US20210040097A1 - Adenosine receptor antagonists and uses thereof - Google Patents

Adenosine receptor antagonists and uses thereof Download PDF

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US20210040097A1
US20210040097A1 US16/978,040 US201916978040A US2021040097A1 US 20210040097 A1 US20210040097 A1 US 20210040097A1 US 201916978040 A US201916978040 A US 201916978040A US 2021040097 A1 US2021040097 A1 US 2021040097A1
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Jiwen Liu
Elfatih Elzein
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Teon Therapeutics Inc
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of A 2B adenosine receptor activity.
  • Adenosine an endogenous nucleoside, ubiquitously exists inside and outside of living cells. It plays multiple physiological roles to maintain the homeostasis of cells, tissues, and organs. Adenosine can exert its biological effects by interacting with a family of adenosine receptors known as A 1 ; A 2A , A 2B , and A 3 adenosine receptors. A 1 adenosine receptors mediate mechanisms of tissue protection, especially for cardioprotection. A 2A adenosine receptors modulate coronary vasodilation and cancer immunity. A 2B adenosine receptors play a role in signaling pathways.
  • a 2B adenosine receptor antagonists are relatively insoluble in aqueous media and/or difficult to formulate using conventional pharmaceutical excipients, and thus can be difficult to formulate in a manner that provides reproducible plasma levels of the compound in mammals, in particular humans.
  • R 4 is C 1 -C 6 alkyl
  • R 6 is selected from hydrogen, and C 1 -C 6 alkyl; or R 4 and R 6 are taken together with the carbon atom to which they are attached to form a carbonyl (C ⁇ O).
  • R 4 is methyl, ethyl, or n-propyl
  • R 6 is selected from hydrogen, methyl, ethyl, and n-propyl
  • R 4 and R 6 are taken together with the carbon atom to which they are attached to form a carbonyl (C ⁇ O).
  • the compound has the following structure of Formula (III):
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.
  • R 1 is ethyl
  • R 2 is n-propyl
  • R 3 is 3-(trifluoromethyl)phenyl.
  • the compound has the following structure:
  • R 5 is R 7 ;
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 8 cycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 8 heterocycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, —CH 2 -(substituted or unsubstituted phenyl), —CH 2 -(substituted or unsubstituted heteroaryl), —CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloalkyl),
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, —CH 2 -(substituted or unsubstituted phenyl), —CH 2 -(substituted or unsubstituted heteroaryl), —CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloalkyl), —CH(R 10 )O—R 11 , or —(CH 2 CH 2 O) n —R 11 ;
  • R 10 is hydrogen and methyl;
  • R 11 is hydrogen, C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, —C( ⁇ O)R 12 , —C( ⁇ O)—OR 12 , —C( ⁇ O)N(R 12 )(R 8 ),
  • the compound has one of the following structures:
  • the compound has one of the following structures:
  • the compound has the following structure of Formula (I):
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 is ethyl
  • R 2 is n-propyl
  • R 3 is 3-(trifluoromethyl)phenyl.
  • the compound has the following structure:
  • R 4 is methyl or ethyl
  • R 5 is hydrogen, R 7 , —C( ⁇ O)R 7 , —C( ⁇ O)—OR 7 , —C( ⁇ O)N(R 7 )(R 8 ), —C( ⁇ O)—SR 7 , or —P( ⁇ O)(OR 9 ) 2
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 8 cycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 8 heterocycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic hetero
  • R 5 is R 7 , —C( ⁇ O)R 7 , —C( ⁇ O)—OR 7 , —C( ⁇ O)N(R 7 )(R 8 ), —C( ⁇ O)—SR 7 , or —P( ⁇ O)(OH) 2 ;
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted bicyclo[1.1.1]pentanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted bicyclo[2.2.2]octanyl, substituted or unsubstituted bicyclo[3.2.1]octanyl, substituted or unsubstituted bicyclo[3.3.0]octanyl, substitute
  • the compound has one of the following structures:
  • the compound has the following structure of Formula (II):
  • Y is selected from —CH 2 —, O, S, —NR 15 —, and —S(O) 2 —;
  • Z is O or S
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 is ethyl
  • R 2 is n-propyl
  • R 3 is 3-(trifluoromethyl)phenyl.
  • the compound has the following structure:
  • the compound has the following structure:
  • the compound has the following structure of Formula (IIa):
  • Y is selected from —CH 2 —, O, S, —NR 15 —, and —S(O) 2 —;
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 is ethyl
  • R 2 is n-propyl
  • R 3 is 3-(trifluoromethyl)phenyl.
  • the compound has the following structure:
  • R 4 is hydrogen;
  • R 6 is hydrogen;
  • R 5 is substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl), —(C(R 10 ) 2 O) m —R 11 , —C( ⁇ O)—(C(R 10 ) 2 O) m —R 11 , —C( ⁇ O)—(CH 2 CH 2 O) n —R 11
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.
  • R 1 is ethyl
  • R 2 is n-propyl
  • R 3 is 3-(trifluoromethyl)phenyl.
  • the compound has the following structure:
  • R 11 is hydrogen, substituted or unsubstituted alkyl, —C( ⁇ O)R 12 , —C( ⁇ O)—OR 12 , —C( ⁇ O)N(R 12 )(R 8 ), or —P( ⁇ O)(OR 9 ) 2 .
  • the compound has one of the following structures:
  • the compound has one of the following structures:
  • R 5 is —C( ⁇ O)—(C(R 10 ) 2 O) m —R 11 , —C( ⁇ O)—(CH 2 CH 2 O) n —R 11 , —C( ⁇ O)—R a or —C( ⁇ O)—OR 7 .
  • the compound has the following structure:
  • R a is substituted or unsubstituted bicyclic cycloalkyl that is a fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro bicyclic cycloalkyl; or R a is substituted or unsubstituted bicyclic heterocycloalkyl that is a fused bicyclic heterocycloalkyl, bridged bicyclic heterocycloalkyl, or spiro bicyclic heterocycloalkyl; or R a is substituted or unsubstituted bicyclic heteroaryl.
  • R a is substituted or unsubstituted bicyclo[1.1.1]pentanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted bicyclo[2.2.2]octanyl, substituted or unsubstituted bicyclo[3.2.1]octanyl, substituted or unsubstituted bicyclo[3.3.0]octanyl, substituted or unsubstituted bicyclo[4.3.0]nonanyl, or substituted or unsubstituted decalinyl.
  • the compound has one of the following structures:
  • R a is substituted or unsubstituted heterocycloalkyl containing at least one O atom in the ring, substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted azapenyl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted pyridin-2-yl, substituted or unsubstituted pyridin-4-yl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl.
  • R a is a substituted or unsubstituted heterocycloalkyl containing at least one O atom in the ring that is substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted dihydrofuranyl, substituted or unsubstituted oxazolidinonyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted tetrahydrothiopyranyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted oxepanyl, substituted or unsubstituted oxazepinyl, or substituted or unsubstituted dioxanyl.
  • R a is a substituted or unsubstituted 5-membered heteroaryl that is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted thiadiazolyl,
  • the compound has one of the following structures:
  • R 1 is ethyl; R 2 is n-propyl; R 3 is 3-(trifluoromethyl)phenyl; R 5 is —C( ⁇ O)—(C(R 10 ) 2 O) m —R 11 , —C( ⁇ O)—(CH 2 CH 2 O) n —R 11 , or —C( ⁇ O)—OR 7 .
  • the compound has one of the following structures:
  • the compound has the following structure:
  • Also described herein is a pharmaceutical formulation, comprising a compound of any one of the compounds disclosed herein, or a pharmaceutically acceptable salt or solvate thereof; and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration to a mammal by oral administration, intravenous administration, or subcutaneous administration.
  • the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a dispersion, a solution, or an emulsion.
  • described herein is a method of modulating the A 2B adenosine receptor in a mammal comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt or solvate thereof.
  • described herein is a method of treating a disease or disorder in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the condition is selected from the group consisting of cardiovascular diseases, fibrosis, neurological disorders, type I hypersensitivity disorders, chronic and acute liver diseases, lung diseases, renal diseases, diabetes, obesity, and cancer.
  • the disease or disorder is cancer.
  • the subject is human.
  • an effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of an effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one day.
  • the compound is administered on a continuous dosing schedule.
  • the compound is administered on a continuous daily dosing schedule.
  • the compounds, compositions, formulations, and methods related to A 2B adenosine receptor antagonists can be used in a method of treating a condition in a subject in need thereof.
  • the condition can be cardiovascular diseases, chronic and acute liver disease, lung disease, renal disease, diabetes, obesity, and/or cancer.
  • Compound 1 is an A 2 B adenosine receptor antagonist, which is a xanthine unsubstituted at 7-position. It can be relatively insoluble in aqueous media and difficult to formulate using conventional pharmaceutical excipients, and thus can be difficult to formulate in a manner that provides reproducible plasma levels of the compound undergoing evaluation in mammals, in particular humans. Accordingly, new prodrugs of the A 2B adenosine receptor antagonist can be developed to improve the formulation, pharmacokinetic profile, and/or bioavailability the A 2B adenosine receptor antagonist.
  • prodrugs can be hydrolyzed by esterase (e.g., in gastrointestinal tract and/or in blood) and converted into Compound 1 in an aqueous solution.
  • esterase e.g., in gastrointestinal tract and/or in blood
  • acid labile prodrugs can be converted into Compound 1 in an acidic environment (e.g., in the stomach).
  • prodrugs, which are stable in the acidic environment and/or stable against hydrolysis by esterase may not be a good prodrug candidate for Compound 1.
  • the compounds, compositions, and/or formulations disclosed herein can be used to treat cancer.
  • adenosine On endothelial cells, for example, adenosine can bind to the A 2 B adenosine receptors, thereby stimulating angiogenesis.
  • a 2 B adenosine receptor stimulation can lead to type I protein kinase A (PKA) isoform activation that can hamper T cell activation through inhibition of T-cell antigen receptor (TCR) proximal kinases Lck and Fyn.
  • PKA protein kinase A
  • TCR T-cell antigen receptor
  • the pro-metastatic Fra-1 transcription factor can also induce A 2B adenosine receptor expression on cancer cells, and thus A 2B adenosine receptor antagonist can inhibit metastasis of Fra-1-expressing cells.
  • a 2B adenosine receptor signaling activation can impair antigen presentation and can also inhibit signal transducer and activator of transcription 1 (STAT1) activation.
  • STAT1 signal transducer and activator of transcription 1
  • the compounds, compositions, and/or formulations disclosed herein can be used to treat fibrosis.
  • a commonly ingested adenosine receptor antagonist, caffeine can block the development of hepatic fibrosis, an effect that may explain the epidemiologic finding that coffee drinking, in a dose-dependent fashion, can reduce the likelihood of death from liver disease.
  • a 2B adenosine receptors can also play a role in the pathogenesis of interstitial fibrosis.
  • Adenosine acting at A 2B adenosine receptors, can stimulate hepatic stellate cell-mediated fibrosis of the liver by increasing production of collagen I and III via two distinct mitogen-activated protein kinase (MAPK)-dependent pathways, extracellular signal-regulated kinase 1/2 (ERK1/2) and p38MAPK, respectively.
  • MAPK mitogen-activated protein kinase
  • ERK1/2 extracellular signal-regulated kinase 1/2
  • p38MAPK extracellular signal-regulated kinase 1/2
  • Over-activation of A 2B adenosine receptors can be involved in liver, lung and heart fibrosis. Accordingly, A 2B adenosine receptors may be a good therapeutic target for fibrosis of the liver, lungs, heart, and/or skin.
  • the compounds, compositions, and/or formulations disclosed herein can be used to treat diabetes and/or obesity.
  • Insensitivity to insulin can exacerbate diabetes and/or obesity.
  • Insulin sensitivity can be decreased by the interaction of adenosine with A 2B adenosine receptors.
  • blocking the A 2B adenosine receptors of individuals with diabetes and/or obesity can benefit patients with these disorders.
  • the compounds, compositions, and/or formulations disclosed herein can be used to treat neurological disorders, such as dementias and Alzheimer's disease.
  • Adenosine acting at A 2B adenosine receptors can over-stimulate cerebral interleukin 6 (IL-6), a cytokine associated with dementias and Alzheimer's disease. Inhibiting the binding of adenosine to A 2B adenosine receptors can therefore mitigate those neurological disorders that are produced by IL-6.
  • IL-6 cerebral interleukin 6
  • the compounds, compositions, and/or formulations disclosed herein can be used to treat type I hypersensitivity disorders, such as chronic obstructive pulmonary disease (COPD), asthma, hay fever, and atopic eczema.
  • type I hypersensitivity disorders can be stimulated by mast cells binding to A 2 B adenosine receptors. Therefore, blocking A 2 B adenosine receptors can provide a therapeutic benefit against such disorders.
  • the term “about” in relation to a reference numerical value can include a range of values plus or minus 10% from that value.
  • the amount “about 10” includes amounts from 9 to 11, including the reference numbers of 9, 10, and 11.
  • the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.
  • prodrug refers to any compound that becomes an active form of a drug (e.g., Compound I) when administered to a subject, e.g., upon metabolic processing of the prodrug.
  • Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • Prodrugs of compound 1 described herein include, but are not limited to, compounds where the nitrogen atom is incorporated into an alkyl carbamate, (acyloxy)alkyl carbamate, acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, N-acyloxyalkoxycarbonyl, N-acyloxyakyl. dihydropyridinepyridinium salt system (redox systems), (phosphoryloxy)methyl carbamate, (acyloxy)alkyl carbamate, and the like.
  • prodrugs of Compound 1 are formed by N-acyloxyalkylation, N-hydroxyalkylation, N-(phosphoryloxy)alkylation, N-acyloxyalkylation, N-hydroxyalkylation, N-(phosphoryloxy)alkylation, N-acylation (amides and carbamates), N-(oxodioxolenyl)methylation, and the like.
  • pharmaceutically acceptable component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation and/or amelioration of the signs, symptoms, or causes of a disease, slowing of disease progression, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
  • treating encompasses administration of at least one compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a mammalian subject, particularly a human subject, in need of such an administration and includes (i) arresting the development of clinical symptoms of the disease, such as cancer, (ii) bringing about a regression in the clinical symptoms of the disease, such as cancer, and/or (iii) prophylactic treatment for preventing the onset of additional symptoms of the disease, such as cancer.
  • subject refers to a mammal that has been or will be the object of treatment, observation or experiment.
  • mammal is intended to have its standard meaning, and encompasses for example humans, dogs, cats, sheep, and cows. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the mammal is a human.
  • Compound 1 can be a derivative or analog if 1, 2, 3, 4, or 5 atoms of compound 1 is replaced by another atom or a functional group (e.g., amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted cycloalkyl) to form the compounds of the disclosure.
  • a functional group e.g., amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted cycloalkyl
  • solvate can include, but is not limited to, a solvate that retains one or more of the activities and/or properties of the compound and that is not undesirable.
  • solvates include, but are not limited to, a compound in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, or combinations thereof.
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.
  • Handbook of Pharmaceutical Salts Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S. M. Berge, L. D. Bighley, D C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use , Weinheim/Zurich: Wiley-VCH/VHCA, 2002.
  • Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
  • salt can include, but are not limited to, salts that retain one or more of the activities and properties of the free acids and bases and that are not undesirable.
  • Illustrative examples of salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzo
  • solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of isolating or purifying the compound with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.
  • stereocenter in a structure disclosed or illustrated herein, the stereocenter can be R or S in each case.
  • stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.
  • compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers.
  • resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of steroisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
  • stereoisomers are obtained by stereoselective synthesis.
  • the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means.
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl.
  • isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • one or more hydrogen atoms of the compounds described herein is replaced with deuterium.
  • amino refers to functional groups that contain a basic nitrogen atom with a lone pair.
  • amino can include the radical —NH 2
  • each R′ is independently H, halo, alkyl, aryl, arylalkyl, cycloalkyl, or acyl.
  • C 1 -C x includes C 1 -C 2 , C 1 -C 3 . . . C 1 -C x .
  • a group designated as “C 1 -C 4 ” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • alkyl refers to an aliphatic hydrocarbon group.
  • the alkyl group is branched or straight chain.
  • the “alkyl” group has 1 to 10 carbon atoms, i.e. a C 1 -C 10 alkyl.
  • a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • an alkyl is a C 1 -C 6 alkyl.
  • the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.
  • an alkyl includes, but is not limited to, methyl, ethyl, propan-1-yl, propan-2-yl, butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, and the like.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
  • lower alkyl can refer to a monoradical branched or unbranched saturated hydrocarbon chains having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.
  • the alkyl when an alkyl is unsaturated, then the alkyl is an alkenyl or alkynyl.
  • alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • an alkenyl group has the formula —C(R) ⁇ CR 2 , wherein R refers to the remaining portions of the alkenyl group, which may be the same or different.
  • R is H or an alkyl.
  • an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like.
  • Non-limiting examples of an alkenyl group include —CH ⁇ CH 2 , —C(CH 3 ) ⁇ CH 2 , —CH ⁇ CHCH 3 , —C(CH 3 ) ⁇ CHCH 3 , and —CH 2 CH ⁇ CH 2 .
  • an alkenyl includes, but is not limited to, ethenyl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, and the like.
  • alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present.
  • an alkenyl group has the formula —C ⁇ C—R, wherein R refers to the remaining portions of the alkynyl group.
  • R is H or an alkyl.
  • an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Non-limiting examples of an alkynyl group include —C ⁇ CH, —C ⁇ CCH 3 —C ⁇ CCH 2 CH 3 , —CH 2 C ⁇ CH.
  • an alkynyl includes, but is not limited to, ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like.
  • alkoxy refers to a (alkyl)O— group, where alkyl is as defined herein.
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoroalkyl is a C 1 -C 6 fluoroalkyl.
  • a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • fluoroalkoxy refers to a (fluoroalkyl)O— group, where fluoroalkyl is as defined herein.
  • halo or halogen refers to fluorine, chlorine, bromine or iodine.
  • heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur (—S—, —S(O)—, —S(O) 2 —), phosporus (—PH—, —P(O) 2 —), or combinations thereof (e.g. —O—P(O) 2 —).
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl.
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • Typical aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, indanyl, indenyl, and the like.
  • aryl is phenyl or a naphthyl.
  • an aryl is a phenyl.
  • an aryl is a C 6 -C 10 aryl.
  • heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls.
  • Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring.
  • a heteroaryl contains 0-4 N atoms, 0-10 atoms, and 0-1 S atoms in the ring.
  • a heteroaryl contains 1-4 N atoms, 0-10 atoms, and 0-1 S atoms in the ring.
  • heteroaryl is a C 1 -C 9 heteroaryl.
  • monocyclic heteroaryl is a C 1 -C 5 heteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • bicyclic heteroaryl is a C 6 -C 9 heteroaryl.
  • arylalkyl refers to an alkyl that is substituted with an aryl group.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, and the like.
  • heteroarylalkyl refers to an alkyl that is substituted with a heteroaryl group.
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • cycloalkyls are monocyclic, bicyclic (spirocyclic, fused or bridged), or polycyclic.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e. (C 3 -C 10 ) cycloalkyl).
  • a cycloalkyl is a (C 3 -C 6 ) cycloalkyl.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl.
  • a cycloalkyl is a C 3 -C 6 cycloalkyl.
  • a cycloalkyl is a monocyclic cycloalkyl.
  • Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • a cycloalkyl is partially unsaturated (“cycloalkenyl”, including but not limited to, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, and the like).
  • heterocycloalkyl or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl.
  • the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl.
  • heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl is a C 2 -C 10 heterocycloalkyl.
  • a heterocycloalkyl is a C 4 -C 10 heterocycloalkyl.
  • a heterocycloalkyl contains 0-2 N atoms in the ring.
  • a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
  • acyl can refer to —C(O)R′, in which R′ is hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl.
  • substituted can refer to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). Typical substituents include, but are
  • substituted or “optionally substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from D, halogen, —CN, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —CO 2 H, —CO 2 alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NH(alkyl), —C( ⁇ O)N(alkyl) 2 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NH(alkyl), —S( ⁇ O) 2 N(alkyl) 2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, ary
  • optional substituents are independently selected from halo, alkyl, heteroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or acyl.
  • optional substituents are independently selected from D, halogen, —CN, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —CO 2 H, —CO 2 (C 1 -C 4 alkyl), —C( ⁇ O)NH 2 , —C( ⁇ O)NH(C 1 -C 4 alkyl), —C( ⁇ O)N(C 1 -C 4 alkyl) 2 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NH(C 1 -C 4 alkyl), —S( ⁇ O) 2 N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, —
  • optional substituents are independently selected from D, halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —CF 3 , —OCH 3 , and —OCF 3 .
  • substituted groups are substituted with one or two of the preceding groups.
  • an optional substituent on an aliphatic carbon atom includes oxo ( ⁇ O).
  • m is 1, 2, 3, 4, 5, or 6. In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2, 3, 4, 5, or 6.
  • n is 1, 2, 3, 4, 5, or 6. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 2, 3, 4, 5, or 6.
  • p is 1, 2, 3, 4, 5, or 6. In some embodiments, p is 1, 2, 3, 4, or 5. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2, 3, 4, 5, or 6.
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, R 1 and R 2 are each independently selected from unsubstituted C 1 -C 3 alkyl. In some embodiments, R 1 is ethyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 1 is ethyl and R 2 is n-propyl.
  • R 3 is selected from substituted or unsubstituted phenyl. In some embodiments, R 3 is substituted phenyl. In some embodiments, R 3 is phenyl substituted by one or more groups independently selected from halogen, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 3 is phenyl substituted by one or more groups independently selected from C 1 -C 4 fluoroalkyl. In some embodiments, R 3 is selected from phenyl substituted with one, two, or three —CF 3 substituents. In some embodiments, R 3 is selected from phenyl substituted with one —CF 3 substituent. In some embodiments, R 3 is
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.
  • R 1 is ethyl
  • R 2 is n-propyl
  • R 3 is 3-(trifluoromethyl)phenyl.
  • R 4 is C 1 -C 6 alkyl and R 6 is selected from hydrogen, and C 1 -C 6 alkyl. In some embodiments, R 4 and R 6 are taken together with the carbon atom to which they are attached to form a carbonyl (C ⁇ O).
  • R 4 is methyl, ethyl, or n-propyl and R 6 is selected from hydrogen, methyl, ethyl, and n-propyl. In some embodiments, R 4 is methyl or ethyl. In some embodiments, R 6 is hydrogen. In some embodiments, R 4 is methyl or ethyl; and R 6 is hydrogen.
  • R 5 is R 7 . In some embodiments, R 5 is —(C ⁇ O)R 7 . In some embodiments, R 5 is —(C ⁇ O)—OR 7 .
  • R 5 is R 7 ;
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 8 cycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 8 heterocycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, —CH 2 -(substituted or unsubstituted phenyl), —CH 2 -(substituted or unsubstituted heteroaryl), —CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloalkyl),
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, —CH 2 -(substituted or unsubstituted phenyl), —CH 2 -(substituted or unsubstituted heteroaryl), —CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloalkyl), —CH(R 10 )O—R 11 , or —(CH 2 CH 2 O) n —R 11 ;
  • R 10 is hydrogen and methyl;
  • R 11 is hydrogen, C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, —C( ⁇ O)R 12 , —C( ⁇ O)—OR 12 , —C( ⁇ O)N(R 12 )(R 8 ),
  • R 7 is C 1 -C 6 alkyl. In some embodiments, R 7 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or n-pentyl.
  • R 7 is —CH(R 10 )O—R 11 , wherein R 11 is —C( ⁇ O)R 12 , and wherein R 12 is unsubstituted alkyl, unsubstituted C 3 -C 10 cycloalkyl.
  • R 12 is methyl, ethyl, n-propyl, n-butyl, or n-pentyl.
  • R 12 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 7 is —CH(R 10 )O—R 11 , wherein R 11 is —P( ⁇ O)(OR 9 ) 2 .
  • R 9 is hydrogen.
  • R 7 is —(CH 2 CH 2 O) n —R 11 , wherein R 11 is unsubstituted alkyl.
  • R 11 is methyl, ethyl, n-propyl, n-butyl, or n-pentyl.
  • R 7 is —CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloalkyl). In some embodiments, R 7 is —CH 2 -(substituted C 5 -C 6 heterocycloalkyl). In some embodiments, R 7 is
  • R 7 is substituted or unsubstituted C 3 -C 10 cycloalkyl. In some embodiments, R 7 is unsubstituted C 3 -C 10 cycloalkyl. In some embodiments, R 7 is monocyclic C 3 -C 10 cycloalkyl. In some embodiments, R 7 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 7 is cyclohexyl. In some embodiments, R 7 is spirocyclic C 3 -C 10 cycloalkyl. In some embodiments, R 7 is adamantyl.
  • R 4 is methyl or ethyl
  • R 5 is hydrogen, R 7 , —C( ⁇ O)R 7 , —C( ⁇ O)—OR 7 , —C( ⁇ O)N(R 7 )(R 8 ), —C( ⁇ O)—SR 7 , or —P( ⁇ O)(OR 9 ) 2
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 8 cycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 8 heterocycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic hetero
  • R 5 is R 7 , —C( ⁇ O)R 7 , —C( ⁇ O)—OR 7 , —C( ⁇ O)N(R 7 )(R 8 ), —C( ⁇ O)—SR 7 , or —P( ⁇ O)(OH) 2 ;
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted bicyclo[1.1.1]pentanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted bicyclo[2.2.2]octanyl, substituted or unsubstituted bicyclo[3.2.1]octanyl, substituted or unsubstituted bicyclo[3.3.0]octanyl, substitute
  • R 5 is R 7 , wherein R 7 is C 1 -C 6 alkyl. In some embodiments, R 7 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or n-pentyl.
  • R 5 is —C( ⁇ O)R 7 , wherein R 7 is C 1 -C 6 alkyl or unsubstituted C 3 -C 10 cycloalkyl. In some embodiments, R 7 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or n-pentyl.
  • R 7 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, s bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0]octanyl, or bicyclo[4.3.0]nonanyl.
  • R 5 is —C( ⁇ O)—OR 7 , wherein R 7 is C 1 -C 6 alkyl or unsubstituted C 3 -C 10 cycloalkyl. In some embodiments, R 7 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or n-pentyl.
  • R 7 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, s bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0]octanyl, or bicyclo[4.3.0]nonanyl.
  • the compound has the following structure of Formula (III):
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.
  • R 1 is ethyl
  • R 2 is n-propyl
  • R 3 is 3-(trifluoromethyl)phenyl.
  • the compound has the following structure:
  • R 5 is R 7 ;
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 8 cycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 8 heterocycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, —CH 2 -(substituted or unsubstituted phenyl), —CH 2 -(substituted or unsubstituted heteroaryl), —CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloalkyl),
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, —CH 2 -(substituted or unsubstituted phenyl), —CH 2 -(substituted or unsubstituted heteroaryl), —CH 2 — (substituted or unsubstituted C 2 -C 8 heterocycloalkyl), —CH(R 10 )O—R 11 , or —(CH 2 CH 2 O) n —R 11 ;
  • R 10 is hydrogen and methyl;
  • R 11 is hydrogen, C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, —C( ⁇ O)R 12 , —C( ⁇ O)—OR 12 , —C( ⁇ O)N(R 12 )(R 8 ),
  • the compound has one of the following structures:
  • the compound has one of the following structures:
  • the compound has the following structure of Formula (I):
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 is ethyl
  • R 2 is n-propyl
  • R 3 is 3-(trifluoromethyl)phenyl.
  • the compound has the following structure:
  • R 4 is methyl or ethyl
  • R 5 is hydrogen, R 7 , —C( ⁇ O)R 7 , —C( ⁇ O)—OR 7 , —C( ⁇ O)N(R 7 )(R 8 ), —C( ⁇ O)—SR 7 , or —P( ⁇ O)(OR 9 ) 2
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic C 3 -C 8 cycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 8 heterocycloalkyl, substituted or unsubstituted bicyclic C 5 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic hetero
  • R 5 is R 7 , —C( ⁇ O)R 7 , —C( ⁇ O)—OR 7 , —C( ⁇ O)N(R 7 )(R 8 ), —C( ⁇ O)—SR 7 , or —P( ⁇ O)(OH) 2 ;
  • R 7 is C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted bicyclo[1.1.1]pentanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted bicyclo[2.2.2]octanyl, substituted or unsubstituted bicyclo[3.2.1]octanyl, substituted or unsubstituted bicyclo[3.3.0]octanyl, substitute
  • the compound has one of the following structures:
  • the compound has the following structure of Formula (II):
  • Y is selected from —CH 2 —, O, S, —NR 15 —, and —S(O) 2 —;
  • Z is O or S
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 is ethyl
  • R 2 is n-propyl
  • R 3 is 3-(trifluoromethyl)phenyl.
  • the compound has the following structure:
  • the compound has the following structure:
  • the compound has the following structure of Formula (IIa):
  • Y is selected from —CH 2 —, O, S, —NR 15 —, and —S(O) 2 —;
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • substituted means that the referenced group is substituted with one or more additional groups individually and independently selected from halogen, —CN, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —CO 2 H, —CO 2 alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NH(alkyl), —C( ⁇ O)N(alkyl) 2 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NH(alkyl), —S( ⁇ O) 2 N(alkyl) 2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, arylsulfoxide, alkylsulfone, and
  • substituted means that the referenced group is substituted with one or more additional groups individually and independently selected from halogen, —CN, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —CO 2 H, —CO 2 alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NH(alkyl), —C( ⁇ O)N(alkyl) 2 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NH(alkyl), —S( ⁇ O) 2 N(alkyl) 2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, and heterocycloalkyl.
  • additional groups individually and independently selected from halogen, —CN, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —CO 2 H, —
  • substituted means that the referenced group is substituted with one or more additional groups individually and independently selected from halogen, —CN, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —CO 2 H, —CO 2 alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NH(alkyl), —C( ⁇ O)N(alkyl) 2 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NH(alkyl), —S( ⁇ O) 2 N(alkyl) 2 , alkyl, fluoroalkyl, alkoxy, and fluoroalkoxy.
  • additional groups individually and independently selected from halogen, —CN, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —CO 2 H, —CO 2 alkyl, —C( ⁇ O)NH 2 , —
  • R 1 is ethyl
  • R 2 is n-propyl
  • R 3 is 3-(trifluoromethyl)phenyl.
  • the compound has the following structure:
  • compounds of Formula (A) include those described in Table 1.
  • m is 1, 2, 3, 4, 5, or 6. In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2, 3, 4, 5, or 6.
  • n is 1, 2, 3, 4, 5, or 6. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 2, 3, 4, 5, or 6.
  • p is 1, 2, 3, 4, 5, or 6. In some embodiments, p is 1, 2, 3, 4, or 5. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2, 3, 4, 5, or 6.
  • R 4 is hydrogen;
  • R 6 is hydrogen;
  • R 5 is substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, -alkyl-(substituted or unsubstituted phenyl), -alkyl-(substituted or unsubstituted heteroaryl), -alkyl-(substituted or unsubstituted cycloalkyl), -alkyl-(substituted or unsubstituted heterocycloalkyl), —(C(R 10 ) 2 O) m —R 11 , —C( ⁇ O)—(C(R 10 ) 2 O) m —R 11 , —C( ⁇ O)—(CH 2 CH 2 O) n —R 11
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, R 1 and R 2 are each independently selected from unsubstituted C 1 -C 3 alkyl. In some embodiments, R 1 is ethyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 1 is ethyl and R 2 is n-propyl.
  • R 3 is selected from substituted or unsubstituted phenyl. In some embodiments, R 3 is substituted phenyl. In some embodiments, R 3 is phenyl substituted by one or more groups independently selected from halogen, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 3 is phenyl substituted by one or more groups independently selected from C 1 -C 4 fluoroalkyl. In some embodiments, R 3 is selected from phenyl substituted with one, two, or three —CF 3 substituents. In some embodiments, R 3 is selected from phenyl substituted with one —CF 3 substituent. In some embodiments, R 3 is
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl; R 3 is selected from substituted or unsubstituted phenyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, and neohexyl.
  • R 1 is ethyl
  • R 2 is n-propyl
  • R 3 is 3-(trifluoromethyl)phenyl.
  • the compound has the following structure:
  • R 11 is hydrogen, substituted or unsubstituted alkyl, —C( ⁇ O)R 12 , —C( ⁇ O)—OR 12 , —C( ⁇ O)N(R 12 )(R 8 ), or —P( ⁇ O)(OR 9 ) 2 .
  • R 11 is substituted or unsubstituted alkyl, —C( ⁇ O)R 12 , —C( ⁇ O)—OR 12 , or —P( ⁇ O)(OR 9 ) 2 .
  • R 11 is —C( ⁇ O)R 12 or —P( ⁇ O)(OR 9 ) 2 .
  • R 11 is —C( ⁇ O)R 12 or —P( ⁇ O)(OH) 2 .
  • the compound has one of the following structures:
  • R 12 is substituted or unsubstituted alkyl or substituted or unsubstituted C 3 -C 10 cycloalkyl. In some embodiments, R 12 is unsubstituted C 1 -C 6 alkyl or unsubstituted C 3 -C 10 cycloalkyl. In some embodiments, R 12 is unsubstituted C 1 -C 3 alkyl. In some embodiments, R 12 is unsubstituted C 3 -C 6 cycloalkyl.
  • the compound has one of the following structures:
  • R 5 is —C( ⁇ O)—(C(R 10 ) 2 O) m —R 11 , —C( ⁇ O)—(CH 2 CH 2 O) n —R 11 , —C( ⁇ O)—R a or —C( ⁇ O)—OR 7 .
  • the compound has the following structure:
  • R a is substituted or unsubstituted bicyclic cycloalkyl that is a fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro bicyclic cycloalkyl; or R a is substituted or unsubstituted bicyclic heterocycloalkyl that is a fused bicyclic heterocycloalkyl, bridged bicyclic heterocycloalkyl, or spiro bicyclic heterocycloalkyl; or R a is substituted or unsubstituted bicyclic heteroaryl.
  • R a is substituted or unsubstituted bicyclo[1.1.1]pentanyl, substituted or unsubstituted bicyclo[2.2.1]heptanyl, substituted or unsubstituted bicyclo[2.2.2]octanyl, substituted or unsubstituted bicyclo[3.2.1]octanyl, substituted or unsubstituted bicyclo[3.3.0]octanyl, substituted or unsubstituted bicyclo[4.3.0]nonanyl, or substituted or unsubstituted decalinyl.
  • the compound has one of the following structures:
  • R a is substituted or unsubstituted heterocycloalkyl containing at least one O atom in the ring, substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted azapenyl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted pyridin-2-yl, substituted or unsubstituted pyridin-4-yl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl.
  • R a is substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrodioxanyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted azapenyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl
  • R a is substituted or unsubstituted tetrahydrodioxanyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyridin-2-yl, substituted or unsubstituted pyridin-4-yl, or substituted or unsubstituted pyrimidinyl.
  • R a is a substituted or unsubstituted heterocycloalkyl containing at least one O atom in the ring that is substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted dihydrofuranyl, substituted or unsubstituted oxazolidinonyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted tetrahydrothiopyranyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted oxepanyl, substituted or unsubstituted oxazepinyl, or substituted or unsubstituted dioxanyl.
  • R a is a substituted or unsubstituted 5-membered heteroaryl that is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted thiadiazolyl.
  • the compound has one of the following structures:
  • R 1 is ethyl; R 2 is n-propyl; R 3 is 3-(trifluoromethyl)phenyl; and R 5 is —C( ⁇ O)—(C(R 10 ) 2 O) m —R 11 , —C( ⁇ O)—(CH 2 CH 2 O) n —R 11 , or —C( ⁇ O)—OR 7 .
  • the compound has one of the following structures:
  • R 5 is —CH 2 -(substituted or unsubstituted C 2 -C 8 heterocycloalkyl). In some embodiments, R 5 is —CH 2 -(substituted C 5 -C 6 heterocycloalkyl). In some embodiments, R 5 is
  • substituted means that the referenced group is substituted with one or more additional groups individually and independently selected from halogen, —CN, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —CO 2 H, —CO 2 alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NH(alkyl), —C( ⁇ O)N(alkyl) 2 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NH(alkyl), —S( ⁇ O) 2 N(alkyl) 2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and
  • substituted means that the referenced group is substituted with one or more additional groups individually and independently selected from halogen, —CN, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —CO 2 H, —CO 2 alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NH(alkyl), —C( ⁇ O)N(alkyl) 2 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NH(alkyl), —S( ⁇ O) 2 N(alkyl) 2 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, and heterocycloalkyl.
  • additional groups individually and independently selected from halogen, —CN, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —CO 2 H, —
  • substituted means that the referenced group is substituted with one or more additional groups individually and independently selected from halogen, —CN, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —CO 2 H, —CO 2 alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NH(alkyl), —C( ⁇ O)N(alkyl) 2 , —S( ⁇ O) 2 NH 2 , —S( ⁇ O) 2 NH(alkyl), —S( ⁇ O) 2 N(alkyl) 2 , alkyl, fluoroalkyl, alkoxy, and fluoroalkoxy.
  • additional groups individually and independently selected from halogen, —CN, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —CO 2 H, —CO 2 alkyl, —C( ⁇ O)NH 2 , —
  • the compound has the following structure:
  • compounds of Formula (B) include those presented in Table 2.
  • the present disclosure provides a compound represented by Formula (I):
  • R 1 , R 2 , R 3 , and R 5 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl; and R 4 is selected from substituted or unsubstituted C 2 -C 10 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.
  • R 1 and R 2 are each independently lower alkyl. In one embodiment, R 1 is ethyl. In one embodiment, R 2 is n-propyl. In one embodiment, R 3 is 3-(trifluoromethyl)phenyl.
  • the compound is represented by:
  • the compound is represented by:
  • R 6 and R 7 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.
  • R 6 and R 7 are each independently hydrogen or lower alkyl.
  • the compound is selected from the group consisting of
  • the present disclosure provides a compound of Formula (II):
  • R 11 , R 12 , and R 13 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl; and R 14 is substituted or unsubstituted cycloalkyl.
  • R 11 and R 12 are each independently lower alkyl. In one embodiment, R 11 is ethyl. In one embodiment, R 12 is n-propyl. In one embodiment, R 13 is 3-(trifluoromethyl)phenyl.
  • the compound is represented by:
  • Y is selected from O, S, substituted or unsubstituted —CH 2 —, —NR 15 —, —S(O) 2 —, and a bond;
  • Z is O or S
  • R 15 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.
  • the compound is represented by:
  • the compound is represented by:
  • Y is selected from O, S, substituted or unsubstituted —CH 2 —, —NR 17 —, —S(O) 2 —, and a bond; and R 16 and R 17 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.
  • the compound is represented by:
  • the present disclosure provides a compound of Formula (III):
  • R 21 , R 22 , R 23 , and R 24 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.
  • R 21 and R 22 are each independently lower alkyl. In one embodiment, R 21 is ethyl. In one embodiment, R 22 is n-propyl. In one embodiment, R 23 is 3-(trifluoromethyl)phenyl.
  • the compound is represented by:
  • the compound is selected from the group consisting of
  • R 25 , R 26 , and R 27 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.
  • R 26 , and R 27 are each independently hydrogen or lower alkyl.
  • the compound is selected from the group consisting of
  • the present disclosure provides a compound of Formula (IV):
  • R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.
  • R 31 and R 32 are each independently lower alkyl. In one embodiment, R 31 is ethyl. In one embodiment, R 32 is n-propyl. In one embodiment, R 33 is 3-(trifluoromethyl)phenyl. In one embodiment, the compound is represented by:
  • the compound is represented by:
  • R 37 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.
  • R 35 , R 36 , and R 37 are each independently hydrogen or lower alkyl.
  • the compound is selected from the group consisting of
  • the present disclosure provides a compound of Formula (V):
  • R 41 , R 42 , R 43 , and R 44 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl; and R 45 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted cycloalkyl.
  • R 41 and R 42 are each independently selected from lower alkyl. In one embodiment, R 41 is ethyl. In one embodiment, R 42 is n-propyl. In one embodiment, R 43 is 3-(trifluoromethyl)phenyl. In one embodiment, when R 45 is not —C(O)R 47 or —P(O)(OR 47 ) 2 , then R 47 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.
  • the compound is represented by:
  • the compound is selected from the group consisting of
  • R 46 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl;
  • X is selected from O, S, substituted or unsubstituted —CH 2 —, —NR 48 —, —S(O) 2 —, and a bond;
  • Z is O or S
  • R 48 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.
  • R 44 and R 46 are each independently hydrogen or lower alkyl.
  • the compound is selected from the group consisting of
  • the present disclosure provides a compound of Formula (VI):
  • R 51 , R 52 , R 53 , and R 55 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl; and R 54 is hydrogen or methyl.
  • R 51 and R 52 are each independently lower alkyl. In one embodiment, R 51 is ethyl. In one embodiment, R 52 is n-propyl. In one embodiment, R 53 is 3-(trifluoromethyl)phenyl.
  • the compound is represented by:
  • the compound is selected from the group consisting of:
  • R 56 , R 57 , and R 58 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.
  • R 56 , R 57 , and R 58 are each independently hydrogen or lower alkyl.
  • the compound is selected from the group consisting of:
  • the present disclosure provides a compound of Formula (VII):
  • X is selected from O, S, substituted or unsubstituted —CH 2 —, —NR 65 —, —S(O) 2 —, and a bond;
  • Z is —SO 2 OH or —S(O)OH
  • R 61 , R 62 , R 63 , R 64 , and R 65 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.
  • R 61 and R 62 are each independently lower alkyl. In one embodiment, R 61 is ethyl. In one embodiment, R 62 is n-propyl. In one embodiment, R 63 is 3-(trifluoromethyl)phenyl.
  • the compound is represented by:
  • R 64 is hydrogen or lower alkyl.
  • the compound is selected from the group consisting of
  • the present disclosure provides a compound of Formula (VIII):
  • X is selected from S, substituted or unsubstituted —CH 2 —, —NR 75 —, and —S(O) 2 —; and R 71 , R 72 , R 73 , R 74 and R 75 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted acyl.
  • R 71 and R 72 are each independently lower alkyl. In one embodiment, R 71 is ethyl. In one embodiment, R 72 is n-propyl. In one embodiment, R 73 is 3-(trifluoromethyl)phenyl.
  • the compound is represented by:
  • R 74 is hydrogen or lower alkyl.
  • the compound is represented by:
  • R 1 , R 2 , and R 3 are each independently H, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl;
  • X is H, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R 1 is unsubstituted alkyl, preferably ethyl.
  • R 2 is unsubstituted alkyl, preferably propyl.
  • R 3 is substituted aryl, preferably 3-(trifluoromethyl)phenyl.
  • the compound can be a compound of Formula (2):
  • X is H, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • the prodrug is the compound of
  • the prodrug is the compound of
  • R 1 and R 2 are each independently amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R 1 , and R 2 are each independently amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • X is O, S, substituted or unsubstituted —CH 2 —, —NR′—, —S(O) 2 —, or a bond;
  • Z is O or S
  • R′ is hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R 1 , and R 2 are each independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • X is O, S, substituted or unsubstituted —CH 2 —, —NR′—, —S(O) 2 —, or a bond; and R and R′ are each independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R is hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R 1 , and R 2 are each independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R 1 , and R 2 are each independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R 1 , and R 2 are each independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R 1 , and R 2 are each independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R 1 is hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R 1 , R 2 , and R 3 are each independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R 1 , R 2 , and R 3 are each independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • X is O, S, substituted or unsubstituted —CH 2 —, —NR′—, —S(O) 2 —, or a bond; and R 1 , R 2 , and R′, are each independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • X is O, S, substituted or unsubstituted —CH 2 —, —NR′—, —S(O) 2 —, or a bond;
  • Z is O or S
  • R is hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R 1 , R 2 , and R 3 are each independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R is hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl; and n is any of 1-5.
  • X is O, S, substituted or unsubstituted —CH 2 —, —NR′—, or —S(O) 2 —; and R′ is hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • R 1 , R 2 , and R 3 are each independently hydrogen, amino, halo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted acyl.
  • Prodrugs of these A 2 B adenosine receptor antagonists can be designed and synthesized in a similar way to the prodrugs of the Compound 1 by substituting the xanthine at 7-position.
  • the compounds described herein are formulated into pharmaceutical compositions.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.
  • the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition.
  • Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action.
  • compositions incorporating a compound described herein may take any physical form that is pharmaceutically acceptable.
  • Pharmaceutical compositions for oral administration are particularly preferred.
  • such pharmaceutical compositions include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions are prepared, including, but not limited to, tablets, chewable tablets, capsules, and solutions.
  • Capsules may be prepared by mixing a compound described herein with a suitable diluent and filling the proper amount of the mixture in capsules.
  • Tablets may be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants, and disintegrators, as well as the compound described herein as an active therapeutic agent. A lubricant in a tablet formulation may help prevent the tablet and punches from sticking in the die. Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. Enteric formulations are often used to protect an active ingredient from the strongly acidic contents of the stomach and to delay disintegration and absorption in the gastrointestinal tract. Such formulations are created by coating a solid dosage form with a film of a polymer that is insoluble in acid environments, and soluble in basic environments. Tablets are often coated with sugar as a flavor and sealant.
  • Compound A can be synthesized according to the scheme below.
  • Step 1 O-(chloromethyl) S-ethyl carbonothioate, sodium iodide and 18-crown-6 are dissolved in toluene and heated to about 100° C. for about 5 hours to yield S-ethyl O-(iodomethyl) carbonothioate.
  • Step 2. n-Butyric acid and tetrabutyl ammonium bisulfate, sodium carbonate are added to a solution of chloro(chloromethoxy)methane in methylene chloride/water at room temperature and stirred overnight to afford solid (((ethylthio)carbonyl)oxy)methyl butyrate.
  • Step 3 O-(chloromethyl) S-ethyl carbonothioate, sodium iodide and 18-crown-6 are dissolved in toluene and heated to about 100° C. for about 5 hours to yield S-ethyl O-(iodomethyl) carbonothioate.
  • Step 2. n
  • Compound B can be synthesized according the scheme below.
  • Step 1 O-(chloromethyl)S-ethyl carbonothioate, sodium iodide, and 18-crown-6 are dissolved in toluene and heated to 100° C. for 5 hours to form S-ethyl O-(iodomethyl) carbonothioate.
  • Step 2. S-ethyl O-(iodomethyl) carbonothioate and dibenzyl hydrogen phosphate are reacted to form 0-(((bis(benzyloxy)phosphoryl)oxy)methyl)S-ethyl carbonothioate.
  • Step 3 O-(chloromethyl)S-ethyl carbonothioate, sodium iodide, and 18-crown-6 are dissolved in toluene and heated to 100° C. for 5 hours to form S-ethyl O-(iodomethyl) carbonothioate.
  • Step 2. S-ethyl O-(iodomethyl) carbonothioate and di
  • Compound D can be synthesized according to the scheme below.
  • Step 1 Chloro(chloromethoxy)methane and dibenzyl hydrogen phosphate is stirred in solution to afford dibenzyl ((chloromethoxy)methyl) phosphate.
  • Step 2. Sodium hydride is added to a DMF solution of dibenzyl ((chloromethoxy)methyl) phosphate and compound 1 at room temperature. The reaction is stirred for about 3 hours. Pd/C in DMSO is added and stirred under H 2 at room temperature for about 5 hours to afford Compound D.
  • Compound E was synthesized according to the steps below.
  • Compound E was synthesized according to the steps below.
  • Compound F was synthesized according to the steps below.
  • Compound G was synthesized according to the steps below.
  • Compound M was synthesized according to the steps below.
  • Compound P was synthesized according to the steps below.
  • Compound T was synthesized according to the steps below.
  • Concentrations of an administered compound and the corresponding metabolite (Compound 1) in rat plasma were determined by a HPLC tandem mass spectrometric (LC/MS/MS) method.
  • 200 ⁇ L of 5 ng/mL Terfenadine and Buspirone was added to in MeOH/Acetonitrile (1:1, v/v) and mixed well.
  • 5 ⁇ L of MeOH was added to all samples and vortexed for 1 min and centrifuged at 4000 rpm for 15 mins. The supernatant was diluted 3 ⁇ with water (with 0.1% FA) and injected for LC/MS/MS analysis.
  • Compound Compound of Formula (A) Compound 1 or (B) Matrix Plasma Plasma Standard Range 1-1000 ng/mL 10-10000 ng/mL Regression Linear Linear Weighting 1/(x * x) 1/(x * x) LLOQ 1 ng/mL 10 ng/mL Internal 5 ng/mL Terfenadine and 5 ng/mL Terfenadine and Standard Buspirone in MeOH/ Buspirone in MeOH/ Acetonitrile (1:1, v/v) Acetonitrile (1:1, v/v)
  • Quantification of compounds were achieved by mass spectrometry using Multiple Reaction Monitoring (MRM) mode, monitoring the transitions specific to each exemplary compound and 447.34>405.20 for Compound 1.
  • MRM Multiple Reaction Monitoring
  • the quantification limit of the assay was 10 ng/mL for Compound 1.
  • Non-compartmental pharmacokinetic parameters were determined using a commercial program WinNonLin Professional, Version 8.0 (Pharsight, Mountain View, Calif.). Plasma concentration at below level of detection was assumed to be Zero for the calculation of means and pharmacokinetic parameters.
  • t1/2 (hr), tmax (hr), Cmax (ng/mL), AUClast (hr*ng/mL), AUCInf (hr*ng/mL), AUC Extr (%), MRTInf (hr), Cmax Ratio (Parent/Pro), AUClast Ratio (Parent/Pro) were determined.
  • Table 3 describes exemplary AUC last data for representative compounds of Formula (A).
  • Table 4 describes exemplary AUC last data for representative compounds of Formula (B).
  • Table 5 describes exemplary AUC last data for Compound 1.
  • a sufficient amount of a compound described herein, or a pharmaceutically acceptable salt thereof is added to water (with optional solubilizer(s), optional buffer(s) and taste masking excipients) to provide a 0.1-20 mg/mL solution.
  • a tablet is prepared by mixing 20-50% by weight of a compound described herein, or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100-500 mg.
  • a pharmaceutical composition for oral delivery 10-500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend.
  • the mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.
  • 1-500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof is placed into Size 4 capsule, or size 1 capsule (hypromellose or hard gelatin) and the capsule is closed.

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