WO2009140464A1 - Methods of administration of thrombopoietin mimetic compounds - Google Patents

Methods of administration of thrombopoietin mimetic compounds Download PDF

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Publication number
WO2009140464A1
WO2009140464A1 PCT/US2009/043901 US2009043901W WO2009140464A1 WO 2009140464 A1 WO2009140464 A1 WO 2009140464A1 US 2009043901 W US2009043901 W US 2009043901W WO 2009140464 A1 WO2009140464 A1 WO 2009140464A1
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optionally substituted
hydrogen
ring
aliphatic
haloaliphatic
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PCT/US2009/043901
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French (fr)
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Gordon R. Loewen
Richard M. Matsumoto
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Ligand Pharmaceuticals, Inc.
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Publication of WO2009140464A1 publication Critical patent/WO2009140464A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol

Definitions

  • the present invention relates to compounds and methods in the fields of chemistry and medicine. More specifically, the present invention relates to compounds that modulate one or more thrombopoietin activity and/or bind to thrombopoietin receptors. Description of the Related Art
  • Thrombopoietin also referred to as c-Mpl ligand, mpl ligand, megapoietin, and megakaryocyte growth and development factor
  • TPO Thrombopoietin
  • c-Mpl ligand also referred to as c-Mpl ligand, mpl ligand, megapoietin, and megakaryocyte growth and development factor
  • TPO activity results from binding of TPO to the TPO receptor (also called MPL).
  • TPO receptor also called MPL.
  • the TPO receptor has been cloned and its amino acid sequence has been described. See e.g., Vigon et al., Proc. Natl. Acad. ScL, 89:5640-5644 (1992), which is incorporated herein by reference in its entirety.
  • TPO modulators may be useful in treating a variety of hematopoietic conditions, including, but not limited to, thrombocytopenia. See e.g., Baser et al. Blood 89:3118-3128 (1997); Fanucchi et al. New Engl. J. Med. 336:404-409 (1997), both of which are incorporated herein by reference in their entirety.
  • patients undergoing certain chemotherapies including but not limited to chemotherapy and/or radiation therapy for the treatment of cancer, may have reduced platelet levels.
  • treating such patients with a selective TPO modulator increases platelet levels.
  • selective TPO modulators stimulate production of glial cells, which may result in repair of damaged nerve cells.
  • an increase in platelet count to a therapeutically beneficial level in a subject occurs after a prolonged period of time during a treatment regimen.
  • the increase in platelet count to a therapeutically beneficial level in a subject using a maintenance dose of a TPO modulator may occur after a week of treatment.
  • One embodiment provides a method of treating thrombocytopenia in a subject in need thereof which comprises administering a TPO modulator, wherein the amount of TPO modulator administered in a single dose is sufficient to increase platelet production.
  • One embodiment provides a method of treating thrombocytopenia in a subject in need thereof which comprises administering a TPO modulator, wherein the amount of TPO modulator administered in a single dose is sufficient to achieve steady state concentration levels for said treatment.
  • One embodiment provides a method of treating neutropenia in a subject in need thereof which comprises administering a TPO modulator, wherein the amount of TPO modulator administered in a single dose is sufficient to increase platelet production.
  • One embodiment provides a method of treating neutropenia in a subject in need thereof which comprises administering a TPO modulator wherein the amount of TPO modulator administered in a single dose is sufficient to achieve steady state concentration levels for said treatment.
  • One embodiment provides a method of increasing platelet production in a subject comprising: administering a TPO modulator in a single dose sufficient to achieve steady state concentration levels.
  • One embodiment provides a method for enhancing the number of peripheral blood stem cells obtained from a donor comprising administering to said donor a TPO modulator in a single dose sufficient to enhance the number of peripheral blood stem cells prior to leukapheresis.
  • FIG. 1 is a graph showing the % change from baseline in platelet counts after treatment with a single dose of compound 1.
  • the single dose of 40 mg, 60 mg, 90 mg and 120 mg is compared to placebo.
  • FIG. 2 is a graph showing the maximum % change from baseline in platelet counts after treatment with a single dose of compound 1.
  • FIG. 3 is a graph showing the % change from baseline in platelet counts. The treatment period is for 14 days and the daily dosage of 5 mg, 7.5 mg and 10 mg is compared to placebo.
  • FIG. 4 is a graph showing the % change from baseline in platelet counts after treatment with or without a loading dose of compound 1.
  • the treatment period is for 14 days and the daily dosage of 7.5 mg, and a daily dosage of 7.5 mg with a 45 mg loading dose is compared to placebo.
  • FIG. 5 is a graph showing the maximum % change from baseline in platelet counts using different treatment methods. The subjects were treated with and without loading doses of compound 1.
  • FIG. 6 is a graph showing the % change from baseline in platelet counts after treatment with 10 mg quantity daily of compound 1 or after treatment with 7.5 mg quantity daily of compound 1 with a 45 mg loading dose as compared to placebo. The treatment period is for 14 days.
  • Standard chemical symbols are used interchangeably with the full names represented by such symbols. Thus, for example, the terms "hydrogen” and “H” are understood to have identical meaning.
  • Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection).
  • Reactions and purification techniques may be performed e.g., using kits according to manufacturer's specifications or as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), which is incorporated herein by reference in its entirety for any purpose.
  • selective binding compound refers to a compound that selectively binds to any portion of one or more target.
  • selective TPO receptor binding compound refers to a compound that selectively binds to any portion of a TPO receptor.
  • selective binding refers to the ability of a selective binding compound to bind to a target receptor with greater affinity than it binds to a non-target receptor.
  • selective binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, or 1000 times greater than the affinity for a non-target.
  • target receptor refers to a receptor or a portion of a receptor capable of being bound by a selective binding compound.
  • a target receptor is a TPO receptor.
  • modulator refers to a compound that alters an activity.
  • a modulator may cause an increase or decrease in the magnitude of a certain activity compared to the magnitude of the activity in the absence of the modulator.
  • a modulator is an inhibitor, which decreases the magnitude of one or more activities.
  • an inhibitor completely prevents one or more biological activities.
  • a modulator is an activator, which increases the magnitude of at least one activity.
  • the presence of a modulator results in a activity that does not occur in the absence of the modulator.
  • selective modulator refers to a compound that selectively modulates a target activity.
  • TPO modulator refers to a compound or drug that modulates at least one TPO activity.
  • TPO modulator includes, but is not limited to "TPO mimic” which refers to a compound, the presence of which results in at least one TPO activity.
  • a pharmaceutical agent refers to a chemical compound or composition capable of inducing a desired therapeutic effect in a subject.
  • a pharmaceutical agent comprises an active agent, which is the agent that induces the desired therapeutic effect.
  • a pharmaceutical agent comprises a prodrug.
  • a pharmaceutical agent comprises inactive ingredients such as carriers, excipients, and the like.
  • selective modulates refers to the ability of a selective modulator to modulate a target activity to a greater extent than it modulates a non-target activity.
  • target activity refers to a biological activity capable of being modulated by a selective modulator.
  • Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, the proliferation and/or differentiation of progenitor cells, generation of platelets, and alleviation of symptoms of a disease or condition.
  • TPO activity refers to a biological activity that results, either directly or indirectly from the presence of TPO.
  • Exemplary TPO activities include, but are not limited to, proliferation and or differentiation of progenitor cells to produce platelets; hematopoiesis; growth and/or development of glial cells; repair of nerve cells; and alleviation of thrombocytopenia.
  • thrombocytopenia refers to a condition wherein the concentration of platelets in the blood of a patient is below what is considered normal for a healthy patient.
  • thrombocytopenia is a platelet count less than 450,000, 400,000, 350,000, 300,000, 250,000, 200,000, 150,000, 140,000, 130,000, 120,000, 110,000, 100,000, 75,000, or 50,000 platelets per microliter of blood.
  • receptor mediated activity refers to any biological activity that results, either directly or indirectly, from binding of a ligand to a receptor.
  • agonist refers to a compound, the presence of which results in a biological activity of a receptor that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the receptor.
  • partial agonist refers to a compound the presence of which results in a biological activity of a receptor that is of the same type as that resulting from the presence of a naturally occurring ligand for the receptor, but of a lower magnitude.
  • antagonist refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of a receptor. In certain embodiments, the presence of an antagonist results in complete inhibition of a biological activity of a receptor.
  • subject means a human or other animal, such as farm animals or laboratory animals (e.g., guinea pig or mice) in which it is desired to increase platelets in the blood.
  • farm animals e.g., guinea pig or mice
  • the term "loading dose” as used herein will be understood to mean a single dose or short duration regimen of a drug having a dosage higher than the maintenance dose administered to the subject to rapidly increase the blood concentration level of the drug.
  • the "loading dose” can increase the blood concentration of the drug to a therapeutically effective level.
  • the "loading dose” can increase the blood concentration of the drug to a therapeutically effective level in conjunction with a maintenance dose of the drug.
  • maintenance dose as used herein will be understood to mean a dose that is serially administered (i.e., at least twice), and which is intended to either slowly raise blood concentration levels of the compound to a therapeutically effective level, or to maintain such a therapeutically effective level.
  • the maintenance dose may be administered once per day, once over a period of days (e.g., up to 30 days), or more than once per day (e.g., up to 4 times per day).
  • carrier refers to a compound that facilitates the incorporation of another compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • terapéuticaally effective amount refers to an amount of a TPO modulator sufficient to achieve a desired therapeutic effect.
  • prodrug refers to an TPO modulator that is converted from a less active form into a corresponding more active form in vivo.
  • pharmaceutically acceptable refers to a formulation of a compound that does not significantly abrogate the biological activity, a pharmacological activity and/or other properties of the compound when the formulated compound is administered to a patient. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a patient.
  • co-administer refers to administering more than one TPO modulator to a patient.
  • co-administered TPO modulators are administered together in a single dosage unit.
  • co-administered TPO modulators are administered separately.
  • co-administered TPO modulators are administered at the same time.
  • coadministered TPO modulators are administered at different times.
  • alkyl refers to an aliphatic hydrocarbon group.
  • An alkyl may be a "saturated alkyl,” which means that it does not contain any alkene or alkyne groups.
  • An alkyl group may be an "unsaturated alkyl,” which means that it comprises at least one alkene or alkyne group.
  • An alkyl, whether saturated or unsaturated, may be branched or straight chain.
  • Alkyls may be cyclic or non-cyclic. Cyclic alkyls may include multicyclic systems including fused alkyl rings. Alkyls may be substituted or unsubstituted.
  • Alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, each of which may be optionally substituted.
  • an alkyl comprises 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the term "alkyl” also includes instances where no numerical range of carbon atoms is designated).
  • lower alkyl refers to an alkyl comprising 1 to 5 carbon atoms.
  • intermediate alkyl refers to an alkyl comprising 5 to 10 carbon atoms.
  • An alkyl may be designated as "C1-C4 alkyl” or similar designations.
  • C 1 -C 4 alkyl indicates an alkyl having one, two, three, or four carbon atoms, e.g., the alkyl is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t- butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl.
  • alkenyl refers to an alkyl group comprising at least one carbon-carbon double bond.
  • alkynyl refers to an alkyl group comprising at least one carbon-carbon triple bond.
  • haloalkyl refers to an alkyl in which at least one hydrogen atom is replaced with a halogen atom. In certain of the embodiments in which two or more hydrogen atom are replaced with halogen atoms, the halogen atoms are all the same as one another. In certain of such embodiments, the halogen atoms are not all the same as one another.
  • straight-chain alkoxy refers to a group comprising the formula: -(CH 2 ) P O- wherein p is any integer. Straight-chain alkoxy does not include substituted or branched alkoxy groups.
  • non-straight-chain-alkoxy-heteroalkyl refers to any heteroalkyl that is not a straight-chain alkoxy heteroalkyl.
  • non-straight-chain-alkoxy heteroalkyls include, but are not limited to: 2,2-isopropyloxy; 1 ,2-propyloxy; 1,1-ethyloxy; methylamino; ethylamino; propylamino; methylpyrrolidino; and methylpiperidino .
  • heterohaloalkyl refers to a heteroalkyl in which at least one hydrogen atom is replaced with a halogen atom.
  • Carbocycle refers to a group comprising a covalently closed ring, wherein each of the atoms forming the ring is a carbon atom.
  • Carbocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycles may be optionally substituted.
  • heterocycle refers to a group comprising a covalently closed ring wherein at least one atom forming the ring is a heteroatom.
  • Heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Any number of those atoms may be heteroatoms (i.e., a heterocyclic ring may comprise one, two, three, four, five, six, seven, eight, nine, or more than nine heteroatoms). In heterocyclic rings comprising two or more heteroatoms, those two or more heteroatoms may be the same or different from one another. Heterocycles may be optionally substituted.
  • Binding to a heterocycle can be at a heteroatom or via a carbon atom.
  • binding for benzo- fused derivatives may be via a carbon of the benzenoid ring.
  • heterocycles include, but are not limited to the following:
  • D, E, F, and G independently represent a heteroatom.
  • Each of D, E, F, and G may be the same or different from one another.
  • heteroatom refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from oxygen, sulfur, nitrogen, and phosphorus, but are not limited to those atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may all be the same as one another, or some or all of the two or more heteroatoms may each be different from the others.
  • aromatic refers to a group comprising a covalently closed ring having a delocalized ⁇ -electron system.
  • Aromatic rings may be formed by five, six, seven, eight, nine, or more than nine atoms.
  • Aromatics may be optionally substituted. Examples of aromatic groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.
  • aromatic includes, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from an aryl, a heteroaryl, a cycloalkyl, a non-aromatic heterocycle, a halo, a hydroxy, an amino, a cyano, a nitro, an alkylamido, an acyl, a Ci_6 alkoxy, a Ci_6 alkyl, a Ci_6 hydroxyalkyl, a Ci_6 aminoalkyl, a Ci_ 6 alkylamino, an alkylsulfenyl, an alkylsulfinyl, an alkylsulfonyl, an sulfamoyl, or a trifluoromethyl.
  • an aromatic group is substituted at one or more of the para, meta, and/or ortho positions.
  • aromatic groups comprising substitutions include, but are not limited to, phenyl, 3-halophenyl, 4-halophenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylphenyl, A- methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 3- cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4-morpholin-4-ylphenyl, A- pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin-l- yl
  • aryl refers to an aromatic group wherein each of the atoms forming the ring is a carbon atom.
  • Aryl rings may be formed by five, six, seven, eight, nine, or more than nine carbon atoms.
  • Aryl groups may be optionally substituted.
  • heteroaryl refers to an aromatic group wherein at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heteroaryl groups may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3_8 heterocyclic groups comprising one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms.
  • heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci_6-alkoxy, Ci_6-alkyl, C 1-6 - hydroxyalkyl, Ci_ 6 -aminoalkyl, Ci_ 6 -alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl.
  • substituents independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci_6-alkoxy, Ci_6-alkyl, C 1-6 - hydroxyalkyl, Ci_ 6 -aminoalkyl, Ci_ 6 -alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfony
  • heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazin
  • the substituents are halo, hydroxy, cyano, O-Ci_6- alkyl, Ci_ 6 -alkyl, hydroxy-Ci_ 6 -alkyl, and amino-Ci_ 6 -alkyl.
  • non-aromatic ring refers to a group comprising a covalently closed ring that does not have a delocalized ⁇ -electron system.
  • cycloalkyl refers to a group comprising a non-aromatic ring wherein each of the atoms forming the ring is a carbon atom. Cycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Cycloalkyls may include multicyclic systems (e.g., fused ring systems). Cycloalkyls may be optionally substituted. In certain embodiments, a cycloalkyl comprises one or more unsaturated bonds.
  • cycloalkyls include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3- cyclohexadiene, 1 ,4-cyclohexadiene, cycloheptane, and cycloheptene.
  • non-aromatic heterocycle refers to a group comprising a non-aromatic ring wherein one or more atoms forming the ring is a heteroatom.
  • Non- aromatic heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms.
  • Non-aromatic heterocycles may be optionally substituted.
  • non-aromatic heterocycles comprise one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups.
  • non-aromatic heterocycles include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1 ,4-dioxane, piperazine, 1,3-oxathiane, 1,4- oxathiin, 1,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-l,3,5-triazine, tetrahydro
  • arylalkyl refers to a group comprising an aryl group bound to an alkyl group.
  • Carbocycloalkyl refers to a group comprising a carbocyclic cycloalkyl ring. Carbocycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycloalkyl groups may be optionally substituted.
  • Rings refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g., aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings may be optionally substituted. Rings may form part of a ring system.
  • carbocycles e.g., aryls and cycloalkyls
  • heterocycles e.g., heteroaryls and non-aromatic heterocycles
  • aromatics e.g., aryls and heteroaryls
  • non-aromatics e.g., cycloalkyls and non-aromatic heterocycles
  • Rings may be optionally substituted. Rings may form part of a ring system.
  • ring system refers to a either a single ring or two or more rings, wherein, if two or more rings are present, the two or more of the rings are fused.
  • fused refers to structures in which two or more rings share one or more bonds.
  • carboxylic acid bioisostere refers to a group that is biologically equivalent to a carboxylic acid.
  • carboxylic acid bioisosteres include, but are not limited to, tetrazole, NHSO 2 R 15 , OC(S)NR 10 R 11 , SC(O)NR 10 R 11 , thiazolidinedione, oxazolidinedione, and l-oxa-2,4-diazolidine-3,5-dione.
  • a carboxylic acid bioisostere comprises the following structure:
  • A, B, and C are each independently selected from O, S, and NH.
  • spacer refers to an atom or group of atoms that separate two or more groups from one another by a desired number of atoms. For example, in certain embodiments, it may be desirable to separate two or more groups by one, two, three, four, five, six, or more than six atoms. In such embodiments, any atom or group of atoms may be used to separate those groups by the desired number of atoms. Spacers are optionally substituted. In certain embodiments, a spacer comprises saturated or unsaturated alkyls, heteroalkyls and/or haloalkyls. In certain embodiments, a spacer comprises atoms that are part of a ring.
  • spacers are provided.
  • 1 atom spacers include, but are not limited to, the following:
  • Examples of 2 atom spacers include, but are not limited to, the following:
  • Ai and Bi represent groups which are separated by the desired number of atoms.
  • 3 atom spacers include, but are not limited to, the following:
  • Ai and Bi represent groups which are separated by the desired number of atoms.
  • the atoms that create the desired separation may themselves be part of a group. That group may be, for example, an alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, or substituted alkyl all of which are optionally substituted.
  • 1-5 atom spacer refers to a spacer that separates two groups by 1, 2, 3, 4, or 5 atoms and does not indicate the total size of the group that constitutes the spacer.
  • the term "linked to form a ring” refers to instances where two atoms that are bound either to a single atom or to atoms that are themselves ultimately bound, are each bound to a linking group, such that the resulting structure forms a ring. That resulting ring comprises the two atoms that are linked to form a ring, the atom (or atoms) that previously linked those atoms, and the linker. For example, if Ai and Bi below are "linked to form a ring" the resulting ring includes Ai, Bi, Ci, and a linking group. Unless otherwise indicated, that linking group may be of any length and may be optionally substituted. Referring to the above example, resulting structures include, but are not limited to: A 1 B 1 like.
  • the two substituents that together form a ring are not immediately bound to the same atom.
  • the resulting ring comprises Ai, Bi, the two atoms that already link Ai and Bi and a linking group.
  • Examples of resulting structures include, but are not limited to:
  • the atoms that together form a ring are separated by three or more atoms.
  • the resulting ring comprises Ai, Bi, the 3 atoms that already link Ai and Bi, and a linking group.
  • Examples of resulting structures include, but are not limited to:
  • nuclear refers to a group being absent from a structure.
  • R refers to a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon).
  • cyano refers to a group of formula -CN.
  • isocyanato refers to a group of formula -NCO.
  • thiocyanato refers to a group of formula -CNS.
  • isothiocyanato refers to a group of formula -NCS.
  • dihydropyrazolylene refers to a di-radical of an optionally substituted dihydropyrazole ring, wherein the dihydropyrazole ring has the structure:
  • pyrazolyl refers to a radical of a pyrzole ring, wherein the pyrzole ring has the structure:
  • radical may be at any position on the ring.
  • esters refers to a chemical moiety with formula -(R) n -COOR', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon), where n is 0 or 1.
  • amide refers to a chemical moiety with formula -(R) n -C(O)NHR' or -(R) n -NHC(O)R', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), where n is 0 or 1.
  • R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), where n is 0 or 1.
  • an amide may be an amino acid or a peptide.
  • amine include such groups that have been esterif ⁇ ed or amidif ⁇ ed. Procedures and specific groups used to achieve esterif ⁇ cation and amidification are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.
  • the term "optionally substituted,” refers to a group in which none, one, or more than one of the hydrogen atoms has been replaced with one or more group(s) individually and independently selected from: alkyl, heteroalkyl, haloalkyl, heteroholoalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, isothiocyanato, is
  • substantially pure means an object species (e.g., compound) is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition).
  • a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all species present.
  • a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all species present in the composition.
  • the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single species.
  • tissue-selective refers to the ability of a compound to modulate a biological activity in one tissue to a greater or lesser degree than it modulates a biological activity in another tissue.
  • the biological activities in the different tissues may be the same or they may be different.
  • the biological activities in the different tissues may be mediated by the same type of target receptor.
  • a tissue-selective compound may modulate receptor mediated biological activity in one tissue and fail to modulate, or modulate to a lesser degree, receptor mediated biological activity in another tissue type.
  • the term "monitoring” refers to observing an effect or absence of any effect. In certain embodiments, one monitors cells after contacting those cells with a compound of the present invention. Examples of effects that may be monitored include, but are not limited to, changes in cell phenotype, cell proliferation, receptor activity, or the interaction between a receptor and a compound known to bind to the receptor.
  • cell phenotype refers to physical or biological characteristics. Examples of characteristics that constitute phenotype included, but are not limited to, cell size, cell proliferation, cell differentiation, cell survival, apoptosis (cell death), or the utilization of a metabolic nutrient (e.g., glucose uptake). Certain changes or the absence of changes in cell phenotype are readily monitored using techniques known in the art.
  • cell proliferation refers to the rate at which cells divide.
  • cells are in situ in an organism.
  • cell are grown in vitro in a vessel.
  • the number of cells growing in a vessel can be quantified by a person skilled in the art (e.g. , by counting cells in a defined area using a microscope or by using laboratory apparatus that measure the density of cells in an appropriate medium).
  • One skilled in that art can calculate cell proliferation by determining the number of cells at two or more times.
  • contacting refers to bringing two or more materials into close enough proximity that they may interact. In certain embodiments, contacting can be accomplished in a vessel such as a test tube, a petri dish, or the like. In certain embodiments, contacting may be performed in the presence of additional materials. In certain embodiments, contacting may be performed in the presence of cells. In certain of such embodiments, one or more of the materials that are being contacted may be inside a cell. Cells may be alive or may dead. Cells may or may not be intact.
  • the term "cohort” as used herein will be understood to mean a group of people who share a common characteristic. Thus a group of people who were born on a day or in a particular period, say 1948, form a birth cohort.
  • the comparison group may be the general population from which the cohort is drawn, or it may be another cohort of persons thought to have had little or no exposure to the substance under investigation, but otherwise similar.
  • Certain compounds that modulate one or more TPO activity and/or bind to TPO receptors play a role in health.
  • compounds of the present invention are useful for treating any of a variety of diseases or conditions.
  • the present invention provides selective TPO modulators.
  • the invention provides selective TPO receptor binding agents.
  • the invention provides methods of making and methods of using selective TPO modulators and/or selective TPO receptor binding agents.
  • selective TPO modulators are agonists, partial agonists, and/or antagonists for the TPO receptor.
  • the present invention provides TPO modulators having the structure of Formula I, II, III, IV, V, or VI:
  • R 1 is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NR 14 R 15 , an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere;
  • each R 2 is independently selected from hydrogen, halogen, OR 14 , NR 14 R 15 , an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R 3 and R 4 are independently selected from hydrogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R 5 is selected from hydrogen, halogen, OR 14 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 haloheteroalkyl;
  • R 7 is selected from CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere;
  • each R 8 and each R 9 is independently selected from hydrogen, OR 16 ,
  • NR 16 R 17 an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, (CH 2 ) m R 18 , and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -Cg ring;
  • R 10 is selected from hydrogen, halogen, oxo, OR 16 , NR 16 R 17 , SR 16 , an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R 11 is selected from hydrogen, halogen, OR 14 , NR 14 R 15 , and SR 14 ; or R 11 and R 4 are linked to form a optionally substituted heterocycle;
  • R 12 is selected from hydrogen, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 haloheteroalkyl;
  • R 13 is selected from hydrogen, halogen, CN, NO 2 , CO 2 R 14 , S(O) 1n R 14 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, Ci-C 4 heteroalkyl, and Ci-C 4 haloheteroalkyl;
  • R 14 is selected from hydrogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 heterohaloalkyl;
  • R 15 is selected from hydrogen, SO 2 R 19 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 heterohaloalkyl;
  • R 16 and R 17 are each independently selected from hydrogen, an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, and (CH 2 ) m R 18 ; or one of R 16 and R 17 is an optionally substituted C 2 -C 6 alkyl and the other of R 16 and R 17 is null; or R 16 and R 17 are linked to form an optionally substituted C 3 -Cg ring;
  • R 18 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R 18 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system;
  • R 19 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, and an optionally substituted aryl;
  • D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • L is NH or null
  • Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
  • U is selected from O, NR 4 , CR 3 R 4 , CO, and null;
  • W is selected from O, NR 4 , CR 3 R 4 , CO, and null;
  • X is N or CR 5 ;
  • Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl;
  • Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6 -CiO aryl and an optionally substituted Ci-Cs heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 heteroalkyl, and an optionally substituted Ci-C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -CiO aryl;
  • m is 0, 1, 2, or 3;
  • n is O or l
  • TPO modulators having the structure of Formula X:
  • R ld is selected from CO 2 R 10d , CONR 10d R lld , SO 3 R 10d , and a carboxylic acid bioisostere;
  • R 2d and R 3d are each independently selected from null, hydrogen, OR 12d , NR 12d R 13d , an optionally substituted Ci-C 4 aliphatic, an optionally substituted C 1 - C 4 haloaliphatic, an optionally substituted Ci-C 4 heteroaliphatic, an optionally substituted ring, and (CH 2 ) md R 14d ; or R 2d and R 3d taken together form an optionally substituted olefin; or R 2 and R 3 are linked to form an optionally substituted C 3 -Cs ring;
  • R 4d is selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), Ci-C 4 aliphatic, Ci-C 4 haloaliphatic, Ci-C 4 heteroaliphatic, and a ring;
  • R 5d is selected from hydrogen, OR 10d , SR 1Od , NHR lld , and CO 2 H;
  • R 6d is selected from hydrogen, OR 12d , NR 12d R 13d , fluorine (F), chlorine (Cl), bromine (Br), Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 heteroalkyl, and a ring;
  • R 7d is selected from hydrogen, an optionally substituted Ci-Cs aliphatic, an optionally substituted Ci-Cs haloaliphatic, an optionally substituted Ci-Cs heteroaliphatic, an optionally substituted Ci-Cs heterohaloaliphatic, an optionally substituted ring, and (CH 2 ) md R 14d ;
  • R 1Od is selected from hydrogen, an optionally substituted Ci-C 4 aliphatic, Ci-C 4 haloaliphatic, Ci-C 4 heteroaliphatic, and a ring;
  • R lld is selected from hydrogen, SO 2 R 15d , Ci-C 4 aliphatic, Ci-C 4 haloaliphatic, Ci-C 4 heteroaliphatic, and a ring;
  • R 12d and R 13d are each independently selected from hydrogen, an optionally substituted Ci-C 4 aliphatic, an optionally substituted Ci-C 4 haloaliphatic, an optionally substituted Ci-C 4 heteroaliphatic, an optionally substituted ring, and (CH 2 ) m R 14d ; or one of R 12d and R 13d is an optionally substituted C 2 -C 6 aliphatic or an optionally substituted ring and the other of R 12d and R ld3 is null; or R 12d and R ld3 are linked to form an optionally substituted C 3 -Cs ring;
  • R 14d is selected from an optionally substituted aryl and an optionally substituted heteroaryl
  • R 15d is selected from hydrogen, Ci-C 3 aliphatic, Ci-C 3 haloaliphatic, and a ring;
  • Yd is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted Ci-C 6 aliphatic, an optionally substituted Ci-C 6 heteroaliphatic, an optionally substituted phenyl, an optionally substituted heteroaryl, an optionally substituted C 3 -Cs heterocycle, and an optionally substituted alicyclic;
  • Zd is selected from: a 2-5 atom spacer selected from an optionally substituted C 6 -CiO aryl and an optionally substituted Ci-Cg heteroaryl, and a 1-5 atom spacer of selected from an optionally substituted Ci-C 6 aliphatic, an optionally substituted Ci-C 6 heteroaliphatic, and an optionally substituted Ci-C 6 haloaliphatic;
  • TPO modulators having the structure of Formula
  • R le is selected from CO 2 R 10e , CONR 10e R lle , SO 3 R 10e , and a carboxylic acid bioisostere;
  • R 2e and R 3e are each independently selected from null, hydrogen, OR 12e , NR 12e R 13e , an optionally substituted C 1 -C 4 aliphatic, an optionally substituted Ci-C 4 haloaliphatic, an optionally substituted Ci-C 4 heteroaliphatic, an optionally substituted ring, and (CH 2 ) m R 14e ; or R 2e and R 3e taken together form an optionally substituted olefin; or R 2e and R 3e are linked to form an optionally substituted C 3 -Cg ring;
  • R 4e is selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), Ci-C 4 aliphatic, Ci-C 4 haloaliphatic, Ci-C 4 heteroaliphatic, and a ring;
  • R 5e is selected from hydrogen, OR 10e , SR 1Oe , NHR lle , and CO 2 H;
  • R 7e is selected from hydrogen, an optionally substituted Ci-C 8 aliphatic, an optionally substituted Ci-Cg haloaliphatic, an optionally substituted Ci-Cg heteroaliphatic, an optionally substituted Ci-Cg heterohaloaliphatic, an optionally substituted ring, and (CH 2 ) H16 R 146 ;
  • R 1Oe is selected from hydrogen, an optionally substituted C1-C4 aliphatic, Ci-C 4 haloaliphatic, Ci-C 4 heteroaliphatic, and a ring;
  • R lle is selected from hydrogen, SO 2 R 15e , Ci-C 4 aliphatic, Ci-C 4 haloaliphatic, Ci-C 4 heteroaliphatic, and a ring;
  • R 12e and R 13e are each independently selected from hydrogen, an optionally substituted Ci-C 4 aliphatic, an optionally substituted Ci-C 4 haloaliphatic, an optionally substituted Ci-C 4 heteroaliphatic, an optionally substituted ring, and (CH 2 ) J116 R 146 ; or one of R 12e and R 13e is an optionally substituted C 2 -C 6 aliphatic or an optionally substituted ring and the other of R 12e and R 13e is null; or R 12e and R 13e are linked to form an optionally substituted C 3 -C 8 ring;
  • R 14e is selected from an optionally substituted aryl and an optionally substituted heteroaryl
  • R 6e is selected from hydrogen, OR 12e , NR 12e R 13e , fluorine (F), chlorine (Cl), bromine (Br), Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 heteroalkyl, and a ring;
  • R 8e and R 9e are each independently selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), CO 2 R 10e , NO 2 , CN, SO 2 R 10e , (CH 2 ) ⁇ R 146 , Ci-C 4 aliphatic, Ci-C 4 haloaliphatic, Ci-C 4 heteroaliphatic, Ci-C 4 heterohaloaliphatic, and a ring;
  • X e is selected from O, S, NR 1Oe , and CR 1Oe R 1Oe ;
  • Q e is selected from O and S;
  • Z e is selected from: a 2-5 atom spacer selected from an optionally substituted C 6 -CiO aryl and an optionally substituted Ci-Cg heteroaryl, and a 1-5 atom spacer of selected from an optionally substituted Ci-C 6 aliphatic, an optionally substituted Ci-C 6 heteroaliphatic, and an optionally substituted Ci-C 6 haloaliphatic;
  • TPO modulators having the structure of Formula
  • R lf is selected from CO 2 R 10f , CONR 10f R llf , SO 3 R 10f , and a carboxylic acid bioisostere;
  • R 2f and R 3f are each independently selected from null, hydrogen, OR 12f , NR 12f R 13f , an optionally substituted C1-C4 aliphatic, an optionally substituted Ci-C 4 haloaliphatic, an optionally substituted Ci-C 4 heteroaliphatic, an optionally substituted ring, and (CH 2 ) mf R 14f ; or R 2f and R 3f taken together form an optionally substituted olefin; or R 2f and R 3f are linked to form an optionally substituted C 3 -Cs ring;
  • R 4f is selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), Ci-C 4 aliphatic, Ci-C 4 haloaliphatic, Ci-C 4 heteroaliphatic, and a ring;
  • R 5f is selected from hydrogen, OR 10f , SR 10f , NHR llf , and CO 2 H;
  • R 6f is selected from hydrogen, OR 12f , NR 12f R 13f , fluorine (F), chlorine (Cl), bromine (Br), C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 heteroalkyl;
  • R 7f is selected from hydrogen, an optionally substituted Ci-C 8 aliphatic, an optionally substituted Ci-Cg haloaliphatic, an optionally substituted Ci-Cg heteroaliphatic, an optionally substituted Ci-Cg heterohaloaliphatic, an optionally substituted ring, and (CH 2 ) mf R 14f ;
  • R 8f and R 9f are each independently selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), CO 2 R 10f , NO 2 , CN, SO 2 R 10f , (CH 2 ) mf R 14f , Ci-C 4 aliphatic, C 1 - C 4 haloaliphatic, Ci-C 4 heteroaliphatic, and Ci-C 4 heterohaloaliphatic;
  • R 10f is selected from hydrogen, an optionally substituted Ci-C 4 aliphatic, Ci-C 4 haloaliphatic, Ci-C 4 heteroaliphatic, and a ring;
  • R llf is selected from hydrogen, SO 2 R 15f , Ci-C 4 aliphatic, Ci-C 4 haloaliphatic, Ci-C 4 heteroaliphatic, and a ring;
  • R 12f and R 13f are each independently selected from hydrogen, an optionally substituted Ci-C 4 aliphatic, an optionally substituted Ci-C 4 haloaliphatic, an optionally substituted Ci-C 4 heteroaliphatic, an optionally substituted ring, and (CH 2 ) mf R lf4 ; or one of R 12f and R 13f is an optionally substituted C 2 -C 6 aliphatic or an optionally substituted ring and the other of R 12f and R 13f is null; or R 12f and R 13f are linked to form an optionally substituted C 3 -C 8 ring;
  • R 14f is selected from an optionally substituted aryl and an optionally substituted heteroaryl
  • R 15f is selected from hydrogen, Ci-C 3 aliphatic, Ci-C 3 haloaliphatic, and a ring;
  • mf is O, 1, or 2;
  • nf is O or l.
  • a TPO modulator of Formula XII can have the structure:
  • Compound 1 can be synthesized according to the methods disclosed in U.S. Pat. No. 7,314, 887, incorporated herein in its entirety.
  • TPO modulators having the structure of Formula XIII:
  • R a is selected from the group consisting of hydrogen, Ci_ 6 alkyl, - (CH 2 ) p OR 4a , -C(O)OR 4a , formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, -S(O) n R 4a , cycloalkyl, -NR 5a R 6a , protected -OH, -CONR 5a R 6a , phosphonic acid, sulfonic acid, phosphinic acid, -SO2NR 5a R 6a , a heterocyclic methylene substituent as represented by Formula (XIII-A),
  • n 0-2
  • Wa and Z a are each independently selected from C, O, S and NR 16a , where R 16a is selected from: hydrogen, alkyl, cycloalkyl, d-Ci 2 aryl, substituted alkyl, substituted cycloalkyl and substituted Ci-Ci2aryl,
  • Va and X a are each independently selected from O, S and NR 16a , where R 16a is selected from: hydrogen, alkyl, cycloalkyl, d-Ci 2 aryl, substituted alkyl, substituted cycloalkyl and substituted Ci-Ci 2 aryl,
  • R 4a is selected from: hydrogen, alkyl, cycloalkyl, Ci-Ci 2 aryl, substituted alkyl, substituted cycloalkyl and substituted d-Ci 2 aryl,
  • R 5a and R 6a are each independently selected from hydrogen, alkyl, substituted alkyl, C 3 _ 6 cycloalkyl, and aryl,
  • T a is absent or selected from O, S and NR 16a , where R 16a is selected from: hydrogen, alkyl, cycloalkyl, Ci-C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted
  • Pa is selected from OR 4a , SR 4a , NR 5a R 6a , and R 4a ,
  • R 25a is selected from: hydrogen, alkyl, cycloalkyl, Ci-C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted and
  • R 30a is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 MyI, substituted alkyl, substituted cycloalkyl and substituted Ci-Ci2aryl,
  • n aa is 0 or l
  • R laa is selected from CO 2 R 10 ", CONR 10b R llb , SO 3 R 10b , and a carboxylic acid bioisostere;
  • R 1Ob is selected from hydrogen, an optionally substituted Ci-C 4 alkyl, an optionally substituted Ci-C 4 haloalkyl, and an optionally substituted Ci-C 4 heteroalkyl,
  • R llb is selected from hydrogen, SO 2 R 15b , an optionally substituted C 1 - C 4 alkyl, an optionally substituted Ci-C 4 haloalkyl, and an optionally substituted Ci-C 4 heteroalkyl,
  • R 12b and R 13b are each independently selected from hydrogen, an optionally substituted Ci-C 4 alkyl, an optionally substituted Ci-C 4 haloalkyl, an optionally substituted Ci-C 4 heteroalkyl, and (CH 2 ) m R 14b ; or R 12b and R 13b are linked to form an optionally substituted C 3 -Cs ring,
  • R 14b is selected from an optionally substituted C 6 -CiO aryl and an optionally substituted C 3 -Ci O heteroaryl,
  • R 15b is selected from hydrogen, an optionally substituted Ci-C 3 alkyl, an optionally substituted Ci-C 3 haloalkyl, and an optionally substituted C 6 -CiO aryl,
  • m is 0-6,
  • Zb is selected from: a 2-5 atom spacer selected from an optionally substituted C 6 -CiO aryl and an optionally substituted C3-C10 heteroaryl, and a 1-5 atom spacer selected from an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 heteroalkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 heteroalkenyl, an optionally substituted C 2 -C 6 haloalkenyl, an optionally substituted C 2 -C 6 alkynyl, and an optionally substituted C 2 -C 6 heteroalkyl;
  • R la , R 2a and R 3a are each independently selected from hydrogen, C 1 . 6 alkyl, -(CH 2 ) p OR 4a , -C(O)OR 4a , formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, -S(O) n R 4a , cycloalkyl, -NR 5a R 6a , protected -OH, -CONR 5a R 6a , phosphonic acid, sulfonic acid, phosphinic acid, -SO 2 NR 5a R 6a , a heterocyclic methylene substituent as represented by Formula (XIII-A), and a substituent as represented by Formula (XIII-B),
  • n is 0-2;
  • Y is a cyclic or polycyclic, unsaturated or saturated, non-aromatic ring containing from 3 to 16 carbon atoms and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N- acylamino, nitro, cyano, halogen, -C(O)OR 4 , -C(O)NR 10 R 11 , -S(O) 2 NR 10 R 11 , -S(O) n R 4 and protected -OH,
  • R 4ab is hydrogen, alkyl, cycloalkyl, Ci-Ci 2 aryl, substituted alkyl, substituted cycloalkyl and substituted Ci-Ci 2 aryl, and
  • R 1Oab and R llab are independently hydrogen, cycloalkyl, C 1 -C 12 MyI, substituted cycloalkyl, substituted Ci-C 12 aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N- acylamino, oxo, hydroxy, -C(O)OR 4ab , -S(O) n R 4ab , -C(O)NR 4ab R 4ab , -S(O) 2 NR 4ab R 4ab , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl and protected -OH,
  • R 1Oab and R llab taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen,
  • TPO modulators having the structure of Formula XIV:
  • Aria is aryl, monocyclic aromatic heterocycle, or bicyclic condensed heterocycle, each of which may be substituted;
  • R lc is aryl or monocyclic aromatic heterocycle, each of which may be substituted;
  • R 2c is a group represented by the following general Formula (XIV-A), (XIV-B) or (XIV-C):
  • n c is an integer of 1 to 3;
  • m c is an integer of 1 to 3, (when n c or m c is an integer of 2 or more, CR 2 ⁇ c R 2ic and CR 22c R 23c may bg identical or different);
  • Xc is O, S, or a group represented by N-R 26c or C(-R 27c )-R 28c ;
  • Ec, Gc, Jc, Lc are independently N or a group represented by C-R 29c , with the proviso that at least one of them is C-R 29c ;
  • R 20c , R 21c , R 22c , R 23c , R 26c , R 27c , R 28c , and R 29c are each independently selected from the group consisting of hydrogen; -OH; -0-lower alkyl; optionally substituted lower alkyl; optionally substituted cycloalkyl; optionally substituted aryl; optionally substituted arylalkyl; optionally substituted aromatic heterocycle; optionally substituted aromatic heterocyclic alkyl; optionally substituted nonaromatic heterocycle; optionally substituted lower alkenyl; optionally substituted lower alkylidene; -COOH; - COO-lower alkyl; -COO-lower alkenyl; -COO-lower alkylene-aryl; -COO-lower alkylene-aromatic heterocycle; carbamoyl and amino, each of which may be substituted with one or more groups selected from the group consisting of lower alkyl and cycloalky
  • R 24c are R 25c are each independently selected from the group consisting of, hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, and optionally substituted nonaromatic heterocycle.
  • a loading dose of a TPO modulator can be administered to a subject to provide a therapeutic amount of the TPO modulator in the subject more rapidly than would occur by repeated smaller doses of the TPO modulator for the treatment of thrombocytopenia or neutropenia.
  • the loading dose of the TPO modulator can be a multiple of the quantity of the TPO modulator administered per day using smaller maintenance doses of said TPO modulator.
  • the loading dose can be from about 2 times to about 24 times the quantity of the TPO modulator administered per day using smaller maintenance doses of the TPO modulator.
  • the loading dose of the TPO modulator can be from about 4 times to about 12 times the quantity of the TPO modulator administered per day using smaller maintenance doses of the TPO modulator.
  • the loading dose can be from about 6 times to about 10 times the quantity of the TPO modulator administered per day using smaller maintenance doses of the TPO modulator.
  • the amount of the TPO modulator administered in a loading dose can be from about 6 mg to about 30 mg, from about 30 mg to about 60 mg, from about 60 mg to about 120 mg, and from about 120 mg to about 600 mg. In a typical embodiment, the amount of the TPO modulator administered in a loading dose can be from about 30 mg to about 120 mg. In a more typical embodiment, the amount of the TPO modulator administered in a loading dose can be from about 30 mg to about 90 mg. In a more typical embodiment, the amount of the TPO modulator administered in a loading dose can be from about 36 mg to about 120 mg. For example, the loading dose can be 45 mg, 60 mg, 80 mg, or 100 mg of the TPO modulator. In a most typical embodiment, the loading dose can be from about 42 to about 78 mg of the TPO modulator.
  • Some embodiments provide a method of increasing blood platelet counts in a subject comprising administering a loading dose of a TPO modulator.
  • the blood platelet counts can increase from about 30% to about 40% from baseline, from about 40% to about 50% from baseline, from about 50% to about 60% from baseline, from about 60% to about 80% from baseline, from about 50% to about 60% from baseline, from about 60% to about 80% from baseline, from about 80% to about 100% from baseline, or from about 100% to about 150% from baseline.
  • the blood platelet counts can increase from about 30% to about 150% from a reading of the blood platelet counts in the subject prior to treatment with the TPO modulator.
  • the amount of TPO modulator administered in a loading dose can be from about 6 mg to about 30 mg, from about 30 mg to about 60 mg, from about 60 mg to about 120 mg, and from about 120 mg to about 600 mg. In a typical embodiment, the amount of the TPO modulator administered in a loading dose can be from about 30 mg to about 90 mg. In a more typical embodiment, the amount of the TPO modulator administered in a loading dose can be from about 36 mg to about 120 mg. For example, the loading dose can be 45 mg, 60 mg, 80 mg, or 100 mg of the TPO modulator. In a most typical embodiment, the loading dose can be from about 42 to about 78 mg of the TPO modulator.
  • Some embodiments provide a method of increasing blood platelet counts in a subject comprising administering a loading dose of a TPO modulator followed by a maintenance dose of a TPO modulator.
  • the amount of maintenance dose of the TPO modulator can be from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 20 mg, about 20 mg to about 100 mg, and about 100 mg to about 400 mg.
  • the amount of maintenance dose can be from about 2 mg to about 25 mg.
  • the amount of maintenance dose can be from about 4 mg to about 15 mg.
  • the amount of maintenance dose can be from about 5 mg to about 10 mg.
  • the amount of maintenance dose can be from about 1 mg to about 100 mg and the amount of loading dose can be from about 6 mg to about 600 mg.
  • the amount of maintenance dose can be from about 1.5 mg to about 40 mg and the amount of loading dose can be from about 9 mg to about 240 mg.
  • the amount of maintenance dose can be from about 2 mg to about 20 mg and the amount of loading dose can be from about 12 mg to about 120 mg.
  • the amount of maintenance dose can be from about 4 mg to about 15 mg and the amount of loading dose can be from about 24 mg to about 90 mg.
  • the amount of maintenance dose can be from about 5 mg to about 10 mg and the amount of loading dose can be from about 30 mg to about 60 mg.
  • Some embodiments provide a method of treating thrombocytopenia in a subject comprising administering a single dose of a TPO modulator from about once every 24 hrs to about once every 20 days.
  • the TPO modulator can be administered once every 24 hrs, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 14 days or once every 20 days.
  • Some embodiments provide a method of treating neutropenia in a subject comprising administering a single dose of a TPO modulator from about once every 24 hrs to about once every 20 days.
  • the TPO modulator can be administered once every 24 hrs, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every days 7, once every 14 days or once every 20 days.
  • the steady state blood plasma concentration can be reached by administration of a single dose of a TPO modulator.
  • the steady state concentration can be reached within 14 days of administration of a single dose of the TPO modulator.
  • the steady state concentration can be reached within 7 days of administration of a single dose of the TPO modulator.
  • the steady state concentration can be reached within 2 days of administration of a single dose of the TPO modulator.
  • the steady state blood plasma concentration can be reached within 24 hrs of administration of a single dose of a TPO modulator.
  • the steady state blood plasma concentration can be reached by administration of TPO modulator in an amount ranging from about 6 mg to about 30 mg, from about 30 mg to about 60 mg, from about 60 mg to about 120 mg, and from about 120 mg to about 600 mg.
  • the amount of the TPO modulator administered in a single dose can be from about 30 mg to about 90 mg.
  • the amount of the TPO modulator administered in a single dose can be from about 36 mg to about 120 mg.
  • the single dose can be 45 mg, 60 mg, 80 mg, or 100 mg of the TPO modulator.
  • the single dose can be from about 42 to about 78 mg of the TPO modulator.
  • the steady state blood plasma concentration can be maintained after administration of a loading dose of a TPO modulator by administering a maintenance dose of the TPO modulator.
  • the amount of the maintenance dose administered per day can be from about 1% to about 75% of the loading dose. In a typical embodiment, the amount of the maintenance dose administered per day can be from about 5% to about 25% of the loading dose. In a more typical embodiment, the amount of the maintenance dose administered per day can be from about 10% to about 20% of the loading dose.
  • a steady state blood plasma concentration of a TPO modulator can be attained in a subject by using a loading dose of a TPO modulator and a subsequent maintenance dose of the TPO modulator.
  • the amount of the maintenance dose administered to the subject per day can be from about 1% to about 75% of the loading dose. In a typical embodiment, the amount of the maintenance dose administered to the subject per day can be from about 5% to about 25% of the loading dose. In a more typical embodiment, the amount of the maintenance dose administered to the subject per day can be from about 10% to about 20% of the loading dose.
  • a treatment regimen including a loading dose of a TPO modulator can increase the blood platelet count in a subject faster than a treatment regimen without a loading dose.
  • the loading dose of the TPO modulator can be administered to the subject on day one of the treatment regimen followed by administration of a maintenance dose during the remainder of the treatment regimen.
  • a treatment regimen can have a maintenance dose of a TPO modulator administered to the subject on day one and continued throughout the remainder of the treatment regimen.
  • the treatment regimen with the loading dose of the TPO modulator can increase the blood platelet count faster than the treatment regimen without the loading dose.
  • the loading dose of the TPO modulator can be from about 4 times to about 12 times the quantity of the TPO modulator administered in the maintenance dose.
  • the loading dose can be from about 30 mg to about 60 mg, from about 60 mg to about 90 mg, from about 90 mg to
  • Some embodiments provide a method of treating thrombocytopenia in a subject comprising administering a TPO modulator with a half- life ranging from about 12 hours to about 45 hours, from about 45 hours to about 100 hours, from about 100 hours to about 180 hours.
  • the TPO modulator can have a half-life ranging from about 60 hours to about 100 hours.
  • the TPO modulator can have a half- life ranging from about 80 hours to about 100 hours.
  • the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 14 days or once every 20 days.
  • the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 14 days or once every 20 days in an amount ranging from about 30 mg to about 250 mg.
  • the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 14 days or once every 20 days in an amount ranging from about 40 mg to about 120 mg.
  • Some embodiments provide a method of treating neutropenia in a subject comprising administering a TPO modulator with a half- life ranging from about 12 hours to about 45 hours, from about 45 hours to about 100 hours, from about 100 hours to about 180 hours.
  • the TPO modulator can have a half-life ranging from about 60 hours to about 100 hours.
  • the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 14 days or once every 20 days.
  • the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 14 days or once every 20 days in an amount ranging from about 30 mg to about 250 mg.
  • the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 14 days or once every 20 days in an amount ranging from about 40 mg to about 120 mg.
  • Some embodiments provide a method of increasing blood platelet count in a subject comprising administering a TPO modulator with a half- life ranging from about 12 hours to about 45 hours, from about 45 hours to about 100 hours, from about 100 hours to about 180 hours.
  • the TPO modulator can have a half-life ranging from about 60 hours to about 100 hours.
  • the TPO modulator can have a half-life ranging from about 80 hours to about 100 hours.
  • the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 14 days or once every 20 days.
  • the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days or once every 4 days.
  • the TPO modulator can be administered to the subject once every 4 days, once every 5 days, once every 6 days, once every 7 days, or once every 8 days.
  • the TPO modulator can be administered to the subject once every 14 days or once every 20 days.
  • the blood platelet count can be increased from a pre-treatment reading by about 30 % to about 100 %.
  • Example 1 Mean Percent Change in Platelets from Baseline with Single Doses of Compound 1
  • the mean maximal percent change in platelet counts in each dose group averaged the maximum platelet counts from all subjects in the group at any time during study evaluations. It was a useful safety parameter for evaluating the mean highest group responses influenced by excessively high platelet counts. No subject reached platelet counts of 600,000/ ⁇ L at any evaluated dose with Compound 1.
  • the mean maximal percent change in platelet counts from BL is shown for all single doses in Figure 2. The data shows that single doses of 40 mg to 60 mg of Compound 1 did not stimulate platelet counts more than 2 times above BL.
  • Compound 1 doses of 5.0, 7.5, and 10.0 mg/day were evaluated for 14 days without loading doses. Platelet counts, adverse events (AEs), vital signs and laboratory parameters were followed for 35 days or longer if needed during multiple doses, until platelet counts returned to within 10% of baseline (BL).
  • the 5.0, 7.5 and 10.0 mg/day dose groups increased the mean platelet counts 37%, 47%, and 82% above the mean counts at BL, respectively.
  • the 10 mg dose group reached the limit of dose escalation (50% above BL) in the protocol.
  • the graphs of platelet counts with time for 14 daily doses of Compound 1 are presented in Figure 3.
  • Idiopathic thrombocytopenic purpura (ITP) indication is believed to need less stimulation of platelets than occurred with 10 mg/day dosing because platelet counts can rise unexpectedly high rapidly in some patients with ITP.
  • the 2.5, 5.0, and 7.5 mg/day doses were examined as potentially optimal for ITP.
  • a loading dose was tested at the start of treatment. A loading dose was given to achieve a steady-state concentration in the blood as early as Day 1 and therefore an earlier onset of the increase in platelet counts. The steady-state condition of systemic drug exposure was considered best for maintaining stabilized platelet counts.
  • the loading dose tested was 6 times the daily dose, based on computations using the I 1 A of Compound 1.
  • a loading dose of 45 mg was given on Day 1 to a cohort of healthy subjects who were to receive the 7.5 mg daily dose for 13 days. This produced an earlier and greater platelet response than occurred with a cohort of healthy subjects who received the 7.5 mg daily dose without a loading dose on Day 1.
  • Figure 4 shows that the loading dose produced an earlier onset of platelet response by at least 6 days and a greater change from the BL platelet counts, when compared with the same treatment without a loading dose.
  • Pharmacokinetic measurements confirmed that use of a loading dose achieved near steady state exposure of Compound 1 in subjects' blood on Day 1.
  • the reason for this response threshold for Compound 1 may be tight binding by serum proteins and platelets so there is little free Compound 1 below 40 mg.
  • the threshold level will depend on the binding affinity of any particular TPO modulator; for Compound 1 it is about 40 mg.
  • Compound 1 binds to serum proteins at about 98.7% For instance, response is seen at single dose activity for 40 mg doses and above, but not below 40 mg.
  • the loading doses of 15 mg for 2.5 mg/day and 35 mg with 5 mg/day did not greatly affect the platelet response or its onset as shown in the Table 1 and Figure 5.

Abstract

The embodiments provide methods of administering a loading dose of a TPO modulator to a subject. The embodiments further provide methods of treating thrombocytopenia and/or neutropenia in a subject. Additionally, the embodiments further provide methods of increasing platelet production and/or enhancing the number of peripheral blood stem cells in a subject.

Description

METHODS OF ADMINISTRATION OF THROMBOPOIETIN MIMETIC
COMPOUNDS
BACKGROUND OF THE INVENTION
Field of the Invention
[0001] The present invention relates to compounds and methods in the fields of chemistry and medicine. More specifically, the present invention relates to compounds that modulate one or more thrombopoietin activity and/or bind to thrombopoietin receptors. Description of the Related Art
[0002] Thrombopoietin (TPO), also referred to as c-Mpl ligand, mpl ligand, megapoietin, and megakaryocyte growth and development factor, is a glycoprotein that has been shown to be involved in production of platelets. See e.g., Wendling, F., et. al, Biotherapy 10(4):269-77 (1998); Kuter D.J. et al., The Oncologist, 1 :98-106(1996); Metcalf, Nature 369: 519-520 (1994), all of which are incorporated herein by reference in their entirety. TPO has been cloned and its amino acid sequence and the cDNA sequence encoding it have been described. See e.g., U.S. 5,766,581; Kuter, D.J. et al., Proc. Natl. Acad. ScL, 91 :11104-11108 (1994); de Sauvage F.V., et al., Nature, 369: 533-538 (1994); Lok, S. et al., Nature 369:565-568 (1994); Wending, F. et al., Nature, 369: 571-574 (1994), all of which are incorporated herein by reference in their entirety.
[0003] In certain instances, TPO activity results from binding of TPO to the TPO receptor (also called MPL). The TPO receptor has been cloned and its amino acid sequence has been described. See e.g., Vigon et al., Proc. Natl. Acad. ScL, 89:5640-5644 (1992), which is incorporated herein by reference in its entirety.
[0004] In certain instances, TPO modulators may be useful in treating a variety of hematopoietic conditions, including, but not limited to, thrombocytopenia. See e.g., Baser et al. Blood 89:3118-3128 (1997); Fanucchi et al. New Engl. J. Med. 336:404-409 (1997), both of which are incorporated herein by reference in their entirety. For example, patients undergoing certain chemotherapies, including but not limited to chemotherapy and/or radiation therapy for the treatment of cancer, may have reduced platelet levels. In certain instances, treating such patients with a selective TPO modulator increases platelet levels. In certain instances, selective TPO modulators stimulate production of glial cells, which may result in repair of damaged nerve cells.
[0005] In certain instances, an increase in platelet count to a therapeutically beneficial level in a subject occurs after a prolonged period of time during a treatment regimen. For example, the increase in platelet count to a therapeutically beneficial level in a subject using a maintenance dose of a TPO modulator may occur after a week of treatment.
SUMMARY OF THE INVENTION
[0006] One embodiment provides a method of treating thrombocytopenia in a subject in need thereof which comprises administering a TPO modulator, wherein the amount of TPO modulator administered in a single dose is sufficient to increase platelet production.
[0007] One embodiment provides a method of treating thrombocytopenia in a subject in need thereof which comprises administering a TPO modulator, wherein the amount of TPO modulator administered in a single dose is sufficient to achieve steady state concentration levels for said treatment.
[0008] One embodiment provides a method of treating neutropenia in a subject in need thereof which comprises administering a TPO modulator, wherein the amount of TPO modulator administered in a single dose is sufficient to increase platelet production.
[0009] One embodiment provides a method of treating neutropenia in a subject in need thereof which comprises administering a TPO modulator wherein the amount of TPO modulator administered in a single dose is sufficient to achieve steady state concentration levels for said treatment.
[0010] One embodiment provides a method of increasing platelet production in a subject comprising: administering a TPO modulator in a single dose sufficient to achieve steady state concentration levels.
[0011] One embodiment provides a method for enhancing the number of peripheral blood stem cells obtained from a donor comprising administering to said donor a TPO modulator in a single dose sufficient to enhance the number of peripheral blood stem cells prior to leukapheresis.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 is a graph showing the % change from baseline in platelet counts after treatment with a single dose of compound 1. The single dose of 40 mg, 60 mg, 90 mg and 120 mg is compared to placebo.
[0013] FIG. 2 is a graph showing the maximum % change from baseline in platelet counts after treatment with a single dose of compound 1.
[0014] FIG. 3 is a graph showing the % change from baseline in platelet counts. The treatment period is for 14 days and the daily dosage of 5 mg, 7.5 mg and 10 mg is compared to placebo.
[0015] FIG. 4 is a graph showing the % change from baseline in platelet counts after treatment with or without a loading dose of compound 1. The treatment period is for 14 days and the daily dosage of 7.5 mg, and a daily dosage of 7.5 mg with a 45 mg loading dose is compared to placebo.
[0016] FIG. 5 is a graph showing the maximum % change from baseline in platelet counts using different treatment methods. The subjects were treated with and without loading doses of compound 1.
[0017] FIG. 6 is a graph showing the % change from baseline in platelet counts after treatment with 10 mg quantity daily of compound 1 or after treatment with 7.5 mg quantity daily of compound 1 with a 45 mg loading dose as compared to placebo. The treatment period is for 14 days.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Detailed Description
[0018] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "includes," and "included," is not limiting. [0019] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose. Definitions
[0020] Unless specific definitions are provided, the nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard chemical symbols are used interchangeably with the full names represented by such symbols. Thus, for example, the terms "hydrogen" and "H" are understood to have identical meaning. Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques may be performed e.g., using kits according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), which is incorporated herein by reference in its entirety for any purpose.
[0021] As used herein, the following terms are defined with the following meanings, unless expressly stated otherwise.
[0022] The term "selective binding compound" refers to a compound that selectively binds to any portion of one or more target.
[0023] The term "selective TPO receptor binding compound" refers to a compound that selectively binds to any portion of a TPO receptor.
[0024] The term "selectively binds" refers to the ability of a selective binding compound to bind to a target receptor with greater affinity than it binds to a non-target receptor. In certain embodiments, selective binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, or 1000 times greater than the affinity for a non-target.
[0025] The term "target receptor" refers to a receptor or a portion of a receptor capable of being bound by a selective binding compound. In certain embodiments, a target receptor is a TPO receptor.
[0026] The term "modulator" refers to a compound that alters an activity. For example, a modulator may cause an increase or decrease in the magnitude of a certain activity compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities. In certain embodiments, an inhibitor completely prevents one or more biological activities. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity. In certain embodiments the presence of a modulator results in a activity that does not occur in the absence of the modulator.
[0027] The term "selective modulator" refers to a compound that selectively modulates a target activity.
[0028] The term "TPO modulator" refers to a compound or drug that modulates at least one TPO activity. The term TPO modulator includes, but is not limited to "TPO mimic" which refers to a compound, the presence of which results in at least one TPO activity.
[0029] The term "pharmaceutical agent" or "drug" refers to a chemical compound or composition capable of inducing a desired therapeutic effect in a subject. In certain embodiments, a pharmaceutical agent comprises an active agent, which is the agent that induces the desired therapeutic effect. In certain embodiments, a pharmaceutical agent comprises a prodrug. In certain embodiments, a pharmaceutical agent comprises inactive ingredients such as carriers, excipients, and the like.
[0030] The term "selectively modulates" refers to the ability of a selective modulator to modulate a target activity to a greater extent than it modulates a non-target activity.
[0031] The term "target activity" refers to a biological activity capable of being modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, the proliferation and/or differentiation of progenitor cells, generation of platelets, and alleviation of symptoms of a disease or condition.
[0032] The term "TPO activity" refers to a biological activity that results, either directly or indirectly from the presence of TPO. Exemplary TPO activities include, but are not limited to, proliferation and or differentiation of progenitor cells to produce platelets; hematopoiesis; growth and/or development of glial cells; repair of nerve cells; and alleviation of thrombocytopenia.
[0033] The term "thrombocytopenia" refers to a condition wherein the concentration of platelets in the blood of a patient is below what is considered normal for a healthy patient. In certain embodiments, thrombocytopenia is a platelet count less than 450,000, 400,000, 350,000, 300,000, 250,000, 200,000, 150,000, 140,000, 130,000, 120,000, 110,000, 100,000, 75,000, or 50,000 platelets per microliter of blood.
[0034] The term "receptor mediated activity" refers to any biological activity that results, either directly or indirectly, from binding of a ligand to a receptor.
[0035] The term "agonist" refers to a compound, the presence of which results in a biological activity of a receptor that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the receptor.
[0036] The term "partial agonist" refers to a compound the presence of which results in a biological activity of a receptor that is of the same type as that resulting from the presence of a naturally occurring ligand for the receptor, but of a lower magnitude.
[0037] The term "antagonist" refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of a receptor. In certain embodiments, the presence of an antagonist results in complete inhibition of a biological activity of a receptor.
[0038] The term "subject," "individual," and "patient" are used herein, for purposes of the specification and claims, to mean a human or other animal, such as farm animals or laboratory animals (e.g., guinea pig or mice) in which it is desired to increase platelets in the blood.
[0039] The term "loading dose" as used herein will be understood to mean a single dose or short duration regimen of a drug having a dosage higher than the maintenance dose administered to the subject to rapidly increase the blood concentration level of the drug. In some embodiments, the "loading dose" can increase the blood concentration of the drug to a therapeutically effective level. In some embodiments, the "loading dose" can increase the blood concentration of the drug to a therapeutically effective level in conjunction with a maintenance dose of the drug.
[0040] The term "maintenance dose" as used herein will be understood to mean a dose that is serially administered (i.e., at least twice), and which is intended to either slowly raise blood concentration levels of the compound to a therapeutically effective level, or to maintain such a therapeutically effective level. The maintenance dose may be administered once per day, once over a period of days (e.g., up to 30 days), or more than once per day (e.g., up to 4 times per day).
[0041] The term "carrier" refers to a compound that facilitates the incorporation of another compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier for improving incorporation of certain organic compounds into cells or tissues.
[0042] The term "therapeutically effective amount" refers to an amount of a TPO modulator sufficient to achieve a desired therapeutic effect.
[0043] The term "prodrug" refers to an TPO modulator that is converted from a less active form into a corresponding more active form in vivo.
[0044] The term "pharmaceutically acceptable" refers to a formulation of a compound that does not significantly abrogate the biological activity, a pharmacological activity and/or other properties of the compound when the formulated compound is administered to a patient. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a patient.
[0045] The term "co-administer" refers to administering more than one TPO modulator to a patient. In certain embodiments, co-administered TPO modulators are administered together in a single dosage unit. In certain embodiments, co-administered TPO modulators are administered separately. In certain embodiments, co-administered TPO modulators are administered at the same time. In certain embodiments, coadministered TPO modulators are administered at different times.
[0046] The term "alkyl" refers to an aliphatic hydrocarbon group. An alkyl may be a "saturated alkyl," which means that it does not contain any alkene or alkyne groups. An alkyl group may be an "unsaturated alkyl," which means that it comprises at least one alkene or alkyne group. An alkyl, whether saturated or unsaturated, may be branched or straight chain. Alkyls may be cyclic or non-cyclic. Cyclic alkyls may include multicyclic systems including fused alkyl rings. Alkyls may be substituted or unsubstituted. Alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, each of which may be optionally substituted.
[0047] In certain embodiments, an alkyl comprises 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the term "alkyl" also includes instances where no numerical range of carbon atoms is designated).
[0048] The term "lower alkyl" refers to an alkyl comprising 1 to 5 carbon atoms. The term "medium alkyl" refers to an alkyl comprising 5 to 10 carbon atoms. An alkyl may be designated as "C1-C4 alkyl" or similar designations. By way of example only, "C1-C4 alkyl" indicates an alkyl having one, two, three, or four carbon atoms, e.g., the alkyl is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t- butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl.
[0049] The term "alkenyl" refers to an alkyl group comprising at least one carbon-carbon double bond.
[0050] The term "alkynyl" refers to an alkyl group comprising at least one carbon-carbon triple bond.
[0051] The term "haloalkyl" refers to an alkyl in which at least one hydrogen atom is replaced with a halogen atom. In certain of the embodiments in which two or more hydrogen atom are replaced with halogen atoms, the halogen atoms are all the same as one another. In certain of such embodiments, the halogen atoms are not all the same as one another.
[0052] The term "heteroalkyl" refers to a group comprising an alkyl and one or more heteroatoms. Certain heteroalkyls are acylalkyls, in which the one or more heteroatoms are within an alkyl chain. Examples of heteroalkyls include, but are not limited to, CH3C(=O)CH2-, CH3C(=O)CH2CH2-, CH3CH2C(=O)CH2CH2-, CH3C(=O)CH2CH2CH2-, CH3OCH2CH2-, CH3NHCH2-, and the like. [0053] The term "straight-chain alkoxy" refers to a group comprising the formula: -(CH2)PO- wherein p is any integer. Straight-chain alkoxy does not include substituted or branched alkoxy groups.
[0054] The term "non-straight-chain-alkoxy-heteroalkyl" refers to any heteroalkyl that is not a straight-chain alkoxy heteroalkyl. Thus, for example, non-straight- chain-alkoxy heteroalkyls include, but are not limited to: 2,2-isopropyloxy; 1 ,2-propyloxy; 1,1-ethyloxy; methylamino; ethylamino; propylamino; methylpyrrolidino; and methylpiperidino .
[0055] The term "olefin" refers to a C=C bond.
[0056] The term "heterohaloalkyl" refers to a heteroalkyl in which at least one hydrogen atom is replaced with a halogen atom.
[0057] The term "carbocycle" refers to a group comprising a covalently closed ring, wherein each of the atoms forming the ring is a carbon atom. Carbocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycles may be optionally substituted.
[0058] The term "heterocycle" refers to a group comprising a covalently closed ring wherein at least one atom forming the ring is a heteroatom. Heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Any number of those atoms may be heteroatoms (i.e., a heterocyclic ring may comprise one, two, three, four, five, six, seven, eight, nine, or more than nine heteroatoms). In heterocyclic rings comprising two or more heteroatoms, those two or more heteroatoms may be the same or different from one another. Heterocycles may be optionally substituted. Binding to a heterocycle can be at a heteroatom or via a carbon atom. For example, binding for benzo- fused derivatives, may be via a carbon of the benzenoid ring. Examples of heterocycles include, but are not limited to the following:
Figure imgf000011_0001
Figure imgf000012_0001
wherein D, E, F, and G independently represent a heteroatom. Each of D, E, F, and G may be the same or different from one another.
[0059] The term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from oxygen, sulfur, nitrogen, and phosphorus, but are not limited to those atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may all be the same as one another, or some or all of the two or more heteroatoms may each be different from the others.
[0060] The term "aromatic" refers to a group comprising a covalently closed ring having a delocalized π-electron system. Aromatic rings may be formed by five, six, seven, eight, nine, or more than nine atoms. Aromatics may be optionally substituted. Examples of aromatic groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl. The term aromatic includes, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from an aryl, a heteroaryl, a cycloalkyl, a non-aromatic heterocycle, a halo, a hydroxy, an amino, a cyano, a nitro, an alkylamido, an acyl, a Ci_6 alkoxy, a Ci_6 alkyl, a Ci_6 hydroxyalkyl, a Ci_6 aminoalkyl, a Ci_6 alkylamino, an alkylsulfenyl, an alkylsulfinyl, an alkylsulfonyl, an sulfamoyl, or a trifluoromethyl. In certain embodiments, an aromatic group is substituted at one or more of the para, meta, and/or ortho positions. Examples of aromatic groups comprising substitutions include, but are not limited to, phenyl, 3-halophenyl, 4-halophenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylphenyl, A- methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 3- cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4-morpholin-4-ylphenyl, A- pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin-l- yl)phenyl.
[0061] The term "aryl" refers to an aromatic group wherein each of the atoms forming the ring is a carbon atom. Aryl rings may be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups may be optionally substituted.
[0062] The term "heteroaryl" refers to an aromatic group wherein at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heteroaryl groups may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3_8 heterocyclic groups comprising one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms. In certain embodiments, heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci_6-alkoxy, Ci_6-alkyl, C1-6- hydroxyalkyl, Ci_6-aminoalkyl, Ci_6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, O-Ci_6- alkyl, Ci_6-alkyl, hydroxy-Ci_6-alkyl, and amino-Ci_6-alkyl.
[0063] The term "non-aromatic ring" refers to a group comprising a covalently closed ring that does not have a delocalized π-electron system. [0064] The term "cycloalkyl" refers to a group comprising a non-aromatic ring wherein each of the atoms forming the ring is a carbon atom. Cycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Cycloalkyls may include multicyclic systems (e.g., fused ring systems). Cycloalkyls may be optionally substituted. In certain embodiments, a cycloalkyl comprises one or more unsaturated bonds. Examples of cycloalkyls include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3- cyclohexadiene, 1 ,4-cyclohexadiene, cycloheptane, and cycloheptene.
[0065] The term "non-aromatic heterocycle" refers to a group comprising a non-aromatic ring wherein one or more atoms forming the ring is a heteroatom. Non- aromatic heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Non-aromatic heterocycles may be optionally substituted. In certain embodiments, non-aromatic heterocycles comprise one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups. Examples of non-aromatic heterocycles include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1 ,4-dioxane, piperazine, 1,3-oxathiane, 1,4- oxathiin, 1,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-l,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3- oxathiolane.
[0066] The term "arylalkyl" refers to a group comprising an aryl group bound to an alkyl group.
[0067] The term "carbocycloalkyl" refers to a group comprising a carbocyclic cycloalkyl ring. Carbocycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycloalkyl groups may be optionally substituted.
[0068] The term "ring" refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g., aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings may be optionally substituted. Rings may form part of a ring system.
[0069] The term "ring system" refers to a either a single ring or two or more rings, wherein, if two or more rings are present, the two or more of the rings are fused. The term "fused" refers to structures in which two or more rings share one or more bonds.
[0070] The term "carboxylic acid bioisostere" refers to a group that is biologically equivalent to a carboxylic acid. For example, carboxylic acid bioisosteres include, but are not limited to, tetrazole, NHSO2R15, OC(S)NR10R11, SC(O)NR10R11, thiazolidinedione, oxazolidinedione, and l-oxa-2,4-diazolidine-3,5-dione. In certain embodiments, a carboxylic acid bioisostere comprises the following structure:
Figure imgf000015_0001
. wherein A, B, and C are each independently selected from O, S, and NH.
[0071] The term "spacer" refers to an atom or group of atoms that separate two or more groups from one another by a desired number of atoms. For example, in certain embodiments, it may be desirable to separate two or more groups by one, two, three, four, five, six, or more than six atoms. In such embodiments, any atom or group of atoms may be used to separate those groups by the desired number of atoms. Spacers are optionally substituted. In certain embodiments, a spacer comprises saturated or unsaturated alkyls, heteroalkyls and/or haloalkyls. In certain embodiments, a spacer comprises atoms that are part of a ring.
[0072] Solely for the purposes of illustration, and without limiting the above definition, some examples of spacers are provided. Examples of 1 atom spacers include, but are not limited to, the following:
Figure imgf000015_0002
Examples of 2 atom spacers include, but are not limited to, the following:
Figure imgf000015_0003
where Ai and Bi represent groups which are separated by the desired number of atoms.
[0073] Examples of 3 atom spacers include, but are not limited to, the following:
Figure imgf000016_0001
where Ai and Bi represent groups which are separated by the desired number of atoms. As is evident from the above examples, the atoms that create the desired separation may themselves be part of a group. That group may be, for example, an alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, or substituted alkyl all of which are optionally substituted. Thus the term "1-5 atom spacer" refers to a spacer that separates two groups by 1, 2, 3, 4, or 5 atoms and does not indicate the total size of the group that constitutes the spacer.
[0074] As used herein, the term "linked to form a ring" refers to instances where two atoms that are bound either to a single atom or to atoms that are themselves ultimately bound, are each bound to a linking group, such that the resulting structure forms a ring. That resulting ring comprises the two atoms that are linked to form a ring, the atom (or atoms) that previously linked those atoms, and the linker. For example, if Ai and Bi below are "linked to form a ring"
Figure imgf000016_0002
the resulting ring includes Ai, Bi, Ci, and a linking group. Unless otherwise indicated, that linking group may be of any length and may be optionally substituted. Referring to the above example, resulting structures include, but are not limited to: A1 B1
Figure imgf000017_0001
like.
[0075] In certain embodiments, the two substituents that together form a ring are not immediately bound to the same atom. For example, if Ai and Bi, below, are linked to form a ring:
Figure imgf000017_0002
, the resulting ring comprises Ai, Bi, the two atoms that already link Ai and Bi and a linking group. Examples of resulting structures include, but are not limited to:
Figure imgf000017_0003
; and the like.
[0076] In certain embodiments, the atoms that together form a ring are separated by three or more atoms. For example, if Ai and Bi, below, are linked to form a ring:
Figure imgf000017_0004
, the resulting ring comprises Ai, Bi, the 3 atoms that already link Ai and Bi, and a linking group. Examples of resulting structures include, but are not limited to:
A1^ B1
• , and the like.
[0077] As used herein, the term "together form a bond" refers to the instance in which two substituents to neighboring atoms are null the bond between the neighboring atoms becomes a double bond. For example, if Ai and Bi below "together form a bond"
Figure imgf000018_0001
the resulting structure is:
Figure imgf000018_0002
[0078] The term "null" refers to a group being absent from a structure. For
example, in the structure ^-" ^ , where in certain instances Xi is N, if Xi is N, one of R' or R" is null, meaning that only three groups are bound to the N.
[0079] The substituent "R" appearing by itself and without a number designation refers to a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon).
[0080] The term "O-carboxy" refers to a group of formula RC(=O)O-.
[0081] The term "C-carboxy" refers to a group of formula -C(=O)OR.
[0082] The term "acetyl" refers to a group of formula -C(=O)CH3.
[0083] The term "trihalomethanesulfonyl" refers to a group of formula X3CS(=O)2- where X is a halogen.
[0084] The term "cyano" refers to a group of formula -CN.
[0085] The term "isocyanato" refers to a group of formula -NCO.
[0086] The term "thiocyanato" refers to a group of formula -CNS.
[0087] The term "isothiocyanato" refers to a group of formula -NCS.
[0088] The term "sulfonyl" refers to a group of formula -S(=O)-R.
[0089] The term "S-sulfonamido" refers to a group of formula -S(=O)2NR.
[0090] The term "N-sulfonamido" refers to a group of formula RS(=O)2NH-.
[0091] The term "trihalomethanesulfonamido" refers to a group of formula X3CS(=O)2NR-.
[0092] The term "O-carbamyl" refers to a group of formula -OC(=O)-NR.
[0093] The term "N-carbamyl" refers to a group of formula ROC(=O)NH-.
[0094] The term "O-thiocarbamyl" refers to a group of formula -OC(=S)-NR.
[0095] The term "N-thiocarbamyl" refers to a group of formula ROC(=S)NH-. [0096] The term "C-amido" refers to a group of formula -C(=O)-NR2. [0097] The term "N-amido" refers to a group of formula RC(=O)NH-. [0098] The term "oxo" refers to a group of formula =0.
[0099] The term "dihydropyrazolylene" refers to a di-radical of an optionally substituted dihydropyrazole ring, wherein the dihydropyrazole ring has the structure:
Figure imgf000019_0001
and wherein the two radicals may be at any positions on the ring.
[0100] The term "pyrazolyl" refers to a radical of a pyrzole ring, wherein the pyrzole ring has the structure:
Figure imgf000019_0002
and wherein the radical may be at any position on the ring.
[0101] The term "ester" refers to a chemical moiety with formula -(R)n-COOR', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon), where n is 0 or 1.
[0102] The term "amide" refers to a chemical moiety with formula -(R)n-C(O)NHR' or -(R)n-NHC(O)R', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), where n is 0 or 1. In certain embodiments, an amide may be an amino acid or a peptide.
[0103] The terms "amine," "hydroxy," and "carboxyl" include such groups that have been esterifϊed or amidifϊed. Procedures and specific groups used to achieve esterifϊcation and amidification are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.
[0104] Unless otherwise indicated, the term "optionally substituted," refers to a group in which none, one, or more than one of the hydrogen atoms has been replaced with one or more group(s) individually and independently selected from: alkyl, heteroalkyl, haloalkyl, heteroholoalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives of amino groups. Such protective derivatives (and protecting groups that may form such protective derivatives) are known to those of skill in the art and may be found in references such as Greene and Wuts, above. In embodiments in which two or more hydrogen atoms have been substituted, the substituent groups may together form a ring.
[0105] Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.
[0106] The term "substantially pure" means an object species (e.g., compound) is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition). In certain embodiments, a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all species present. In certain embodiments, a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all species present in the composition. In certain embodiments, the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single species.
[0107] The term "tissue-selective" refers to the ability of a compound to modulate a biological activity in one tissue to a greater or lesser degree than it modulates a biological activity in another tissue. The biological activities in the different tissues may be the same or they may be different. The biological activities in the different tissues may be mediated by the same type of target receptor. For example, in certain embodiments, a tissue-selective compound may modulate receptor mediated biological activity in one tissue and fail to modulate, or modulate to a lesser degree, receptor mediated biological activity in another tissue type.
[0108] The term "monitoring" refers to observing an effect or absence of any effect. In certain embodiments, one monitors cells after contacting those cells with a compound of the present invention. Examples of effects that may be monitored include, but are not limited to, changes in cell phenotype, cell proliferation, receptor activity, or the interaction between a receptor and a compound known to bind to the receptor.
[0109] The term "cell phenotype" refers to physical or biological characteristics. Examples of characteristics that constitute phenotype included, but are not limited to, cell size, cell proliferation, cell differentiation, cell survival, apoptosis (cell death), or the utilization of a metabolic nutrient (e.g., glucose uptake). Certain changes or the absence of changes in cell phenotype are readily monitored using techniques known in the art.
[0110] The term "cell proliferation" refers to the rate at which cells divide. In certain embodiments, cells are in situ in an organism. In certain embodiments, cell are grown in vitro in a vessel. The number of cells growing in a vessel can be quantified by a person skilled in the art (e.g. , by counting cells in a defined area using a microscope or by using laboratory apparatus that measure the density of cells in an appropriate medium). One skilled in that art can calculate cell proliferation by determining the number of cells at two or more times.
[0111] The term "contacting" refers to bringing two or more materials into close enough proximity that they may interact. In certain embodiments, contacting can be accomplished in a vessel such as a test tube, a petri dish, or the like. In certain embodiments, contacting may be performed in the presence of additional materials. In certain embodiments, contacting may be performed in the presence of cells. In certain of such embodiments, one or more of the materials that are being contacted may be inside a cell. Cells may be alive or may dead. Cells may or may not be intact.
[0112] The term "cohort" as used herein will be understood to mean a group of people who share a common characteristic. Thus a group of people who were born on a day or in a particular period, say 1948, form a birth cohort. The comparison group may be the general population from which the cohort is drawn, or it may be another cohort of persons thought to have had little or no exposure to the substance under investigation, but otherwise similar. Certain compounds
[0113] Certain compounds that modulate one or more TPO activity and/or bind to TPO receptors play a role in health. In certain embodiments, compounds of the present invention are useful for treating any of a variety of diseases or conditions.
[0114] In certain embodiments, the present invention provides selective TPO modulators. In certain embodiments, the invention provides selective TPO receptor binding agents. In certain embodiments, the invention provides methods of making and methods of using selective TPO modulators and/or selective TPO receptor binding agents. In certain embodiments, selective TPO modulators are agonists, partial agonists, and/or antagonists for the TPO receptor.
[0115] In certain embodiments, the present invention provides TPO modulators having the structure of Formula I, II, III, IV, V, or VI:
Figure imgf000022_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
[0116] R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; [0117] each R2 is independently selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
[0118] R3 and R4 are independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
[0119] R5 is selected from hydrogen, halogen, OR14, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
[0120] R6 is selected from an optionally substituted C1-C10 alkyl, an optionally substituted C1-C10 haloalkyl, and an optionally substituted Ci-Ci0 heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R6 is selected from - (CH2)mR18, -C(O)NHR18, -C≡CR18, -CR3=CR4R18, and =CR3R18;
[0121] R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere;
[[0( 122] each R8 and each R9 is independently selected from hydrogen, OR16,
NR16R17, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, (CH2)mR18, and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-Cg ring;
[0123] R10 is selected from hydrogen, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
[0124] R11 is selected from hydrogen, halogen, OR14, NR14R15, and SR14; or R11 and R4 are linked to form a optionally substituted heterocycle;
[0125] R12 is selected from hydrogen, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
[0126] R13 is selected from hydrogen, halogen, CN, NO2, CO2R14, S(O)1nR14, C1-C4 alkyl, C1-C4 haloalkyl, Ci-C4 heteroalkyl, and Ci-C4 haloheteroalkyl;
[0127] R14 is selected from hydrogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
[0128] R15 is selected from hydrogen, SO2R19, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl; [0129] R16 and R17 are each independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, and (CH2)mR18; or one of R16 and R17 is an optionally substituted C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R17 are linked to form an optionally substituted C3-Cg ring;
[0130] R18 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R18 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system;
[0131] R19 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, and an optionally substituted aryl;
[0132] D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
[0133] E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
[0134] L is NH or null;
[0135] Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle;
[0136] U is selected from O, NR4, CR3R4, CO, and null;
[0137] W is selected from O, NR4, CR3R4, CO, and null;
[0138] X is N or CR5;
[0139] Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl;
[0140] Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C6-CiO aryl and an optionally substituted Ci-Cs heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 heteroalkyl, and an optionally substituted Ci-C6 haloalkyl, each optionally fused with an optionally substituted C6-CiO aryl;
[0141] m is 0, 1, 2, or 3; and
[0142] n is O or l;
[0143] each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S- sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, =0, =S, amino, and protected derivatives of amino groups.
[0144] In an embodiment are TPO modulators having the structure of Formula X:
Figure imgf000025_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
[0145] Rld is selected from CO2R10d, CONR10dRlld, SO3R10d, and a carboxylic acid bioisostere; [0146] R2d and R3d are each independently selected from null, hydrogen, OR12d, NR12dR13d, an optionally substituted Ci-C4 aliphatic, an optionally substituted C1- C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mdR14d; or R2d and R3d taken together form an optionally substituted olefin; or R2 and R3 are linked to form an optionally substituted C3-Cs ring;
[0147] R4d is selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
[0148] R5d is selected from hydrogen, OR10d, SR1Od, NHRlld, and CO2H;
[0149] R6d is selected from hydrogen, OR12d, NR12dR13d, fluorine (F), chlorine (Cl), bromine (Br), Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 heteroalkyl, and a ring;
[0150] R7d is selected from hydrogen, an optionally substituted Ci-Cs aliphatic, an optionally substituted Ci-Cs haloaliphatic, an optionally substituted Ci-Cs heteroaliphatic, an optionally substituted Ci-Cs heterohaloaliphatic, an optionally substituted ring, and (CH2)mdR14d;
[0151] R1Od is selected from hydrogen, an optionally substituted Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
[0152] Rlld is selected from hydrogen, SO2R15d, Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
[0153] R12d and R13d are each independently selected from hydrogen, an optionally substituted Ci-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mR14d; or one of R12d and R13d is an optionally substituted C2-C6 aliphatic or an optionally substituted ring and the other of R12d and Rld3 is null; or R12d and Rld3 are linked to form an optionally substituted C3-Cs ring;
[0154] R14d is selected from an optionally substituted aryl and an optionally substituted heteroaryl;
[0155] R15d is selected from hydrogen, Ci-C3 aliphatic, Ci-C3 haloaliphatic, and a ring;
[0156] Yd is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted Ci-C6 aliphatic, an optionally substituted Ci-C6 heteroaliphatic, an optionally substituted phenyl, an optionally substituted heteroaryl, an optionally substituted C3-Cs heterocycle, and an optionally substituted alicyclic; [0157] Zd is selected from: a 2-5 atom spacer selected from an optionally substituted C6-CiO aryl and an optionally substituted Ci-Cg heteroaryl, and a 1-5 atom spacer of selected from an optionally substituted Ci-C6 aliphatic, an optionally substituted Ci-C6 heteroaliphatic, and an optionally substituted Ci-C6 haloaliphatic;
[0158] md is 0, 1, or 2; and [0159] nd is 0 or l. [0160] In an embodiment are TPO modulators having the structure of Formula
XI:
Figure imgf000027_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
[0161] Rle is selected from CO2R10e, CONR10eRlle, SO3R10e, and a carboxylic acid bioisostere;
[0162] R2e and R3e are each independently selected from null, hydrogen, OR12e, NR12eR13e, an optionally substituted C1-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)m R14e; or R2e and R3e taken together form an optionally substituted olefin; or R2e and R3e are linked to form an optionally substituted C3-Cg ring;
[0163] R4e is selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
[0164] R5e is selected from hydrogen, OR10e, SR1Oe, NHRlle, and CO2H; [0165] R7e is selected from hydrogen, an optionally substituted Ci-C8 aliphatic, an optionally substituted Ci-Cg haloaliphatic, an optionally substituted Ci-Cg heteroaliphatic, an optionally substituted Ci-Cg heterohaloaliphatic, an optionally substituted ring, and (CH2)H16R146;
[0166] R1Oe is selected from hydrogen, an optionally substituted C1-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
[0167] Rlle is selected from hydrogen, SO2R15e, Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
[0168] R12e and R13e are each independently selected from hydrogen, an optionally substituted Ci-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)J116R146; or one of R12e and R13e is an optionally substituted C2-C6 aliphatic or an optionally substituted ring and the other of R12e and R13e is null; or R12e and R13e are linked to form an optionally substituted C3-C8 ring;
[0169] R14e is selected from an optionally substituted aryl and an optionally substituted heteroaryl; and
Figure imgf000028_0001
[0172] R6e is selected from hydrogen, OR12e, NR12eR13e, fluorine (F), chlorine (Cl), bromine (Br), Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 heteroalkyl, and a ring;
[0173] R8e and R9e are each independently selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), CO2R10e, NO2, CN, SO2R10e, (CH2)^R146, Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, Ci-C4 heterohaloaliphatic, and a ring;
[0174] Xe is selected from O, S, NR1Oe, and CR1OeR1Oe;
[0175] Qe is selected from O and S;
[0176] Ze is selected from: a 2-5 atom spacer selected from an optionally substituted C6-CiO aryl and an optionally substituted Ci-Cg heteroaryl, and a 1-5 atom spacer of selected from an optionally substituted Ci-C6 aliphatic, an optionally substituted Ci-C6 heteroaliphatic, and an optionally substituted Ci-C6 haloaliphatic;
[0177] me is 0, 1, or 2; and [0178] ne is 0 or 1. [0179] In an embodiment are TPO modulators having the structure of Formula
XII:
Figure imgf000029_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
[0180] Rlf is selected from CO2R10f, CONR10fRllf, SO3R10f, and a carboxylic acid bioisostere;
[0181] R2f and R3f are each independently selected from null, hydrogen, OR12f, NR12fR13f, an optionally substituted C1-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfR14f; or R2f and R3f taken together form an optionally substituted olefin; or R2f and R3f are linked to form an optionally substituted C3-Cs ring;
[0182] R4f is selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
[0183] R5f is selected from hydrogen, OR10f, SR10f, NHRllf, and CO2H;
[0184] R6f is selected from hydrogen, OR12f, NR12fR13f, fluorine (F), chlorine (Cl), bromine (Br), C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 heteroalkyl; [0185] R7f is selected from hydrogen, an optionally substituted Ci-C8 aliphatic, an optionally substituted Ci-Cg haloaliphatic, an optionally substituted Ci-Cg heteroaliphatic, an optionally substituted Ci-Cg heterohaloaliphatic, an optionally substituted ring, and (CH2)mfR14f;
[0186] R8f and R9f are each independently selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), CO2R10f, NO2, CN, SO2R10f, (CH2)mfR14f, Ci-C4 aliphatic, C1- C4 haloaliphatic, Ci-C4 heteroaliphatic, and Ci-C4 heterohaloaliphatic;
[0187] R10f is selected from hydrogen, an optionally substituted Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
[0188] Rllf is selected from hydrogen, SO2R15f, Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
[0189] R12f and R13f are each independently selected from hydrogen, an optionally substituted Ci-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfRlf4; or one of R12f and R13f is an optionally substituted C2-C6 aliphatic or an optionally substituted ring and the other of R12f and R13f is null; or R12f and R13f are linked to form an optionally substituted C3-C8 ring;
[0190] R14f is selected from an optionally substituted aryl and an optionally substituted heteroaryl;
[0191] R15f is selected from hydrogen, Ci-C3 aliphatic, Ci-C3 haloaliphatic, and a ring;
[0192] mf is O, 1, or 2; and
[0193] nf is O or l.
[0194] In certain embodiments a TPO modulator of Formula XII can have the structure:
Figure imgf000031_0001
Compound 1.
[0195] Compound 1 can be synthesized according to the methods disclosed in U.S. Pat. No. 7,314, 887, incorporated herein in its entirety.
[0196] In an embodiment are TPO modulators having the structure of Formula XIII:
Figure imgf000031_0002
wherein:
[0197] Ra is selected from the group consisting of hydrogen, Ci_6alkyl, - (CH2)pOR4a, -C(O)OR4a, formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, -S(O)nR4a, cycloalkyl, -NR5aR6a, protected -OH, -CONR5aR6a, phosphonic acid, sulfonic acid, phosphinic acid, -SO2NR5aR6a, a heterocyclic methylene substituent as represented by Formula (XIII-A),
Figure imgf000031_0003
(XIII-A)
a substituent as represented by Formula (XIII-B),
Figure imgf000032_0001
(XIII-B) and a substituent as represented by Formula (XIII-C),
Figure imgf000032_0002
(XIII-C)
where,
[0198] p is 0-6,
[0199] n is 0-2,
[0200] m is 0-2,
[0201] Wa and Za are each independently selected from C, O, S and NR16a, where R16a is selected from: hydrogen, alkyl, cycloalkyl, d-Ci2aryl, substituted alkyl, substituted cycloalkyl and substituted Ci-Ci2aryl,
[0202] Va and Xa are each independently selected from O, S and NR16a, where R16a is selected from: hydrogen, alkyl, cycloalkyl, d-Ci2aryl, substituted alkyl, substituted cycloalkyl and substituted Ci-Ci2aryl,
[0203] R4a is selected from: hydrogen, alkyl, cycloalkyl, Ci-Ci2aryl, substituted alkyl, substituted cycloalkyl and substituted d-Ci2aryl,
[0204] R5a and R6a are each independently selected from hydrogen, alkyl, substituted alkyl, C3_6cycloalkyl, and aryl,
[0205] or R5a and R6a taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, [0206] Ta is absent or selected from O, S and NR16a, where R16a is selected from: hydrogen, alkyl, cycloalkyl, Ci-C12aryl, substituted alkyl, substituted cycloalkyl and substituted
Figure imgf000033_0001
[0207] Pa is selected from OR4a, SR4a, NR5aR6a, and R4a,
[0208] R25a is selected from: hydrogen, alkyl, cycloalkyl, Ci-C12aryl, substituted alkyl, substituted cycloalkyl and substituted
Figure imgf000033_0002
and
[0209] R30a is selected from: hydrogen, alkyl, cycloalkyl, C1-C12MyI, substituted alkyl, substituted cycloalkyl and substituted Ci-Ci2aryl,
[0210] naa is 0 or l,
[0211] Rlaa is selected from CO2R10", CONR10bRllb, SO3R10b, and a carboxylic acid bioisostere;
[0212] R2aa and R3aa are each independently selected from hydrogen, OR12b, NR12bR13b, =NR12b, an optionally substituted Ci-C4 alkyl, an optionally substituted Ci-C4 haloalkyl, an optionally substituted Ci-C4 heteroalkyl, and (CH2)mR14b, or R2aa and R3aa are independently absent or taken together form an optionally substituted olefin or are linked to form an optionally substituted C3-Cs ring or one of R2aa or R3aa is linked to Rlaa to form an optionally substituted C3-Cs ring,
[0213] R1Ob is selected from hydrogen, an optionally substituted Ci-C4 alkyl, an optionally substituted Ci-C4 haloalkyl, and an optionally substituted Ci-C4 heteroalkyl,
[0214] Rllb is selected from hydrogen, SO2R15b, an optionally substituted C1- C4 alkyl, an optionally substituted Ci-C4 haloalkyl, and an optionally substituted Ci-C4 heteroalkyl,
[0215] R12b and R13b are each independently selected from hydrogen, an optionally substituted Ci-C4 alkyl, an optionally substituted Ci-C4 haloalkyl, an optionally substituted Ci-C4 heteroalkyl, and (CH2)mR14b; or R12b and R13b are linked to form an optionally substituted C3-Cs ring,
[0216] R14b is selected from an optionally substituted C6-CiO aryl and an optionally substituted C3-CiO heteroaryl,
[0217] R15b is selected from hydrogen, an optionally substituted Ci-C3 alkyl, an optionally substituted Ci-C3 haloalkyl, and an optionally substituted C6-CiO aryl,
[0218] m is 0-6,
[0219] Zb is selected from: a 2-5 atom spacer selected from an optionally substituted C6-CiO aryl and an optionally substituted C3-C10 heteroaryl, and a 1-5 atom spacer selected from an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 heteroalkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 heteroalkenyl, an optionally substituted C2-C6 haloalkenyl, an optionally substituted C2-C6 alkynyl, and an optionally substituted C2-C6 heteroalkyl;
[0220] Rla, R2a and R3a are each independently selected from hydrogen, C1. 6alkyl, -(CH2)pOR4a, -C(O)OR4a, formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, -S(O)nR4a, cycloalkyl, -NR5aR6a, protected -OH, -CONR5aR6a, phosphonic acid, sulfonic acid, phosphinic acid, -SO2NR5aR6a, a heterocyclic methylene substituent as represented by Formula (XIII-A), and a substituent as represented by Formula (XIII-B),
[0221] where,
[0222] p is 0-6,
[0223] n is 0-2; and
[0224] Y is a cyclic or polycyclic, unsaturated or saturated, non-aromatic ring containing from 3 to 16 carbon atoms and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N- acylamino, nitro, cyano, halogen, -C(O)OR4, -C(O)NR10R11, -S(O)2NR10R11, -S(O)nR4 and protected -OH,
[0225] where n is 0-2,
[0226] R4ab is hydrogen, alkyl, cycloalkyl, Ci-Ci2aryl, substituted alkyl, substituted cycloalkyl and substituted Ci-Ci2aryl, and
[0227] R1Oab and Rllab are independently hydrogen, cycloalkyl, C1-C12MyI, substituted cycloalkyl, substituted Ci-C12aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N- acylamino, oxo, hydroxy, -C(O)OR4ab, -S(O)nR4ab, -C(O)NR4abR4ab, -S(O)2NR4abR4ab, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl and protected -OH,
[0228] or R1Oab and Rllab taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen,
[0229] and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
[0230] In another embodiment are TPO modulators having the structure of Formula XIV:
Figure imgf000035_0001
XIV
wherein:
[0231] Aria is aryl, monocyclic aromatic heterocycle, or bicyclic condensed heterocycle, each of which may be substituted;
[0232] Rlc is aryl or monocyclic aromatic heterocycle, each of which may be substituted;
[0233] R2c is a group represented by the following general Formula (XIV-A), (XIV-B) or (XIV-C):
Figure imgf000035_0002
Figure imgf000035_0003
Jc=z Lc
(XIV-C) Gc^ JM . Ec
[0234] wherein nc is an integer of 1 to 3;
[0235] mc is an integer of 1 to 3, (when nc or mc is an integer of 2 or more, CR2θcR2ic and CR22cR23c may bg identical or different);
[0236] Xc is O, S, or a group represented by N-R26c or C(-R27c)-R28c;
[0237] Ec, Gc, Jc, Lc are independently N or a group represented by C-R29c, with the proviso that at least one of them is C-R29c;
[0238] R20c, R21c, R22c, R23c, R26c, R27c, R28c, and R29c are each independently selected from the group consisting of hydrogen; -OH; -0-lower alkyl; optionally substituted lower alkyl; optionally substituted cycloalkyl; optionally substituted aryl; optionally substituted arylalkyl; optionally substituted aromatic heterocycle; optionally substituted aromatic heterocyclic alkyl; optionally substituted nonaromatic heterocycle; optionally substituted lower alkenyl; optionally substituted lower alkylidene; -COOH; - COO-lower alkyl; -COO-lower alkenyl; -COO-lower alkylene-aryl; -COO-lower alkylene-aromatic heterocycle; carbamoyl and amino, each of which may be substituted with one or more groups selected from the group consisting of lower alkyl and cycloalkyl, each of which may be substituted with halogen, -OH, -0-lower alkyl, or -O-aryl; - NHCO-lower alkyl; or oxo; and
[0239] R24c are R25c are each independently selected from the group consisting of, hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, and optionally substituted nonaromatic heterocycle.
Treatment Regimens
[0240] In some embodiments, a loading dose of a TPO modulator can be administered to a subject to provide a therapeutic amount of the TPO modulator in the subject more rapidly than would occur by repeated smaller doses of the TPO modulator for the treatment of thrombocytopenia or neutropenia.
[0241] It was discovered that certain compounds that modulate TPO activity require a significant period of time to achieve a therapeutic effect. Accordingly, in some embodiments, the loading dose of the TPO modulator can be a multiple of the quantity of the TPO modulator administered per day using smaller maintenance doses of said TPO modulator. For example, the loading dose can be from about 2 times to about 24 times the quantity of the TPO modulator administered per day using smaller maintenance doses of the TPO modulator. In a typical embodiment, the loading dose of the TPO modulator can be from about 4 times to about 12 times the quantity of the TPO modulator administered per day using smaller maintenance doses of the TPO modulator. In a more typical embodiment, the loading dose can be from about 6 times to about 10 times the quantity of the TPO modulator administered per day using smaller maintenance doses of the TPO modulator.
[0242] The amount of the TPO modulator administered in a loading dose can be from about 6 mg to about 30 mg, from about 30 mg to about 60 mg, from about 60 mg to about 120 mg, and from about 120 mg to about 600 mg. In a typical embodiment, the amount of the TPO modulator administered in a loading dose can be from about 30 mg to about 120 mg. In a more typical embodiment, the amount of the TPO modulator administered in a loading dose can be from about 30 mg to about 90 mg. In a more typical embodiment, the amount of the TPO modulator administered in a loading dose can be from about 36 mg to about 120 mg. For example, the loading dose can be 45 mg, 60 mg, 80 mg, or 100 mg of the TPO modulator. In a most typical embodiment, the loading dose can be from about 42 to about 78 mg of the TPO modulator.
[0243] Some embodiments provide a method of increasing blood platelet counts in a subject comprising administering a loading dose of a TPO modulator. In some embodiments, the blood platelet counts can increase from about 30% to about 40% from baseline, from about 40% to about 50% from baseline, from about 50% to about 60% from baseline, from about 60% to about 80% from baseline, from about 50% to about 60% from baseline, from about 60% to about 80% from baseline, from about 80% to about 100% from baseline, or from about 100% to about 150% from baseline. For example, the blood platelet counts can increase from about 30% to about 150% from a reading of the blood platelet counts in the subject prior to treatment with the TPO modulator. In some embodiments, the amount of TPO modulator administered in a loading dose can be from about 6 mg to about 30 mg, from about 30 mg to about 60 mg, from about 60 mg to about 120 mg, and from about 120 mg to about 600 mg. In a typical embodiment, the amount of the TPO modulator administered in a loading dose can be from about 30 mg to about 90 mg. In a more typical embodiment, the amount of the TPO modulator administered in a loading dose can be from about 36 mg to about 120 mg. For example, the loading dose can be 45 mg, 60 mg, 80 mg, or 100 mg of the TPO modulator. In a most typical embodiment, the loading dose can be from about 42 to about 78 mg of the TPO modulator.
[0244] Some embodiments provide a method of increasing blood platelet counts in a subject comprising administering a loading dose of a TPO modulator followed by a maintenance dose of a TPO modulator. In some embodiments, the amount of maintenance dose of the TPO modulator can be from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 20 mg, about 20 mg to about 100 mg, and about 100 mg to about 400 mg. In a typical embodiment, the amount of maintenance dose can be from about 2 mg to about 25 mg. In a more typical embodiment, the amount of maintenance dose can be from about 4 mg to about 15 mg. In an exemplary embodiment, the amount of maintenance dose can be from about 5 mg to about 10 mg.
[0245] In some embodiments, the amount of maintenance dose can be from about 1 mg to about 100 mg and the amount of loading dose can be from about 6 mg to about 600 mg. For example, the amount of maintenance dose can be from about 1.5 mg to about 40 mg and the amount of loading dose can be from about 9 mg to about 240 mg. In a typical embodiment, the amount of maintenance dose can be from about 2 mg to about 20 mg and the amount of loading dose can be from about 12 mg to about 120 mg. In a more typical embodiment, the amount of maintenance dose can be from about 4 mg to about 15 mg and the amount of loading dose can be from about 24 mg to about 90 mg. In an exemplary embodiment, the amount of maintenance dose can be from about 5 mg to about 10 mg and the amount of loading dose can be from about 30 mg to about 60 mg.
[0246] Some embodiments provide a method of treating thrombocytopenia in a subject comprising administering a single dose of a TPO modulator from about once every 24 hrs to about once every 20 days. For example, the TPO modulator can be administered once every 24 hrs, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 14 days or once every 20 days.
[0247] Some embodiments provide a method of treating neutropenia in a subject comprising administering a single dose of a TPO modulator from about once every 24 hrs to about once every 20 days. For example, the TPO modulator can be administered once every 24 hrs, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every days 7, once every 14 days or once every 20 days.
[0248] In some embodiments, the steady state blood plasma concentration can be reached by administration of a single dose of a TPO modulator. For example, in some embodiments, the steady state concentration can be reached within 14 days of administration of a single dose of the TPO modulator. In some embodiments, the steady state concentration can be reached within 7 days of administration of a single dose of the TPO modulator. In some embodiments, the steady state concentration can be reached within 2 days of administration of a single dose of the TPO modulator.
[0249] In some embodiments, the steady state blood plasma concentration can be reached within 24 hrs of administration of a single dose of a TPO modulator. For example, the steady state blood plasma concentration can be reached by administration of TPO modulator in an amount ranging from about 6 mg to about 30 mg, from about 30 mg to about 60 mg, from about 60 mg to about 120 mg, and from about 120 mg to about 600 mg. In a typical embodiment, the amount of the TPO modulator administered in a single dose can be from about 30 mg to about 90 mg. In a more typical embodiment, the amount of the TPO modulator administered in a single dose can be from about 36 mg to about 120 mg. For example, the single dose can be 45 mg, 60 mg, 80 mg, or 100 mg of the TPO modulator. In a most typical embodiment, the single dose can be from about 42 to about 78 mg of the TPO modulator.
[0250] In some embodiments, the steady state blood plasma concentration can be maintained after administration of a loading dose of a TPO modulator by administering a maintenance dose of the TPO modulator. In some embodiments, the amount of the maintenance dose administered per day can be from about 1% to about 75% of the loading dose. In a typical embodiment, the amount of the maintenance dose administered per day can be from about 5% to about 25% of the loading dose. In a more typical embodiment, the amount of the maintenance dose administered per day can be from about 10% to about 20% of the loading dose.
[0251] In some embodiments, a steady state blood plasma concentration of a TPO modulator can be attained in a subject by using a loading dose of a TPO modulator and a subsequent maintenance dose of the TPO modulator. In some embodiments, the amount of the maintenance dose administered to the subject per day can be from about 1% to about 75% of the loading dose. In a typical embodiment, the amount of the maintenance dose administered to the subject per day can be from about 5% to about 25% of the loading dose. In a more typical embodiment, the amount of the maintenance dose administered to the subject per day can be from about 10% to about 20% of the loading dose.
[0252] In some embodiments, a treatment regimen including a loading dose of a TPO modulator can increase the blood platelet count in a subject faster than a treatment regimen without a loading dose. For example, the loading dose of the TPO modulator can be administered to the subject on day one of the treatment regimen followed by administration of a maintenance dose during the remainder of the treatment regimen. In contrast, a treatment regimen can have a maintenance dose of a TPO modulator administered to the subject on day one and continued throughout the remainder of the treatment regimen. The treatment regimen with the loading dose of the TPO modulator can increase the blood platelet count faster than the treatment regimen without the loading dose. In a typical embodiment, the loading dose of the TPO modulator can be from about 4 times to about 12 times the quantity of the TPO modulator administered in the maintenance dose. For example, if the loading dose is 30 mg of the TPO modulator than the maintenance dose can range from about 2.5 mg to about 7.5 mg of the TPO modulator, if the loading dose is 45 mg of the TPO modulator than the maintenance dose can range from about 3.75 mg to about 11.25 mg of the TPO modulator, if the loading dose is 60 mg of the TPO modulator than the maintenance dose can range from about 5 mg to about 15 mg of the TPO modulator, if the loading dose is 80 mg of the TPO modulator than the maintenance dose can range from about 6.5 mg to about 20 mg of the TPO modulator, and if the loading dose is 100 mg of the TPO modulator than the maintenance dose can range from about 8 mg to about 25 mg of the TPO modulator. In some embodiments, the loading dose can be from about 30 mg to about 60 mg, from about 60 mg to about 90 mg, from about 90 mg to about 120 mg, from about 120 mg to about 250 mg, and from 250 mg to about 500 mg.
[0253] Some embodiments provide a method of treating thrombocytopenia in a subject comprising administering a TPO modulator with a half- life ranging from about 12 hours to about 45 hours, from about 45 hours to about 100 hours, from about 100 hours to about 180 hours. For example, the TPO modulator can have a half-life ranging from about 60 hours to about 100 hours. In a typical embodiment, the TPO modulator can have a half- life ranging from about 80 hours to about 100 hours.
[0254] In some embodiments, the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 14 days or once every 20 days. In a typical embodiment, the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 14 days or once every 20 days in an amount ranging from about 30 mg to about 250 mg. In an exemplary embodiment, the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 14 days or once every 20 days in an amount ranging from about 40 mg to about 120 mg.
[0255] Some embodiments provide a method of treating neutropenia in a subject comprising administering a TPO modulator with a half- life ranging from about 12 hours to about 45 hours, from about 45 hours to about 100 hours, from about 100 hours to about 180 hours. For example, the TPO modulator can have a half-life ranging from about 60 hours to about 100 hours.
[0256] In some embodiments, the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 14 days or once every 20 days. In a typical embodiment, the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 14 days or once every 20 days in an amount ranging from about 30 mg to about 250 mg. In an exemplary embodiment, the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 9 days, once every 14 days or once every 20 days in an amount ranging from about 40 mg to about 120 mg. [0257] Some embodiments provide a method of increasing blood platelet count in a subject comprising administering a TPO modulator with a half- life ranging from about 12 hours to about 45 hours, from about 45 hours to about 100 hours, from about 100 hours to about 180 hours. For example, the TPO modulator can have a half-life ranging from about 60 hours to about 100 hours. In a typical embodiment, the TPO modulator can have a half-life ranging from about 80 hours to about 100 hours. The TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 14 days or once every 20 days. In some embodiments, the TPO modulator can be administered to the subject once every 24 hours, once every 2 days, once every 3 days or once every 4 days. In some embodiments, the TPO modulator can be administered to the subject once every 4 days, once every 5 days, once every 6 days, once every 7 days, or once every 8 days. In some embodiments, the TPO modulator can be administered to the subject once every 14 days or once every 20 days. The blood platelet count can be increased from a pre-treatment reading by about 30 % to about 100 %.
The following examples further illustrate and support the clinical efficacy of the present disclosure: Example 1 Mean Percent Change in Platelets from Baseline with Single Doses of Compound 1
[0258] These studies were conducted in 54 healthy male volunteers. Single doses were tested at 1, 5, 10, 20, 40, 60, 90, and 120 mg Compound 1. Subjects were randomized to 8-subject cohorts; in each cohort six subjects received Compound 1 treatment, and two received placebo treatment. Oral absorption was predictable and PK parameters were linear with dose. Compound 1 was determined to have a half-life in humans of approximately 90 hr (3.75 days).
[0259] Starting at a single dose of 40 mg, there was a significant mean increase in platelet counts of 29% above baseline (BL), at 60 mg platelet counts were 22%, at 90 mg platelet counts increased to 43%, and at 120 mg platelet counts had increased to 55.7% above BL, which exceeded the limit for dose escalations. The placebo group had an increase of mean platelet counts of 10.3% above BL. The increase in platelet counts with time for single doses of Compound 1 is seen in Figure 1. [0260] The increase in platelet counts from single doses of Compound 1 appeared to be generally proportional to the Compound 1 dose, except for the 40 mg cohort. The higher platelet counts at 40 mg may have been related to the limited cohort size (N = 4). The ability of Compound 1 to substantially increase platelet counts for at least one week from single doses of > 40 mg was observed.
[0261] The mean maximal percent change in platelet counts in each dose group averaged the maximum platelet counts from all subjects in the group at any time during study evaluations. It was a useful safety parameter for evaluating the mean highest group responses influenced by excessively high platelet counts. No subject reached platelet counts of 600,000/μL at any evaluated dose with Compound 1. The mean maximal percent change in platelet counts from BL is shown for all single doses in Figure 2. The data shows that single doses of 40 mg to 60 mg of Compound 1 did not stimulate platelet counts more than 2 times above BL.
Example 2
Compound 1 Multiple Doses Correlating With Platelet Increase Mean %-Change from Baseline with 5, 7.5 and 10 mg Without Loading dose
[0262] Compound 1 doses of 5.0, 7.5, and 10.0 mg/day were evaluated for 14 days without loading doses. Platelet counts, adverse events (AEs), vital signs and laboratory parameters were followed for 35 days or longer if needed during multiple doses, until platelet counts returned to within 10% of baseline (BL). The 5.0, 7.5 and 10.0 mg/day dose groups increased the mean platelet counts 37%, 47%, and 82% above the mean counts at BL, respectively. The 10 mg dose group reached the limit of dose escalation (50% above BL) in the protocol. The graphs of platelet counts with time for 14 daily doses of Compound 1 are presented in Figure 3.
[0263] The platelet count increases for doses of 5.0 and 7.5 mg/day were clearly separated from changes seen in the group receiving placebo, despite the data variability due to the small number of patients. The 10 mg dose produced a more rapid increase in platelets, than seen in subjects treated with lower doses. The increases in platelet counts were also seen earlier (between Days 6 and 8) in subjects treated with 10 mg than in subjects treated with lower drug doses. Example 3
Compound 1 Multiple Doses with or without First Day Loading dose of 6 times 7.5 mg Daily Dosing
[0264] The Idiopathic thrombocytopenic purpura (ITP) indication is believed to need less stimulation of platelets than occurred with 10 mg/day dosing because platelet counts can rise unexpectedly high rapidly in some patients with ITP. The 2.5, 5.0, and 7.5 mg/day doses were examined as potentially optimal for ITP. In order to evoke an earlier onset of increases in platelet counts at these doses, a loading dose was tested at the start of treatment. A loading dose was given to achieve a steady-state concentration in the blood as early as Day 1 and therefore an earlier onset of the increase in platelet counts. The steady-state condition of systemic drug exposure was considered best for maintaining stabilized platelet counts. The loading dose tested was 6 times the daily dose, based on computations using the I1A of Compound 1. A loading dose of 45 mg was given on Day 1 to a cohort of healthy subjects who were to receive the 7.5 mg daily dose for 13 days. This produced an earlier and greater platelet response than occurred with a cohort of healthy subjects who received the 7.5 mg daily dose without a loading dose on Day 1.
[0265] When a first day loading dose was added to 7.5 mg/day dosing, it increased the response and its onset was earlier. The loading dose was 45 mg, 6 times the daily dose. For Compound 1 the half life of the drug in blood indicates that a loading dose of 6 X daily dose (6 X 7.5 = 45) will bring the drug to steady state maintenance levels within the 1st day.
[0266] Figure 4 shows that the loading dose produced an earlier onset of platelet response by at least 6 days and a greater change from the BL platelet counts, when compared with the same treatment without a loading dose. Pharmacokinetic measurements confirmed that use of a loading dose achieved near steady state exposure of Compound 1 in subjects' blood on Day 1.
[0267] The mean maximal percent changes in platelet counts from baseline (BL) are shown for all multiple doses in Figure 5. (The mean maximal percent change in platelet counts in each dose group averages the maximum platelet counts from all subjects in the group at any time during study observations.) There was significant activity and dose proportionality in the mean maximal percent change in platelets from BL. The loading dose did not have a significant effect on the percent change in platelets until the 7.5 mg dose when it contributed to an additional 30% increase from BL. The data indicated that multiple Compound 1 doses, with or without a loading dose, did not stimulate platelet counts more than 2 times above BL for a normal platelet level.
[0268] The 2.5 mg/day, 5.0 mg/day, and 7.5 mg/day doses of Compound 1 were tested with a loading dose. The 2.5 mg/day dose with a 15 mg loading dose produced a mean 22.5% increase in platelets, 5.0 mg/day with a 30 mg loading dose produced a mean 41% increase in platelets, and 7.5 mg/day with a 45 mg loading dose produced a mean 76% increase in platelets, above their respective mean platelet counts at baseline. This compared with a 12.4% mean for placebo. These results are shown in Figure 6.
[0269] The tested Compound 1 doses, with or without a loading dose, were very well tolerated (Figure 6). The earlier steady state of Compound 1 concentration achieved with a loading dose should lead to an earlier and potentially more stable platelet response. The half-life of Compound 1 should also lead to a slow gradual decline in normal platelets (approximately 2 to 3 weeks) when Compound 1 administration is terminated.
[0270] There is a dose onset to the response enhancement by a loading dose for Compound 1. The response enhancement seems to begin at loading doses of about 40 mg Compound 1 and should continue at higher doses See Table 1 below for loading doses of 15 mg for 2.5 mg daily dose, 30 mg for 5mg daily dose and 45 mg for 7.5 mg daily dose.
[0271] The reason for this response threshold for Compound 1 may be tight binding by serum proteins and platelets so there is little free Compound 1 below 40 mg. The threshold level will depend on the binding affinity of any particular TPO modulator; for Compound 1 it is about 40 mg. Compound 1 binds to serum proteins at about 98.7% For instance, response is seen at single dose activity for 40 mg doses and above, but not below 40 mg. The loading doses of 15 mg for 2.5 mg/day and 35 mg with 5 mg/day did not greatly affect the platelet response or its onset as shown in the Table 1 and Figure 5. Table 1
Figure imgf000045_0001
Figure imgf000046_0001
^Comparing max. %-change from baseline in Active vs. Placebo using ANOVA model, data was rank-transformed and p-values were adjusted for multiplicity.
Summary of Phase I Efficacy
[0272] Compound 1 Single Doses
• Statistically increased platelets at 40, 60, 90 and 120 mg compared to Placebo
• 90 mg increased platelets up to 41% at Day 16; 120 mg to 56% at Day 12
• Onset of activity started Day 3-6
• Linear Pharmacokinetics with dose; 90 hour half-life
• Supports a once-a-week dose regimen with a 90 hour half-life [0273] Compound 1 Multiple Doses
• Increased platelets at all doses tested with statistically significant differences at 7.5mg QD, 7.5mg QD w/ 45mg Dl load, and lOmg QD compared to Placebo.
• Platelets increased approximately proportional to Compound 1 exposure
• 1 Omg QD increased platelets up to 83% at Day 22
• 45 mg Day-1 loading dose with 7.5 mg QD x 13 days o increased platelets to 76% at Day 18 o advanced the platelet response curve substantially earlier with a sharper rise in platelet counts [0274] Linear pharmacokinetics observed with multiple doses

Claims

WHAT IS CLAIMED IS:
1. A method of treating thrombocytopenia in a subject in need thereof which comprises administering a single dose of a TPO modulator wherein the amount of TPO modulator administered in a single dose is sufficient to increase platelet production at least about 10% from an initial baseline level.
2. The method of Claim 1, wherein the platelet count is increased from about 35% to about 100% from an initial baseline level within 20 days of administration of the single dose.
3. The method of Claim 1, wherein TPO modulator has a half-life ranging from about 60 hours to about 120 hours.
4. The method of Claim 1, wherein a steady state concentration is reached using the single dose of the TPO modulator.
5. The method of Claim 4 further comprising administering a maintenance dose of the TPO modulator sufficient to maintain the steady state concentration.
6. The method of Claim 5, wherein the amount of the TPO modulator administered to the subject in the maintenance dose is from about 3 mg/day to about 150 mg/ day.
7. The method of Claim 6, wherein the amount of the TPO modulator administered to the subject in the maintenance dose is from about 5 mg/day to about 15 mg/ day.
8. The method of Claim 7, wherein the single dose of the TPO modulator is from about 4 times to about 10 times the maintenance dose of the TPO modulator.
9. The method of Claim 5, wherein the steady state concentration is reached within 14 days of administration of the single dose of the TPO modulator.
10. The method of Claim 5, wherein the steady state concentration is reached within 7 days of administration of the single dose of the TPO modulator.
11. The method of Claim 5, wherein the steady state concentration is reached within 2 days of administration of the single dose of the TPO modulator.
12. The method of Claim 5, wherein the steady state concentration is reached within 24 hours of administration of the single dose of the TPO modulator.
13. The method of Claim 1 wherein the TPO modulator is a compound having the formula XII:
Figure imgf000048_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
Rlf is selected from CO2R10f, CONR10fRllf, SO3R10f, and a carboxylic acid bioisostere;
R2f and R3f are each independently selected from null, hydrogen, OR12f, NR12fR13f, an optionally substituted C1-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfR14f; or R2f and R3f taken together form an optionally substituted olefin; or R2f and R3f are linked to form an optionally substituted C3-Cs ring;
R ,4f is selected from hydrogen, fluorine (F), Chlorine (Cl), Bromine (Br), C1- C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
R5f is selected from hydrogen, OR10f, SR10f, NHRllf, and CO2H; R6f is selected from hydrogen, OR12f, NR12fR13f, fluorine (F), chlorine (Cl), bromine (Br), Ci -C4 alkyl, Ci-C4 haloalkyl, and Ci-C4 heteroalkyl;
R7f is selected from hydrogen, an optionally substituted Ci-Cs aliphatic, an optionally substituted Ci-Cg haloaliphatic, an optionally substituted Ci-Cg heteroaliphatic, an optionally substituted Ci-Cg heterohaloaliphatic, an optionally substituted ring, and (CH2)mfR14f;
R8f and R9f are each independently selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), CO2R10f, NO2, CN, SO2R10f, (CH2)mfR14f, Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and Ci-C4 heterohaloaliphatic;
R10f is selected from hydrogen, an optionally substituted Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
Rllf is selected from hydrogen, SO2R15f, C1-C4 aliphatic, C1-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
R12f and R13f are each independently selected from hydrogen, an optionally substituted Ci-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfRlf4; or one of R12f and R13f is an optionally substituted C2-C6 aliphatic or an optionally substituted ring and the other of R12f and R13f is null; or R12f and R13f are linked to form an optionally substituted C3-Cg ring;
R14f is selected from an optionally substituted aryl and an optionally substituted heteroaryl;
R15f is selected from hydrogen, C1-C3 aliphatic, C1-C3 haloaliphatic, and a ring; mf is 0, 1, or 2; and nf is 0 or 1.
14. The method of Claim 13 wherein the TPO modulator is compound 1 having the formula:
Figure imgf000050_0001
Compound 1.
15. A method of treating thrombocytopenia in a subject in need thereof which comprises administering a single dose of a TPO modulator wherein the amount of TPO modulator administered in a single dose is sufficient to achieve steady state concentration levels of the TPO modulator in said subject.
16. The method of Claim 15 further comprising administering a maintenance dose of the TPO modulator sufficient to maintain the steady state concentration.
17. The method of Claim 16, wherein the amount of the TPO modulator administered to the subject in the maintenance dose is from about 3 mg/day to about 150 mg/ day.
18. The method of Claim 17, wherein the amount of TPO modulator administered to the subject in the maintenance dose is from about 5 mg/day to about 15 mg/ day.
19. The method of Claim 18, wherein the single dose of the TPO modulator is from about 4 times to about 10 times the maintenance dose of the TPO modulator.
20. The method of Claim 16, wherein the steady state concentration is reached within 14 days of administration of the single dose of the TPO modulator.
21. The method of Claim 16, wherein the steady state concentration is reached within 7 days of administration of the single dose of the TPO modulator.
22. The method of Claim 16, wherein the steady state concentration is reached within 2 days of administration of the single dose of the TPO modulator.
23. The method of Claim 16, wherein the steady state concentration is reached within 24 hours of administration of the single dose of the TPO modulator.
24. The method of Claim 15 wherein the TPO modulator is a compound having the formula XII:
Figure imgf000051_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
Rlf is selected from CO2R10f, CONR10fRllf, SO3R10f, and a carboxylic acid bioisostere;
R2f and R3f are each independently selected from null, hydrogen, OR12f, NR12fR13f, an optionally substituted C1-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfR14f; or R2f and R3f taken together form an optionally substituted olefin; or R2f and R3f are linked to form an optionally substituted C3-Cg ring; R4f is selected from hydrogen, fluorine (F), Chlorine (Cl), Bromine (Br), C1- C4 aliphatic, C1-C4 haloaliphatic, C1-C4 heteroaliphatic, and a ring;
R5f is selected from hydrogen, OR10f, SR10f, NHRllf, and CO2H;
R6f is selected from hydrogen, OR12f, NR12fR13f, fluorine (F), chlorine (Cl), bromine (Br), Ci -C4 alkyl, Ci -C4 haloalkyl, and Ci-C4 heteroalkyl;
R7f is selected from hydrogen, an optionally substituted Ci-Cs aliphatic, an optionally substituted Ci-Cg haloaliphatic, an optionally substituted Ci-Cg heteroaliphatic, an optionally substituted Ci-Cg heterohaloaliphatic, an optionally substituted ring, and (CH2)mfR14f;
R8f and R9f are each independently selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), CO2R10f, NO2, CN, SO2R10f, (CH2)mfR14f, Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and Ci-C4 heterohaloaliphatic;
R10f is selected from hydrogen, an optionally substituted Ci-C4 aliphatic, C1-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
Rllf is selected from hydrogen, SO2R15f, C1-C4 aliphatic, C1-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
R12f and R13f are each independently selected from hydrogen, an optionally substituted Ci-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfRlf4; or one of R12f and R13f is an optionally substituted C2-C6 aliphatic or an optionally substituted ring and the other of R12f and R13f is null; or R12f and R13f are linked to form an optionally substituted C3-Cg ring;
R14f is selected from an optionally substituted aryl and an optionally substituted heteroaryl;
R15f is selected from hydrogen, C1-C3 aliphatic, C1-C3 haloaliphatic, and a ring; mf is 0, 1, or 2; and nf is 0 or 1.
25. The method of Claim 24 wherein the TPO modulator is compound 1 having the formula:
Figure imgf000053_0001
Compound 1.
26. A method of treating neutropenia in a subject in need thereof which comprises administering a single dose of a TPO modulator wherein the amount of TPO modulator administered in a single dose is sufficient to increase platelet production at least about 10% from an initial baseline level.
27. The method of Claim 26, wherein the platelet count is increased from about 35% to about 100% from an initial baseline level within 20 days of administration of the single dose.
28. The method of Claim 26, wherein TPO modulator has a half- life ranging from about 60 hours to about 120 hours.
29. The method of Claim 26, wherein a steady state concentration is reached using the single dose of the TPO modulator.
30. The method of Claim 29 further comprising administering a maintenance dose of the TPO modulator sufficient to maintain the steady state concentration.
31. The method of Claim 30, wherein the amount of the TPO modulator administered to the subject in the maintenance dose is from about 3 mg/day to about 150 mg/ day.
32. The method of Claim 31, wherein the amount of the TPO modulator administered to the subject in the maintenance dose is from about 5 mg/day to about 15 mg/ day.
33. The method of Claim 32, wherein the single dose of the TPO modulator is from about 4 times to about 10 times the maintenance dose of the TPO modulator.
34. The method of Claim 29, wherein the steady state concentration is reached within 14 days of administration of the single dose of the TPO modulator.
35. The method of Claim 29, wherein the steady state concentration is reached within 7 days of administration of the single dose of the TPO modulator.
36. The method of Claim 29, wherein the steady state concentration is reached within 2 days of administration of the single dose of the TPO modulator.
37. The method of Claim 29, wherein the steady state concentration is reached within 24 hours of administration of the single dose of the TPO modulator.
38. The method of Claim 26 wherein the TPO modulator is a compound having the formula XII:
Figure imgf000055_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
Rlf is selected from CO2R10f, CONR10fRllf, SO3R10f, and a carboxylic acid bioisostere;
R2f and R3f are each independently selected from null, hydrogen, OR12f, NR12fR13f, an optionally substituted Ci -C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfR14f; or R2f and R3f taken together form an optionally substituted olefin; or R2f and R3f are linked to form an optionally substituted C3-Cs ring;
R4f is selected from hydrogen, fluorine (F), Chlorine (Cl), Bromine (Br), C1- C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
R5f is selected from hydrogen, OR10f, SR10f, NHRllf, and CO2H;
R6f is selected from hydrogen, OR12f, NR12fR13f, fluorine (F), chlorine (Cl), bromine (Br), Ci-C4 alkyl, Ci-C4 haloalkyl, and Ci-C4 heteroalkyl;
R7f is selected from hydrogen, an optionally substituted Ci-Cs aliphatic, an optionally substituted Ci-Cs haloaliphatic, an optionally substituted Ci-Cs heteroaliphatic, an optionally substituted Ci-Cs heterohaloaliphatic, an optionally substituted ring, and (CH2)mfR14f;
R8f and R9f are each independently selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), CO2R10f, NO2, CN, SO2R10f, (CH2)mfR14f, Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and Ci-C4 heterohaloaliphatic; R10f is selected from hydrogen, an optionally substituted C1-C4 aliphatic, C1-C4 haloaliphatic, C1-C4 heteroaliphatic, and a ring;
Rllf is selected from hydrogen, SO2R15f, Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
R12f and R13f are each independently selected from hydrogen, an optionally substituted Ci-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfRlf4; or one of R12f and R13f is an optionally substituted C2-C6 aliphatic or an optionally substituted ring and the other of R12f and R13f is null; or R12f and R13f are linked to form an optionally substituted C3-Cs ring;
R14f is selected from an optionally substituted aryl and an optionally substituted heteroaryl;
R15f is selected from hydrogen, C1-C3 aliphatic, C1-C3 haloaliphatic, and a ring; mf is 0, 1, or 2; and nf is 0 or 1.
39. The method of Claim 39 wherein the TPO modulator is compound 1 having the formula:
Figure imgf000056_0001
Compound 1.
40. A method of treating neutropenia in a subject in need thereof which comprises administering a single dose of a TPO modulator sufficient to achieve steady state concentration levels of the TPO modulator in said subject.
41. The method of Claim 40, wherein a steady state concentration is reached using the single dose of the TPO modulator.
42. The method of Claim 41 further comprising administering a maintenance dose of the TPO modulator sufficient to maintain the steady state concentration.
43. The method of Claim 42, wherein the amount of the TPO modulator administered to the subject in the maintenance dose is from about 3 mg/day to about 150 mg/ day.
44. The method of Claim 43, wherein the amount of the TPO modulator administered to the subject in the maintenance dose is from about 5 mg/day to about 15 mg/ day.
45. The method of Claim 44, wherein the single dose of the TPO modulator is from about 4 times to about 10 times the maintenance dose of the TPO modulator.
46. The method of Claim 45, wherein the steady state concentration is reached within 14 days of administration of the single dose of the TPO modulator.
47. The method of Claim 42, wherein the steady state concentration is reached within 7 days of administration of the single dose of the TPO modulator.
48. The method of Claim 42, wherein the steady state concentration is reached within 2 days of administration of the single dose of the TPO modulator.
49. The method of Claim 42, wherein the steady state concentration is reached within 24 hours of administration of the single dose of the TPO modulator.
50. The method of Claim 40 wherein the TPO modulator is a compound having the formula XII:
Figure imgf000058_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
Rlf is selected from CO2R10f, CONR10fRllf, SO3R10f, and a carboxylic acid bioisostere;
R2f and R3f are each independently selected from null, hydrogen, OR12f, NR12fR13f, an optionally substituted Ci -C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfR14f; or R2f and R3f taken together form an optionally substituted olefin; or R2f and R3f are linked to form an optionally substituted C3-Cs ring;
R4f is selected from hydrogen, fluorine (F), Chlorine (Cl), Bromine (Br), C1- C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
R5f is selected from hydrogen, OR10f, SR10f, NHRllf, and CO2H;
R6f is selected from hydrogen, OR12f, NR12fR13f, fluorine (F), chlorine (Cl), bromine (Br), Ci-C4 alkyl, Ci-C4 haloalkyl, and Ci-C4 heteroalkyl;
R7f is selected from hydrogen, an optionally substituted Ci-Cs aliphatic, an optionally substituted Ci-Cs haloaliphatic, an optionally substituted Ci-Cs heteroaliphatic, an optionally substituted Ci-Cs heterohaloaliphatic, an optionally substituted ring, and (CH2)mfR14f;
R8f and R9f are each independently selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), CO2R10f, NO2, CN, SO2R10f, (CH2)mfR14f, Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and Ci-C4 heterohaloaliphatic; R10f is selected from hydrogen, an optionally substituted C1-C4 aliphatic, C1-C4 haloaliphatic, C1-C4 heteroaliphatic, and a ring;
Rllf is selected from hydrogen, SO2R15f, Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
R12f and R13f are each independently selected from hydrogen, an optionally substituted Ci-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfRlf4; or one of R12f and R13f is an optionally substituted C2-C6 aliphatic or an optionally substituted ring and the other of R12f and R13f is null; or R12f and R13f are linked to form an optionally substituted C3-Cs ring;
R14f is selected from an optionally substituted aryl and an optionally substituted heteroaryl;
R15f is selected from hydrogen, C1-C3 aliphatic, C1-C3 haloaliphatic, and a ring; mf is 0, 1, or 2; and nf is 0 or 1.
51. The method of Claim 50 wherein the TPO modulator is compound 1 having the formula:
Figure imgf000059_0001
Compound 1.
52. A method of increasing platelet production in a subject comprising: administering a single dose of a TPO modulator sufficient to achieve steady state concentration levels of the TPO modulator in said subject.
53. The method of Claim 52, wherein the platelet count is increased from about 35% to about 100% from an initial baseline level within 20 days of administration of the single dose.
54. The method of Claim 52, wherein TPO modulator has a half-life ranging from about 60 hours to about 120 hours.
55. The method of Claim 52, wherein the platelet production is increased prior to platelet pheresis, blood donation or platelet donation.
56. The method of Claim 52 wherein the TPO modulator is a compound having the formula XII:
Figure imgf000060_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
Rlf is selected from CO2R10f, CONR10fRllf, SO3R10f, and a carboxylic acid bioisostere;
R2f and R3f are each independently selected from null, hydrogen, OR12f, NR12fR13f, an optionally substituted C1-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfR14f; or R2f and R3f taken together form an optionally substituted olefin; or R2f and R3f are linked to form an optionally substituted C3-Cs ring; R4f is selected from hydrogen, fluorine (F), Chlorine (Cl), Bromine (Br), C1- C4 aliphatic, C1-C4 haloaliphatic, C1-C4 heteroaliphatic, and a ring;
R5f is selected from hydrogen, OR10f, SR10f, NHRllf, and CO2H;
R6f is selected from hydrogen, OR12f, NR12fR13f, fluorine (F), chlorine (Cl), bromine (Br), Ci -C4 alkyl, Ci -C4 haloalkyl, and Ci-C4 heteroalkyl;
R7f is selected from hydrogen, an optionally substituted Ci-Cs aliphatic, an optionally substituted Ci-Cg haloaliphatic, an optionally substituted Ci-Cg heteroaliphatic, an optionally substituted Ci-Cg heterohaloaliphatic, an optionally substituted ring, and (CH2)mfR14f;
R8f and R9f are each independently selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), CO2R10f, NO2, CN, SO2R10f, (CH2)mfR14f, Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and Ci-C4 heterohaloaliphatic;
R10f is selected from hydrogen, an optionally substituted Ci-C4 aliphatic, C1-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
Rllf is selected from hydrogen, SO2R15f, C1-C4 aliphatic, C1-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
R12f and R13f are each independently selected from hydrogen, an optionally substituted Ci-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfRlf4; or one of R12f and R13f is an optionally substituted C2-C6 aliphatic or an optionally substituted ring and the other of R12f and R13f is null; or R12f and R13f are linked to form an optionally substituted C3-Cg ring;
R14f is selected from an optionally substituted aryl and an optionally substituted heteroaryl;
R15f is selected from hydrogen, C1-C3 aliphatic, C1-C3 haloaliphatic, and a ring; mf is 0, 1, or 2; and nf is 0 or 1.
57. The method of Claim 56 wherein the TPO modulator is compound 1 having the formula:
Figure imgf000062_0001
Compound 1.
58. A method of enhancing platelet production in a subject comprising: administering a single dose of a TPO modulator sufficient to achieve steady state concentration levels of the TPO modulator in said subject.
59. The method of Claim 58, wherein the platelet count is increased from about 35% to about 100% from an initial baseline level within 20 days of administration of the single dose.
60. The method of Claim 58, wherein TPO modulator has a half- life ranging from about 60 hours to about 120 hours.
61. The method of Claim 58, wherein the platelet production is increased prior to platelet pheresis, blood donation or platelet donation.
62. The method of Claim 58 wherein the TPO modulator is a compound having the formula XII:
Figure imgf000063_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
Rlf is selected from CO2R10f, CONR10fRllf, SO3R10f, and a carboxylic acid bioisostere;
R2f and R3f are each independently selected from null, hydrogen, OR12f, NR12fR13f, an optionally substituted Ci -C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfR14f; or R2f and R3f taken together form an optionally substituted olefin; or R2f and R3f are linked to form an optionally substituted C3-Cs ring;
R4f is selected from hydrogen, fluorine (F), Chlorine (Cl), Bromine (Br), C1- C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
R5f is selected from hydrogen, OR10f, SR10f, NHRllf, and CO2H;
R6f is selected from hydrogen, OR12f, NR12fR13f, fluorine (F), chlorine (Cl), bromine (Br), Ci-C4 alkyl, Ci-C4 haloalkyl, and Ci-C4 heteroalkyl;
R7f is selected from hydrogen, an optionally substituted Ci-Cs aliphatic, an optionally substituted Ci-Cs haloaliphatic, an optionally substituted Ci-Cs heteroaliphatic, an optionally substituted Ci-Cs heterohaloaliphatic, an optionally substituted ring, and (CH2)mfR14f;
R8f and R9f are each independently selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), CO2R10f, NO2, CN, SO2R10f, (CH2)mfR14f, Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and Ci-C4 heterohaloaliphatic; R10f is selected from hydrogen, an optionally substituted C1-C4 aliphatic, C1-C4 haloaliphatic, C1-C4 heteroaliphatic, and a ring;
Rllf is selected from hydrogen, SO2R15f, Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
R12f and R13f are each independently selected from hydrogen, an optionally substituted Ci-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfRlf4; or one of R12f and R13f is an optionally substituted C2-C6 aliphatic or an optionally substituted ring and the other of R12f and R13f is null; or R12f and R13f are linked to form an optionally substituted C3-Cs ring;
R14f is selected from an optionally substituted aryl and an optionally substituted heteroaryl;
R15f is selected from hydrogen, C1-C3 aliphatic, C1-C3 haloaliphatic, and a ring; mf is 0, 1, or 2; and nf is 0 or 1.
63. The method of Claim 67 wherein the TPO modulator is compound 1 having the formula:
Figure imgf000064_0001
Compound 1.
64. A method for enhancing the number of peripheral blood stem cells obtained from a donor comprising administering to said donor a single dose of a TPO modulator sufficient to enhance the number of peripheral blood stem cells prior to leukapheresis.
65. The method of Claim 64 further comprising co-administering a hematopoietic- cell mobilizing agent selected from the group consisting of: a colony stimulating factor, cytokine, chemokine, interleukin or cytokine receptor agonist, adhesion molecule antagonists or antibodies.
66. The method of Claim 65, wherein the mobilizing agent is selected from the group consisting of G-CSF, GM-CSF, TPO, EPO, Gro-beta, IL-8, Cytoxan, VLA-4 inhibitors, SCF, FLT3 ligand or a biologically active derivative of G-CSF, GM-CSF, TPO, EPO, Gro-beta and IL-8.
67. The method of Claim 64 wherein the TPO modulator is a compound having the formula XII:
Figure imgf000065_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
Rlf is selected from CO2R10f, CONR10fRllf, SO3R10f, and a carboxylic acid bioisostere;
R2f and R3f are each independently selected from null, hydrogen, 0R12f, NR12fR13f, an optionally substituted C1-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfR14f; or R2f and R3f taken together form an optionally substituted olefin; or R2f and R3f are linked to form an optionally substituted C3-Cg ring; R4f is selected from hydrogen, fluorine (F), Chlorine (Cl), Bromine (Br), C1- C4 aliphatic, C1-C4 haloaliphatic, C1-C4 heteroaliphatic, and a ring;
R5f is selected from hydrogen, OR10f, SR10f, NHRllf, and CO2H;
R6f is selected from hydrogen, OR12f, NR12fR13f, fluorine (F), chlorine (Cl), bromine (Br), Ci -C4 alkyl, Ci -C4 haloalkyl, and Ci-C4 heteroalkyl;
R7f is selected from hydrogen, an optionally substituted Ci-Cs aliphatic, an optionally substituted Ci-Cg haloaliphatic, an optionally substituted Ci-Cg heteroaliphatic, an optionally substituted Ci-Cg heterohaloaliphatic, an optionally substituted ring, and (CH2)mfR14f;
R8f and R9f are each independently selected from hydrogen, fluorine (F), chlorine (Cl), bromine (Br), CO2R10f, NO2, CN, SO2R10f, (CH2)mfR14f, Ci-C4 aliphatic, Ci-C4 haloaliphatic, Ci-C4 heteroaliphatic, and Ci-C4 heterohaloaliphatic;
R10f is selected from hydrogen, an optionally substituted Ci-C4 aliphatic, C1-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
Rllf is selected from hydrogen, SO2R15f, C1-C4 aliphatic, C1-C4 haloaliphatic, Ci-C4 heteroaliphatic, and a ring;
R12f and R13f are each independently selected from hydrogen, an optionally substituted Ci-C4 aliphatic, an optionally substituted Ci-C4 haloaliphatic, an optionally substituted Ci-C4 heteroaliphatic, an optionally substituted ring, and (CH2)mfRlf4; or one of R12f and R13f is an optionally substituted C2-C6 aliphatic or an optionally substituted ring and the other of R12f and R13f is null; or R12f and R13f are linked to form an optionally substituted C3-Cg ring;
R14f is selected from an optionally substituted aryl and an optionally substituted heteroaryl;
R15f is selected from hydrogen, C1-C3 aliphatic, C1-C3 haloaliphatic, and a ring; mf is 0, 1, or 2; and nf is 0 or 1.
68. The method of Claim 67 wherein the TPO modulator is compound 1 having the formula:
Figure imgf000067_0001
Compound 1.
PCT/US2009/043901 2008-05-16 2009-05-14 Methods of administration of thrombopoietin mimetic compounds WO2009140464A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060084682A1 (en) * 2002-12-13 2006-04-20 Heerding Dirk A Thrombopoietin mimetics
WO2006047344A1 (en) * 2004-10-25 2006-05-04 Ligand Pharmaceuticals, Inc. Thrombopoietin activity modulating compounds and methods

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060084682A1 (en) * 2002-12-13 2006-04-20 Heerding Dirk A Thrombopoietin mimetics
WO2006047344A1 (en) * 2004-10-25 2006-05-04 Ligand Pharmaceuticals, Inc. Thrombopoietin activity modulating compounds and methods

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JENKINS ET AL.: "Phase 1 Clinical Study of Eltrombopag, an Oral non-peptide Thrombopoietin Receptor Agonist.", BLOOD JOURNAL, vol. 109, 27 February 2007 (2007-02-27), pages 4739 - 4741 *

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