide, 4-(6-(4-fluorophenylcarbamoyl)pyrimidin-4-ylamino)benzoic acid, N-(4-fluorophenyl)-6-(methyl(phenyl)amino)pyrimidine-4-carboxamide, 6-(benzo[d] [ 1 ,3]dioxol-5-ylamino)-N-(4-fluorophenyl)pyrimidine-4- carboxamide, 6-(4-carbamoylphenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide, N-(benzo[d] [ 1 ,3]dioxol-5-yl)-6-(phenylamino)pyrimidine-4-carboxamide, N-(4-fluorophenyl)-6-(3-(methylsulfonyl)phenylamino)pyrimidine-4- carboxamide,
N-(4-fluorophenyl)-6-(6-hydroxypyridin-3-ylamino)pyrimidine-4-carboxamide,
6-amino-N-(4-fluorophenyl)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(3-hydroxyphenylamino)pyrimidine-4-carboxamide,
6-(phenylamino)-N-(4-(trifluoromethyl)phenyl)pyrimidine-4-carboxamide,
N-isobutyl-6-(phenylamino)pyrimidine-4-carboxamide,
6-(phenylamino)-N-(thiophen-2-ylmethyl)pyrimidine-4-carboxamide,
N-(3-fluorophenyl)-6-(phenylamino)pyrimidine-4-carboxamide,
N-(4-chlorophenyl)-6-(phenylamino)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(6-methoxypyridin-3-ylamino)pyrimidine-4-carboxamide,
6-(3,5-difluoro-4-hydroxyphenylamino)-N-(4-fluorophenyl)pyrimidine-4- carboxamide,
N-(4-fluorophenyl)-6-(piperidin- 1 -yl)pyrimidine-4-carboxamide,
N-(3-(methylsulfonyl)phenyl)-6-(phenylamino)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(4-(methylcarbamoyl)phenylamino)pyrimidine-4- carboxamide,
N-(4-fluorophenyl)-6-(3-hydroxypropylamino)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(isobutylamino)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(4-hydroxy-3-methylphenylamino)pyrimidine-4- carboxamide,
N-(4-fluorophenyl)-6-morpholinopyrimidine-4-carboxamide,
6-(4,4-difluoropiperidin-l-yl)-N-(4-fluorophenyl)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-phenoxypyrimidine-4-carboxamide,
6-(phenylamino)-N-(pyridin-3-yl)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(indolin- 1 -yl)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-(p-tolylamino)pyrimidine-4-carboxamide,
6-(3,4-dihydroquinolin-l(2H)-yl)-N-(4-fluorophenyl)pyrimidine-4-carboxamide,
N-(4-fluorophenyl)-6-((trans)-4-hydroxycyclohexylamino)pyrimidine-4- carboxamide,
N-(3-fluorophenyl)-6-(3-hydroxyphenylamino)pyrimidine-4-carboxamide, N-(4-fluorophenyl)-N-methyl-6-(methyl(phenyl)amino)pyrimidine-4- carboxamide,
6-(2H-benzo[b] [ 1 ,4]oxazin-4(3H)-yl)-N-(4-fluorophenyl)pyrimidine-4- carboxamide,
N-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-6-(4-(morpholine-4- carbonyl)piperazin-l-yl)pyrirnidine-4-carboxamide,
N-(4-fluorophenyl)-6-(methyl((2-methylfuran-3-yl)methyl)amino)pyrimidine-4- carboxamide,
N-(4-luorophenyl)-6-(4-(moφholine-4-carbonyl)piperazin-l-yl)pyrimidine-4- carboxamide,
N-(4-fluorophenyl)-6-(4-(moφholine-4-carbonyl)phenylamino) pyrimidine-4- carboxamide,
6-(ethyl(phenyl)amino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide,
N-methyl-6-(methyl(phenyl)amino)pyrimidine-4-carboxamide, or
4-(6-(Naphthalen-2-yl)pyrimidin-4-ylamino)phenol, or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.
36. A compound, or a tautomer, enantiomer, pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, wherein the compound is: N-Phenyl-6-(phenylamino)pyrimidine-4-carboxamide, 6-(4-Hydroxyphenylamino)-N-phenylpyrimidine-4-carboxamide, N-(4-Ruorophenyl)-6-(4-hydroxyphenylamino)pyrimidine-4-carboxamide, N-(4-Fluorophenyl)-6-(4-fluorophenylamino)pyrimidine-4-carboxamide, N-(4-Fluorophenyl)-6-(4-methoxyphenylamino)pyrimidine-4-carboxamide, 6-(3-Chlorophenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide, N-(4-Fluorophenyl)-6-(3-fluorophenylamino)pyrimidine-4-carboxamide, N-(4-Ruorophenyl)-6-(phenylamino)pyrimidine-4-carboxamide, 6-(Cyclohexylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide, 6-(Benzofuran-5-ylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide, 6-(4-Fluorobenzylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide, 6-(Benzylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide, 6-(4-Cyanophenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide, N-(4-Fluorophenyl)-6-(4-(trifluoromethyl)phenylamino)pyrimidine-4- carboxamide,
N-(4-Fluorophenyl)-6-(4-chlorophenylamino)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(2-oxoindolin-5-ylamino)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(6-hydroxypyridin-3-ylamino)pyrimidine-4-carboxamide,
6-(Phenylamino)-N-(4-(trifluoromethyl)phenyl)pyrimidine-4-carboxamide,
6-(3,5-Difluoro-4-hydroxyphenylamino)-N-(4-fluorophenyl)pyrimidine-4- carboxamide,
6-(Phenylamino)-N-(pyridin-3-yl)pyrimidine-4-carboxamide, 6-(3,4-Dihydroquinolin- 1 (2H)-yl)-N-(4-fluorophenyl)pyrimidine-4- carboxamide,
N-(4-Fluorophenyl)-6-(4-(morpholine-4-carbonyl)phenylamino)pyrimidine-4- carboxamide,
6-(4-(Ethyl(2-hydroxyethyl)amino)phenylamino)-N-(4-fluorophenyl)pyrimidine-
4-carboxamide,
6-(Ethyl(phenyl)amino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide, N-(4-Fluorophenyl)-6-(methyl ((2-methylfuran-3-yl)rnethyl)amino)pyrimidine-4- carboxamide,
N-(3-Fluorophenyl)-6-(3-hydroxyphenylamino)pyrimidine-4-carboxamide,
6-(4-Chlorophenylamino)-N-phenylpyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(thiophen-3-ylmethylamino)pyrimidine-4-carboxamide,
N-(4-Ruorophenyl)-6-(furan-3-ylmethylamino)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(furan-2-ylmethylamino)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(thiophen-2-ylmethylamino)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(2-methoxyphenylamino)pyrimidine-4-carboxamide,
N-(4-Ruorophenyl)-6-(6-methoxypyridin-3-ylamino)pyrimidine-4-carboxamide,
6-(4-Acetamidophenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide,
N-(4-Ruorophenyl)-6-(4-(methylsulfonamido)phenylamino)pyrimidine-4- carboxamide,
N-(4-Ruorophenyl)-6-(2-hydroxyethylamino)pyrimidine-4-carboxamide, N-(4-Fluorophenyl)-6-(thiophen-3-ylamino)pyrimidine-4-carboxamide, 6-(4-Carbamoylphenylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide, N-(4-Fluorophenyl)-6-(methyl(phenyl)amino)pyrimidine-4-carboxamide, 6-(Benzo[d][l,3]dioxol-5-ylamino)-N-(4-fluorophenyl)pyrimidine-4- carboxamide,
4-(6-(4-Fluorophenylcarbamoyl)pyrimidin-4-ylamino)benzoic acid,
6-(Phenylamino)-N-(thiophen-2-ylmethyl)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(4-(methylcarbamoyl)phenylamino)pyrimidine-4- carboxamide,
6-(Ethylamino)-N-(4-fluorophenyl)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(3-hydroxyphenylamino)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(3-hydroxypropylamino)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(isobutylamino)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(p-tolylamino)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(indolin- 1 -yl)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-((trans)-4-hydroxycyclohexylamino)pyrimidine-4- carboxamide,
6-(2H-Benzo[b] [ 1 ,4]oxazin-4(3H)-yl)-N-(4-fluorophenyl)pyrimidine-4- carboxamide,
N-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)-6-(4-(morpholine-4-carbonyl) piperazin- 1 -yl)pyrimidine-4-carboxamide,
N-Methyl-6-(methyl(phenyl)amino)pyrimidine-4-carboxamide,
N-(4-tert-Butylphenyl)-6-(phenylamino)pyrimidine-4-carboxamide,
Ethyl 4-(6-(4-fluorophenylcarbamoyl)pyrimidin-4-ylamino)phenylcarbamate,
N-Cyclohexyl-6-(phenylamino)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(3-(methylsulfonyl)phenylamino)pyrimidine-4- carboxamide,
N-Isobutyl-6-(phenylamino)pyrimidine-4-carboxamide,
N-(3-(Methylsulfonyl)phenyl)-6-(phenylamino)pyrimidine-4-carboxamide,
N-(3-Fluorophenyl)-6-(phenylamino)pyrimidine-4-carboxamide,
N-(4-Chlorophenyl)-6-(phenylamino)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(piperidin- 1 -yl)pyrimidine-4-carboxamide,
N-(4-Fluorophenyl)-6-(4-hydroxy-3-methylphenylamino)pyrimidine-4- carboxamide,
N-(4-Fluorophenyl)-6-morpholinopyrimidine-4-carboxamide, 6-(4,4-Difluoropiperidin-l-yl)-N-(4-fluorophenyl)pyrimidine-4-carboxamide, N-(4-Fluorophenyl)-6-(4-(moφholine-4-carbonyl)piperazin-l-yl)pyrimidine-4- carboxamide,
N-(4-Ruorophenyl)-6-phenoxypyrimidine-4-carboxamide,
N-(4-Ruorophenyl)-N-methyl-6-(methyl(phenyl)amino)pyrimidine-4- carboxamide,
4-(6-(Naphthalen-2-yl)pyrimidin-4-ylamino)phenol,
N-(Benzo[d] [ 1 ,3]dioxol-5-yl)-6-(phenylamino)pyrimidine-4-carboxamide, or
6-Amino-N-(4-fluorophenyl)pyrimidine-4-carboxamide.
37. A pharmaceutical composition comprising the compound of claim 36 and a pharmaceutically acceptable excipient or carrier.
38. Use of the compound of claim 36 in the manufacture of a medicament for the treatment of Duchenne muscular dystrophy, Becker muscular dystrophy, or cachexia.
PCT/EP2009/006099 2008-08-22 2009-08-21 Compounds for treatment of duchenne muscular dystrophy WO2010020432A2 (en)

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JP5603770B2 (en) 2007-05-31 2014-10-08 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング CCR2 receptor antagonist and use thereof
JP2012512834A (en) 2008-12-19 2012-06-07 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Cyclic pyrimidine-4-carboxamides as CCR2 receptor antagonists for the treatment of inflammation, asthma and COPD
PL2493895T3 (en) 2009-10-29 2017-10-31 Vectura Ltd N-containing heteroaryl derivatives as jak3 kinase inhibitors
CN102933579B (en) 2009-12-17 2015-07-15 贝林格尔.英格海姆国际有限公司 New ccr2 receptor antagonists and uses thereof
WO2011141477A1 (en) 2010-05-12 2011-11-17 Boehringer Ingelheim International Gmbh New ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments
WO2011141474A1 (en) 2010-05-12 2011-11-17 Boehringer Ingelheim International Gmbh Novel ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments
EP2571870B1 (en) 2010-05-17 2015-01-21 Boehringer Ingelheim International GmbH Ccr2 antagonists and uses thereof
JP5636094B2 (en) 2010-05-25 2014-12-03 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング CCR2 receptor antagonist
WO2011151251A1 (en) 2010-06-01 2011-12-08 Boehringer Ingelheim International Gmbh New ccr2 antagonists
US8569331B2 (en) 2010-11-01 2013-10-29 Arqule, Inc. Substituted benzo[f]lmidazo[1,2-d]pyrido[2,3-b][1,4]diazepine compounds
ES2564972T3 (en) 2011-03-18 2016-03-30 Bayer Intellectual Property Gmbh N- (3-carbamoylphenyl) -1H-pyrazol-5-carboxamide derivatives and their use to combat animal parasites
JP5786258B2 (en) 2011-07-15 2015-09-30 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Novel and selective CCR2 antagonist
EA027451B1 (en) * 2011-08-30 2017-07-31 Схди Фаундейшн, Инк. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions and use thereof
WO2013046136A1 (en) 2011-09-27 2013-04-04 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh
UY34632A (en) 2012-02-24 2013-05-31 Novartis Ag OXAZOLIDIN- 2- ONA COMPOUNDS AND USES OF THE SAME
US9296733B2 (en) 2012-11-12 2016-03-29 Novartis Ag Oxazolidin-2-one-pyrimidine derivative and use thereof for the treatment of conditions, diseases and disorders dependent upon PI3 kinases
AP2015008707A0 (en) 2013-03-14 2015-09-30 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh
GB201412010D0 (en) 2014-07-04 2014-08-20 Summit Corp Plc Treatment of hypertransaminasemia
SG11201700341PA (en) 2014-07-17 2017-02-27 Chdi Foundation Inc Methods and compositions for treating hiv-related disorders
WO2016020288A1 (en) 2014-08-04 2016-02-11 Nuevolution A/S Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases
ES2811098T3 (en) 2015-07-02 2021-03-10 Centrexion Therapeutics Corp (4 - ((3r, 4r) -3-methoxytetrahydro-pyrano-4-ylamino) piperidin-1-yl) (5-methyl-6 - (((2r, 6s) -6- (p-tolyl) citrate tetrahydro-2hpyrano-2-yl) methylamino) pyrimidin-4-yl) methanone
MA47013A (en) 2015-10-21 2018-08-29 Otsuka Pharma Co Ltd BENZOLACTAM COMPOUNDS USED AS KINASE PROTEIN INHIBITORS
MX2018013413A (en) 2016-05-26 2019-06-06 Zeno Royalties & Milestones Llc Egfr inhibitor compounds.
CA3026149A1 (en) 2016-06-02 2017-12-07 Cadent Therapeutics, Inc. Potassium channel modulators
EP3571193B1 (en) 2017-01-23 2021-12-01 Cadent Therapeutics, Inc. Potassium channel modulators
GB201706327D0 (en) 2017-04-20 2017-06-07 Otsuka Pharma Co Ltd A pharmaceutical compound
US10793551B2 (en) 2017-10-19 2020-10-06 Effector Therapeutics Inc. Benzimidazole-indole inhibitors of Mnk1 and Mnk2
MA53978A (en) 2018-10-22 2021-09-01 Cadent Therapeutics Inc CRYSTALLINE FORMS OF POTASSIUM CHANNEL MODULATORS
CN109851565A (en) * 2019-01-28 2019-06-07 苏州华诺医药有限公司 A kind of preparation method of the chloro- 2- methylthiopyrimidine of 4,6- bis-
EP4076657A1 (en) 2019-12-20 2022-10-26 Nuevolution A/S Compounds active towards nuclear receptors
CA3174176A1 (en) 2020-03-31 2021-10-07 Sanne Schroder Glad Compounds active towards nuclear receptors
MX2022012260A (en) 2020-03-31 2022-11-30 Nuevolution As Compounds active towards nuclear receptors.
TW202208347A (en) 2020-05-06 2022-03-01 德商拜耳廠股份有限公司 Novel heteroaryl-triazole compounds as pesticides

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7829560B2 (en) * 2004-07-08 2010-11-09 Arqule, Inc. 1,4-disubstituted naphthalenes as inhibitors of P38 MAP kinase
CA2612227C (en) * 2005-06-14 2014-04-22 Taigen Biotechnology Co., Ltd. Pyrimidine compounds
SI1986633T1 (en) * 2006-02-10 2015-03-31 Summit Corporation Plc Treatment of duchenne muscular dystrophy
US20080293785A1 (en) * 2006-04-11 2008-11-27 Connolly Peter J Substituted benzothiazole kinase inhibitors
GB0614579D0 (en) * 2006-07-21 2006-08-30 Black James Foundation Pyrimidine derivatives

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