WO2014201332A1 - Combinaisons pharmaceutiques utiles pour traiter la polyarthrite rhumatoïde - Google Patents

Combinaisons pharmaceutiques utiles pour traiter la polyarthrite rhumatoïde Download PDF

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Publication number
WO2014201332A1
WO2014201332A1 PCT/US2014/042275 US2014042275W WO2014201332A1 WO 2014201332 A1 WO2014201332 A1 WO 2014201332A1 US 2014042275 W US2014042275 W US 2014042275W WO 2014201332 A1 WO2014201332 A1 WO 2014201332A1
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Prior art keywords
compound
formula
pharmaceutical composition
aliphatic
administered
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PCT/US2014/042275
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English (en)
Inventor
Thomas Carl Hoock
Ajit Bhiwaji CHAVAN
Yingxue CHEN
Varun Garg
Jiayin Huang
Lisa Ann MAHNKE
Sarah Marie ROBERTSON
Kathryn Lea Sewell
Lori Kell Taylor
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Vertex Pharmaceuticals Incorporated
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Publication of WO2014201332A1 publication Critical patent/WO2014201332A1/fr

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • the present invention relates to pharmaceutical combinations and methods for treating or lessening the severity of rheumatoid arthritis with a compound of Formula I and a second API.
  • the Janus kinases are a family of tyrosine kinases consisting of JAK1 , JAK2, JAK3, and TYK2.
  • the JAKs play a critical role in cytokine signaling.
  • the down-stream substrates of the JAK family of kinases include the signal transducer and activator of transcription (STAT) proteins. JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as SLE, rheumatoid arthritis (RA), and
  • JAK kinases represent an established therapeutic target for these diseases.
  • JAK kinases are an established therapeutic target for treating SLE, RA, spondyloarthropathies including peripheral spondyloarthropathy, axial
  • the invention relates to pharmaceutical compositions and methods for treating or lessening the severity of rheumatoid arthritis with a compound of Formula I or a combination of a compound of Formula I and a co-therapy.
  • the present invention provides a method for treating or lessening the severity of rheumatoid arthritis or other disease mediated by an abnormal immune response comprising administering to a patient in need thereof a corticosteroid and a compound of Formula I
  • X 1 is N or CR 4 ;
  • R 2 is H or halo;
  • R 3 is
  • R 4 is H or halo
  • R 1 is R" is H or an unsubstituted C 1-2 aliphatic
  • R is an unsubstituted C 1-4 aliphatic; R is an unsubstituted C1 aliphatic; R is a Cj.3 aliphatic optionally substituted with up to 3 occurrences of F; and R 14 is H or unsubstituted Ci -2 alkyl.
  • R is H or F.
  • R 3 is H or CI.
  • each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R and R is
  • R 14 is H or methyl.
  • R is an unsubstituted Ci -3 aliphatic.
  • R is a Ci -3 aliphatic substituted with 1-3 occurrences of F.
  • R 7 is a group selected from -CH 2 CH 3 , -CH2CF3, - ⁇ 3 ⁇ 40 ⁇ 2 0 ⁇ 3 , or
  • the compound of Formula I is selected from Table 1.
  • the compound of Formula I is administered at least once per day.
  • the compound of Formula I is administered from 1 to 4 times per day. [0016] In some embodiments, the compound of Formula I is orally administered to the patient in need thereof.
  • At least about 20 mg of the compound of Formula I is administered to the patient at least once per day.
  • At least about 100 mg of the compound of Formula I is administered to the patient once per day.
  • At least about 150 mg of the compound of Formula I is administered to the patient once per day.
  • At least about 200 mg of the compound of Formula I is administered to the patient once per day.
  • At least about 20 mg of the compound of Formula I is administered to the patient twice per day.
  • At least about 50 mg of the compound of Formula I is administered to the patient twice per day.
  • At least about 100 mg of the compound of Formula I is administered to the patient twice per day.
  • At least about 150 mg of the compound of Formula I is administered to the patient twice per day.
  • the corticosteroid is hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisone, prednisolone, methylprednisone, methylprednisolone, or any combination thereof.
  • the corticosteroid is prednisone.
  • the corticosteroid is methylprednisone.
  • the corticosteroid is orally administered to the patient in need thereof.
  • At least about 5 mg of corticosteroid is administered at least once per week.
  • At least about 8 mg of corticosteroid is administered at least once per week.
  • At least about 8 mg of corticosteroid is administered at least twice per week.
  • the corticosteroid is prednisone or methylprednisone.
  • Another aspect of the present invention provides a method for treating or lessening the severity of rheumatoid arthritis comprising administering to a patient in need thereof a corticosteroid and a pharmaceutical composition comprising a compound of Formula I
  • X 1 is N or CR 4 ;
  • R 2 is H or halo;
  • R 3 is
  • R 4 is H or halo
  • R 1 is R" is H or an unsubstituted C 1-2 aliphatic
  • R is an unsubstituted C 1- aliphatic; R is an unsubstituted C 1-4 aliphatic; R is a C1.3 aliphatic optionally substituted with up to 3 occurrences of F; and R 14 is H or unsubstituted Cj. 2 alkyl.
  • R 2 is H or F.
  • R is H or CI.
  • each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R and R is
  • R 14 is H or methyl.
  • R is an unsubstituted Ci -3 aliphatic.
  • R is a Ci -3 aliphatic substituted with 1-3 occurrences of F.
  • R 7 is a group selected from -CH 2 CH 3 , -CH 2 CF 3 ,
  • the compound of Formula I is selected from Table 1.
  • the pharmaceutical composition further comprises a tablet.
  • the tablet further comprises a diluent, a binder, a glidant, a disintegrant, a surfactant, a lubricant, or any combination thereof.
  • the tablet comprises at least about 10 mg of the compound of Formula I.
  • the tablet comprises from about 15 mg to about 100 mg of the compound of Formula I.
  • the tablet is administered at least once per day.
  • Some embodiments further comprise administering once per day at least one tablet comprising the pharmaceutical composition.
  • each tablet further comprises from about 20 mg to about 100 mg of the compound of Formula I.
  • the corticosteroid is hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisone, prednisolone, methylprednisone, methylprednisolone, or any combination thereof.
  • the corticosteroid is prednisone.
  • the corticosteroid is methylprednisone.
  • the corticosteroid is orally administered to the patient in need thereof.
  • At least about 5 mg of corticosteroid is administered at least once per week.
  • At least about 8 mg of corticosteroid is administered at least once per week.
  • At least about 8 mg of corticosteroid is administered at least twice per week.
  • the corticosteroid is prednisone or methylprednisone.
  • Another aspect of the present invention provides a method for treating or lessening the severity of rheumatoid arthritis comprising administering to a patient in need thereof a corticosteroid and compound of Formula I
  • X 1 is N or CR 4 ;
  • R 2 is H or halo;
  • R 3 is
  • R 4 is H or halo;
  • R 1 is ;
  • R" is H or an unsubstituted C 1-2 aliphatic;
  • R is an unsubstituted C 1-4 aliphatic;
  • R 9 is an unsubstituted C 1-4 aliphatic;
  • R 7 is a Ci-3 aliphatic optionally substituted with up to 3 occurrences of F;
  • R 14 is H or unsubstituted Ci -2 alkyl, or a pharmaceutically acceptable salt thereof wherein at least about 25 mg of the compound of Formula I is administered to the patient at least once per day.
  • from about 25 mg to about 250 mg of the compound of formula I is administered to the patient once per day or twice per day.
  • from about 100 mg to about 200 mg of the compound of formula I is administered to the patient once per day or twice per day.
  • the corticosteroid is hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisone, prednisolone, methylprednisone, methylprednisolone, or any combination thereof.
  • the corticosteroid is prednisone.
  • the corticosteroid is methylprednisone.
  • the corticosteroid is orally administered to the patient in need thereof.
  • At least about 5 mg of corticosteroid is administered at least once per week.
  • At least about 8 mg of corticosteroid is administered at least once per week.
  • At least about 8 mg of corticosteroid is administered at least twice per week.
  • the corticosteroid is prednisone or methylprednisone.
  • R is H or F.
  • R 3 is H or CI.
  • each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R and R is independently selected from methyl or ethyl.
  • R 14 is H or methyl.
  • R is an unsubstituted Ci -3 aliphatic.
  • R is a C 1 .3 aliphatic substituted with 1-3 occurrences of F.
  • R 7 is a group selected from -CH 2 CH 3 , -CH 2 CF 3 ,
  • the compound of Formula I is selected from Table 1.
  • Another aspect of the present invention provides a pharmaceutical composition comprising a corticosteroid and a
  • X 1 is N or CR 4 ;
  • R 2 is H or halo;
  • R 3 is
  • R 1 is ;
  • R" is H or an unsubstituted Ci-2 aliphatic;
  • R is an unsubstituted CM aliphatic;
  • R is an unsubstituted C 1-4 aliphatic;
  • R is a Ci -3 aliphatic optionally substituted with up to 3 occurrences of F;
  • R 14 is H or unsubstituted Ci -2 alkyl.
  • R 2 is H or F.
  • R 3 is H or CI.
  • each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R and R is
  • R 14 is H or methyl.
  • R is an unsubstituted Ci -3 aliphatic.
  • R is a C 1.3 aliphatic substituted with 1-3 occurrences of F.
  • R is a group selected from -CH2CH 3 , -CH 2 CF 3 ,
  • the compound of Formula I is selected from Table 1 , below.
  • the corticosteroid is hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisone, prednisolone, methylprednisone, methylprednisolone, or any combination thereof.
  • FIG. 1 is a plot of mean plasma concentration as a function of time generated from the study the effect of Compound 1 on PK of prednisone described in Example 18.
  • FIG. 2 is a plot of mean plasma concentration as a function of time generated from the study the effect of Compound 1 on PK of prednisolone described in Example 18.
  • FIG. 3 is a plot of mean plasma concentration as a function of time generated from the study the effect of Compound 1 on PK of methylprednisone described in Example 18. DETAILED DESCRIPTION
  • the present invention provides methods of treating or lessening the severity of rheumatoid arthritis comprising the administration of a compound of Formula I and a corticosteroid, and pharmaceutical compositions thereof.
  • the term "active pharmaceutical ingredient” or “API” refers to a biologically active compound.
  • One exemplary API is a corticosteroid (e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone).
  • Another exemplary API includes a protein kinase inhibitor (e.g., a JAK inhibitor) such as a compound of Formula I:
  • R is H or halo
  • R is H or halo
  • R 4 is H or halo
  • R" is H or an unsubstituted Ci -2 aliphatic
  • R 8 is an unsubstituted C aliphatic
  • R 9 is an unsubstituted C aliphatic
  • R is a C 1-3 aliphatic optionally substituted with up to 3 occurrences of F.
  • R 14 is H or unsubstituted C 1-2 alkyl.
  • a "protein kinase inhibitor” refers to a compound that exhibits biological activity characterized by blocking the action of one or more protein kinases.
  • an "excipient” is an inactive ingredient in a pharmaceutical composition.
  • excipients include fillers or diluents, wetting agents (e.g., surfactants), binders, glidants, lubricants, disintegrants, or the like.
  • a "disintegrant” is an excipient that hydrates a pharmaceutical composition and aids in tablet dispersion. Examples of disintegrants include sodium croscarmellose and/or sodium starch glycolate.
  • a "diluent” or “filler” is an excipient that adds bulkiness to a pharmaceutical composition.
  • fillers include lactose, sorbitol, celluloses, calcium phosphates, starches, sugars (e.g., mannitol, sucrose, or the like) or any combination thereof.
  • a "wetting agent” or a “surfactant” is an excipient that imparts pharmaceutical compositions with enhanced solubility and/or wetability.
  • wetting agents include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan mono-oleate (e.g., TweenTM), or any combination thereof.
  • a "binder” is an excipient that imparts a pharmaceutical composition with enhanced cohesion or tensile strength (e.g., hardness).
  • binders include dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethyl cellulose).
  • a "glidant” is an excipient that imparts a pharmaceutical
  • compositions with enhanced flow properties include colloidal silica and/or talc.
  • a "colorant” is an excipient that imparts a pharmaceutical composition with a desired color.
  • examples of colorants include commercially available pigments such as FD&C Blue # 1 Aluminum Lake, FD&C Blue #2, other FD&C Blue colors, titanium dioxide, iron oxide, and/or combinations thereof.
  • a "lubricant” is an excipient that is added to pharmaceutical compositions that are pressed into tablets.
  • the lubricant aids in compaction of granules into tablets and ejection of a tablet of a pharmaceutical composition from a die press.
  • examples of lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, or any combination thereof.
  • Friability refers to the property of a tablet to remain intact and withhold its form despite an external force of pressure. Friability can be quantified using the mathematical expression presented in equation 1 :
  • % friabiliy 100 x ⁇ (1 ) wherein Wo is the original weight of the tablet and the final weight of the tablet after it is put through the friabilator.
  • Friability is measured using a standard USP testing apparatus that tumbles experimental tablets for 100 revolutions. Some tablets of the present invention have a friability of less than about 1% (e.g., less than about 0.75%, less than about 0.50%, or less than about 0.30%).
  • compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • aliphatic encompasses the terms alkyl, alkenyl, alkynyl, each of which being optionally substituted as set forth below.
  • an "alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1-12 (e.g., 1-3, 1-8, 1-6, or 1-4) carbon atoms.
  • An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl.
  • An alkyl group can be substituted (i.e., optionally substituted) with one or more substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino,
  • substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalky
  • heterocycloalkylalkyl carbonylamino
  • heteroarylcarbonylamino heteroarylcarbonylamino
  • amino e.g., aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino
  • sulfonyl e.g.,
  • substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-S0 2 -amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.
  • carboxyalkyl such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl
  • cyanoalkyl hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (al
  • an "alkenyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to allyl, isoprenyl, 2-butenyl, and 2-hexenyl.
  • alkenyl group can be optionally substituted with one or more substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or
  • heterocycloalkenyl aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g.,
  • heteroarylcarbonylamino heteroaralkylcarbonylamino alkylaminocarbonyl
  • heteroarylaminocarbonyl amino [e.g., aliphaticamino, cycloaliphaticamino,
  • heterocycloaliphaticamino or aliphaticsulfonylamino
  • sulfonyl e.g., alkyl-S0 2 -,
  • cycloaliphatic-S02-, or aryl-SCV cycloaliphatic-S02-, or aryl-SCV
  • sulfinyl sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.
  • substituted alkenyls include cyanoalkenyl,
  • alkoxyalkenyl acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl,
  • (sulfonylamino)alkenyl such as (alkyl-S0 2 -amino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or haloalkenyl.
  • an "alkynyl” group refers to an aliphatic carbon group that contains
  • An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl.
  • An alkynyl group can be optionally substituted with one or more substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl
  • aliphaticsulfanyl or cycloaliphaticsulfanyl [e.g., aliphaticsulfanyl or cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl or cycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-S0 2 -, aliphaticamino-S0 2 -, or cycloaliphatic-
  • amido e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,
  • cycloalkylaminocarbonyl heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino,
  • an “amido” encompasses both “aminocarbonyl” and
  • carbonylamino when used alone or in connection with another group refer to an amido group such as -N(R x )-C(0)-R Y or -C(0)-N(R x ) 2 , when used terminally, and -C(0)-N(R x )- or -N(R x )-C(0)- when used internally, wherein R x and R Y can be aliphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl or heteroaraliphatic.
  • amido groups examples include alkylamido (such as alkylcarbonylamino or
  • alkylaminocarbonyl (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido .
  • an "amino" group refers to -NR X R Y wherein each of R x and R Y is independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,
  • amino groups include alkylamino, dialkylamino, or arylamino.
  • amino is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NR -. R has the same meaning as defined above.
  • aralkyl refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic.
  • the bicyclic and tricyclic groups include benzo fused 2-3 membered carbocyclic rings.
  • a benzofused group includes phenyl fused with two or more
  • An aryl is optionally substituted with one or more substituents including aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;
  • substituents including aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;
  • sulfonyl e.g., aliphatic-SCb- or amino-S02-]
  • sulfinyl e.g., aliphatic-S(O)- or cycloaliphatic-S(O)-
  • sulfanyl e.g., aliphatic- S-]
  • cyano halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl.
  • an aryl can be unsubstituted.
  • Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di (such as /?,m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyl)aryl,
  • aminocarbonyl)aryl (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (afylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g.,
  • (sulfamoyl)aryl [e.g., (aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;
  • an "araliphatic” such as an “aralkyl” group refers to an aliphatic group (e.g., a C alkyl group) that is substituted with an aryl group.
  • "Aliphatic,” “alkyl,” and “aryl” are defined herein.
  • An example of an araliphatic such as an aralkyl group is benzyl.
  • an "aralkyl” group refers to an alkyl group (e.g., a CM alkyl group) that is substituted with an aryl group. Both “alkyl” and “aryl” have been defined above. An example of an aralkyl group is benzyl.
  • An aralkyl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
  • substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [e.g., cyclo
  • heteroaralkyloxy aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
  • heteroarylcarbonylamino or heteroaralkylcarbonylamino] cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
  • a "bicyclic ring system” includes 8-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common).
  • Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls.
  • a "cycloaliphatic” group encompasses a “cycloalkyl” group and a “cycloalkenyl” group, each of which being optionally substituted as set forth below.
  • a "cycloalkyl” group refers to a saturated carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms.
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl,
  • bicyclo[2.2.2]octyl bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl .
  • a "cycloalkenyl” group refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds.
  • Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.
  • a cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic,
  • sulfonyl e.g., alkyl-S0 2 - and aryl-S0 2 -
  • sulfmyl e.g., al
  • heterocycloaliphatic encompasses a heterocycloalkyl group and a heterocycloalkenyl group, each of which being optionally substituted as set forth below.
  • a “heterocycloalkyl” group refers to a 3-10 membered mono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof).
  • heterocycloalkyl group examples include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[6]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dio
  • heterocycloalkyl group can be fused with a phenyl moiety to form structures, such as tetrahydroisoquinoline, which would be categorized as heteroaryls.
  • a "heterocycloalkenyl” group refers to a mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S).
  • Monocyclic and bicyclic heterocycloaliphatics are numbered according to standard chemical nomenclature.
  • a heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy,
  • substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy,
  • heteroaryloxy e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)
  • heterocycloaliphaticcarbonylamino ((heterocycloaliphatic) aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino] nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl,
  • sulfonyl e.g., alkylsulfonyl or arylsulfonyl
  • sulfinyl
  • heteroaryl group refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom
  • a heteroaryl group includes a benzofused ring system having 2 to 3 rings.
  • a benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[Z>]furyl, benzo [b]thiophenyl, quinolinyl, or isoquinolinyl).
  • heteroaryl examples include pyridyl, lH-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[l,3]dioxole, benzo[b]furyl, benzo [b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo- 1,2,5-thiadiazolyl, or 1,8-naphth
  • monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
  • 1,3,4-thiadiazolyl 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.
  • Monocyclic heteroaryls are numbered according to standard chemical nomenclature.
  • bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[6]furyl, benzo [6]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo [bjfuryl, bexo[6]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl.
  • Bicyclic heteroaryls are numbered according to standard chemical nomenclature.
  • a heteroaryl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic;
  • heterocycloaliphatic (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;
  • heterocycloaliphatic aliphatic
  • carbonyl or (heteroaraliphatic)carbonyl]
  • sulfonyl e.g., aliphaticsulfonyl or aminosulfonyl
  • sulfinyl e.g., aliphaticsulfinyl
  • sulfanyl e.g., aliphaticsulfanyl
  • a heteroaryl can be unsubstituted.
  • Non-limiting examples of substituted heteroaryls include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl];
  • aminoheteroaryl e.g., ((alkylsulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl,
  • alkylsulfonyl heteroaryl
  • hydroxyalkyl heteroaryl
  • alkoxyalkyl heteroaryl
  • heterocycloaliphatic heteroaryl
  • cycloaliphatic heteroaryl
  • nitrogenalkyl heteroaryl
  • (cyanoalkyl)heteroaryl (cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl, and (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl].
  • heteroaralkyl group refers to an aliphatic group (e.g., a C alkyl group) that is substituted with a heteroaryl group.
  • heteroaryl refers to an alkyl group (e.g., a Ci -4 alkyl group) that is substituted with a heteroaryl group. Both “alkyl” and “heteroaryl” have been defined above.
  • a heteroaralkyl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,
  • substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (he
  • alkylcarbonyloxy aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino
  • heteroarylcarbonylamino heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
  • cyclic moiety and “cyclic group” refer to mono-, bi-, and tri-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined.
  • bridged bicyclic ring system refers to a bicyclic
  • bridged bicyclic ring systems include, but are not limited to, adamantanyl, norboraanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, l-azabicyclo[2.2.2]octyl,
  • a bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
  • substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycl
  • heteroaralkyloxy aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
  • heteroarylcarbonylamino heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
  • an "acyl” group refers to a formyl group or R x -C(0)- (such as alkyl-C(O)-, also referred to as “alkylcarbonyl”) where R x and "alkyl” have been defined previously.
  • R x and "alkyl” have been defined previously.
  • Acetyl and pivaloyl are examples of acyl groups.
  • an “aroyl” or “heteroaroyl” refers to an aryl-C(O)- or a
  • heteroaryl-C(O)- respectively.
  • the aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.
  • alkoxy refers to an alkyl-O- group where “alkyl” has been defined previously.
  • a “carbamoyl” group refers to a group having the structure
  • R x and R Y have been defined above and R z can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.
  • a "carboxy” group refers to -COOH, -COOR x , -OC(0)H,
  • haloaliphatic refers to an aliphatic group substituted with 1-3 halogen.
  • haloalkyl includes the group -CF 3 .
  • mercapto refers to -SH.
  • a "sulfo" group refers to -SO3H or -S0 3 R x when used terminally or -S(0) 3 - when used internally.
  • a "sulfamide” group refers to the structure -NR X -S(0)2-NR Y R Z when used terminally and -NR x -S(0) 2 -NR Y - when used internally, wherein R x , R Y , and R z have been defined above.
  • a "sulfamoyl” group refers to the structure -0-S(0) 2 -NR Y R z wherein R Y and R z have been defined above.
  • a "sulfonamide” group refers to the structure -S(0) 2 -NR x R Y or -NR x -S(0) 2 -R z when used terminally; or -S(0) 2 -NR x - or -NR X -S(0) 2 - when used internally, wherein R x , R Y , and R z are defined above.
  • sulfanyl group refers to -S-R x when used terminally and -S- when used internally, wherein R x has been defined above.
  • sulfanyls include aliphatic-S-, cycloaliphatic-S-, aryl-S-, or the like.
  • a "sulfinyl” group refers to -S(0)-R x when used terminally and -S(O)- when used internally, wherein R x has been defined above.
  • exemplary sulfinyl groups include aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic))-S(0)-, cycloalkyl-S(O)-, heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, or the like.
  • a "sulfonyl” group refers to-S(0) 2 -R x when used terminally and -S(0) 2 - when used internally, wherein R has been defined above.
  • exemplary sulfonyl groups include aliphatic-S(0) 2 -, aryl-S(0) 2 -, (cycloaliphatic(aliphatic))-S(0)2-,
  • a "sulfoxy" group refers to -0-SO-R x or -SO-0-R x , when used terminally and -O-S(O)- or -S(0)-0- when used internally, where R x has been defined above.
  • halogen or halo group refers to fluorine, chlorine, bromine or iodine.
  • alkoxycarbonyl which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as alkyl-O-C(O)-.
  • alkoxyalkyl refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.
  • phospho refers to phosphinates and phosphonates.
  • phosphinates and phosphonates include -P(0)(R p ) 2 , wherein R p is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl, heteroaryl, cycloaliphatic or amino.
  • aminoalkyl refers to the structure (R x ) 2 N-alkyl-.
  • cyanoalkyl refers to the structure (NC)-alkyl-.
  • urea refers to the structure -NR x -CO-NR Y R z and a
  • thiourea refers to the structure -NR X -CS-NR Y R Z when used terminally and
  • the term "vicinal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.
  • the term “geminal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom.
  • terminal refers to the location of a group within a substituent.
  • a group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure.
  • Carboxyalkyl i.e., R x O(0)C-alkyl is an example of a carboxy group used terminally.
  • a group is internal when the group is present in the middle of a substituent of the chemical structure.
  • Alkylcarboxy e.g., alkyl-C(0)0- or alkyl-OC(O)-
  • alkylcarboxyaryl e.g., alkyl-C(0)0-aryl- or alkyl-O(CO)-aryl-
  • carboxy groups used internally are examples of carboxy groups used internally.
  • an "aliphatic chain” refers to a branched or straight aliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups).
  • a straight aliphatic chain has the structure -[CH2] V -, where v is 1-12.
  • a branched aliphatic chain is a straight aliphatic chain that is substituted -[CQQ] V - where Q is independently a hydrogen or an aliphatic group; however, Q shall be an aliphatic group in at least one instance.
  • the term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.
  • substituted or unsubstituted compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituents such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • Formula I encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each of the specific groups for the variables R 1 , R 2 , R 3 , R 4 , R 5 , R', and other variables contained therein can be optionally substituted with one or more substituents described herein. Each substituent of a specific group is further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl.
  • an alkyl group can be substituted with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl.
  • the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl.
  • substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • Specific substituents are described above in the definitions and below in the description of compounds and examples thereof.
  • an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.
  • a ring substituent such as a heterocycloalkyl
  • substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
  • stable or chemically feasible refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • an "effective amount” is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy
  • patient refers to a mammal, including a human.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ,3 C- or 14 C- enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents.
  • excipient is an inactive ingredient in a pharmaceutical composition.
  • excipients include.
  • a "disintegrant” is an excipient that hydrates a pharmaceutical composition and aids in tablet dispersion.
  • disintegrants include sodium croscarmellose and/or sodium starch glycolate.
  • a "diluent” or “filler” is an excipient that adds bulkiness to a pharmaceutical composition.
  • fillers include lactose, sorbitol, celluloses, calcium phosphates, starches, sugars (e.g., mannitol, sucrose, or the like) or any combination thereof.
  • a "wetting agent” or a “surfactant” is an excipient that imparts pharmaceutical compositions with enhanced solubility and/or wetability.
  • wetting agents include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan mono-oleate (e.g., TweenTM), or any combination thereof.
  • a "binder” is an excipient that imparts a pharmaceutical composition with enhanced cohesion or tensile strength (e.g., hardness).
  • binders include dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethyl cellulose).
  • a "glidant” is an excipient that imparts a pharmaceutical
  • compositions with enhanced flow properties include colloidal silica and/or talc.
  • a "colorant” is an excipient that imparts a pharmaceutical composition with a desired color.
  • colorants include commercially available pigments such as FD&C Blue # 1 Aluminum Lake, FD&C Blue #2, other FD&C Blue colors, titanium dioxide, iron oxide, and/or combinations thereof.
  • Other colorants include commercially available pigments such as FD&C Green #3.
  • a "lubricant” is an excipient that is added to pharmaceutical compositions that are pressed into tablets. The lubricant aids in compaction of granules into tablets and ejection of a tablet of a pharmaceutical composition from a die press. Examples of lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, or any combination thereof.
  • Friability refers to the property of a tablet to remain intact and withhold its form despite an external force of pressure. Friability can be quantified using the mathematical expression presented in equation 1 :
  • Friability is measured using a standard USP testing apparatus that tumbles experimental tablets for 100 revolutions. Some tablets of the present invention have a friability of less than about 1% (e.g., less than about 0.75%, less than about 0.50%, or less than about 0.30%).
  • DMARD refers to a disease-modifying antirheumatoid drug.
  • examples of DMARDs include adalimumab, leflunomide, sulfasalazine, infliximab, minocycline, rituximab, golimumab, or any combination thereof.
  • One aspect of the present invention provides a method for treating or lessening the severity of rheumatoid arthritis (e.g., active rheumatoid arthritis) comprising administering to a patient in need thereof a corticosteroid and com ound of Formula I
  • X 1 is N or CR 4 ;
  • R 2 is H or halo
  • R 3 is H or halo
  • R 4 is H or halo
  • R" is H or an unsubstituted C 1-2 aliphatic
  • R is an unsubstituted CM aliphatic
  • R 9 is an unsubstituted Ci-4 aliphatic
  • R 7 is a Ci-3 aliphatic optionally substituted with up to 3 occurrences of F.
  • R 14 is H or unsubstituted Ci -2 alkyl.
  • R is H or F.
  • R 3 is H or CI.
  • each of R and R is independently selected from methyl
  • each of R and R is independently selected from methyl or ethyl.
  • R 14 is H or methyl.
  • R 7 is an unsubstituted Cj-3 aliphatic.
  • R 7 is a C1-3 aliphatic substituted with 1-3 occurrences of F.
  • R 7 is a group selected from -CH 2 CH3, -CH2CF3,
  • the compound of Formula I is selected from Table 1 :
  • the compound of Formula I is administered at least once per day (e.g., q.d. or b.i.d. administration). In other embodiments, the compound of Formula I is administered at least twice per day (e.g., b.i.d. administration).
  • the compound of Formula I is orally administered to the patient.
  • At least about 20 mg e.g., at least about 25 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, or at least about 250 mg
  • at least about 100 mg of the compound of Formula I is administered to the patient once per day.
  • at least about 200 mg of the compound of Formula I is administered to the patient once per day.
  • At least about 20 mg e.g., at least about 25 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, or at least about 250 mg
  • at least about 20 mg e.g., at least about 25 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, or at least about 250 mg
  • at least about 20 mg e.g., at least about 25 mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, or at least about 250 mg
  • the corticosteroid is hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisone, prednisolone, methylprednisone, methylprednisolone, or any combination thereof.
  • the corticosteroid is prednisone, prednisolone,
  • methylprednisone or methylprednisolone.
  • the corticosteroid is methylprednisone or
  • the corticosteroid is orally administered to the patient in need thereof.
  • At least about 5 mg of corticosteroid is administered at least once per week.
  • methylprednisone, or methylprednisolone is administered at least once per week. In some instances, from about 8 mg to about 15 mg of prednisone or prednisolone is orally administered at least once per week. In other instances, from about 6 mg to about 12 mg of methylprednisone or methylprednisolone is orally administered at least once per week.
  • At least about 8 mg of corticosteroid is administered at least once per week.
  • At least about 5 mg of corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • from about 8 mg to about 15 mg of prednisone or prednisolone is orally administered at least twice per week.
  • from about 6 mg to about 12 mg of methylprednisone or methylprednisolone is orally administered at least twice per week.
  • the corticosteroid is prednisone or methylprednisone.
  • the corticosteroid is administered concurrently with the compound of Formula I. In other embodiments, the corticosteroid is administered prior to or subsequent to the administration of the compound of Formula I.
  • Another aspect of the present invention provides a method for treating or lessening the severity of rheumatoid arthritis comprising administering to a patient in need thereof a corticosteroid and a pharmaceutical composition comprising a compound of Formula I
  • X 1 is N or CR 4 ;
  • R is H or halo
  • R 3 is H or halo
  • R" is H or an unsubstituted Ci. 2 aliphatic
  • R is an unsubstituted CM aliphatic
  • R 9 is an unsubstituted C aliphatic
  • R 7 is a Ci- 3 aliphatic optionally substituted with up to 3 occurrences of F.
  • R 14 is H or unsubstituted d -2 alkyl.
  • R is H or F.
  • R is H or CI.
  • each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R and R is independently selected from methyl or ethyl.
  • R 14 is H or methyl.
  • R 7 is an unsubstituted C 1 .3 aliphatic.
  • R 7 is a C 1 -3 aliphatic substituted with 1-3 occurrences of F.
  • R 7 is a group selected from -CH 2 CH 3 , -CH 2 CF 3 ,
  • the compound of Formula I is a compound selected from Table 1.
  • the pharmaceutical composition further comprises an oral formulation (e.g., tablet).
  • the pharmaceutical composition further comprises a tablet.
  • the tablet further comprises a diluent, a binder, a glidant, a disintegrant, a surfactant, a lubricant, or any combination thereof.
  • the tablet is administered at least once per day (e.g., q.d. or b.i.d. administration).
  • the tablet comprises at least about 10 mg (e.g., at least about 15 mg, at least about 20 mg, at least about 25mg, at least about 50 mg, at least about 75 mg, at least about 100 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 250 mg,) of the compound of Formula I.
  • the tablet comprises from about 5 mg to about 150 mg (e.g., from about 10 mg to about 100 mg, 20 mg to about 75 mg, or from about 25 mg to about 50 mg) of the compound of Formula I.
  • Some embodiments further comprise administering once per day at least one tablet (e.g., 1-6 tablets) comprising the pharmaceutical composition.
  • at least one tablet e.g., 1-6 tablets
  • administering once per day at least one tablet (e.g., 1-6 tablets) comprising the pharmaceutical composition.
  • embodiments further comprise administering once per day at least one table comprising from about 5 mg to about 150 mg (e.g., from about 10 mg to about 100 mg, 20 mg to about 75 mg, or from about 25 mg to about 50 mg) of the compound of Formula I.
  • at least one table comprising from about 5 mg to about 150 mg (e.g., from about 10 mg to about 100 mg, 20 mg to about 75 mg, or from about 25 mg to about 50 mg) of the compound of Formula I.
  • Some embodiments further comprise administering twice per day at least one tablet comprising the pharmaceutical composition.
  • some embodiments further comprise administering twice per day at least one table comprising from about 5 mg to about 150 mg (e.g., from about 10 mg to about 100 mg, 20 mg to about 75 mg, or from about 25 mg to about 50 mg) of the compound of Formula I.
  • the pharmaceutical composition comprises:
  • X 1 is N or CR 4 ;
  • R is H or halo
  • R 3 is H or halo
  • R 4 is H or halo
  • R" is H or an unsubstituted Ci -2 aliphatic
  • R is an unsubstituted C aliphatic
  • R 9 is an unsubstituted C aliphatic
  • R 7 is a Ci-3 aliphatic optionally substituted with up to 3 occurrences of F; and R 14 is H or unsubstituted Ci. 2 alkyl;
  • X 1 is N, CH, or CF.
  • R" is H or methyl.
  • R is H or F.
  • R is an unsubstituted CM aliphatic, for example a straight or branched unsubstituted Ci -4 aliphatic.
  • R 9 is an unsubstituted C aliphatic, for example a straight or branched unsubstituted C 1-4 aliphatic.
  • each of R 8 and R 9 is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl, each of which is unsubstituted.
  • each of R and R is independently selected from methyl or ethyl.
  • R 14 is H or methyl.
  • R is an unsubstituted C 1.3 aliphatic.
  • R is a straight or branched unsubstituted C ⁇ aliphatic.
  • R 7 is a C 1-3 aliphatic substituted with 1-3 occurrences of F.
  • R 7 is a group selected from -CH 2 CH 3 , -CH 2 CF 3 ,
  • the pharmaceutical composition comprises from about 20 mg to about 250 mg (e.g., from about 25 mg to about 200 mg, from about 50 mg to about 175 mg, or from about 75 mg to about 150 mg) of a compound of Formula I.
  • the pharmaceutical composition comprises about 25 mg of a compound of Formula I. [0233] In some embodiments, the pharmaceutical composition comprises about 50 mg of a compound of Formula I.
  • the pharmaceutical composition comprises about 75 mg of a compound of Formula I.
  • the pharmaceutical composition comprises about 100 mg of a compound of Formula I.
  • the pharmaceutical composition comprises about 150 mg of a compound of Formula I.
  • the pharmaceutical composition comprises about 200 mg of a compound of Formula I.
  • the pharmaceutical composition comprises from about 20 mg to about 200 mg (e.g., from about 25 mg to about 100 mg) of a compound selected from Table 1.
  • the pharmaceutical composition comprises about 25 mg of a - compound selected from Table 1.
  • the pharmaceutical composition comprises about 50 mg of a compound selected from Table 1.
  • the pharmaceutical composition comprises about 75 mg of a compound selected from Table 1.
  • the pharmaceutical composition comprises about 100 mg of a compound selected from Table 1.
  • the pharmaceutical composition comprises about 150 mg of a compound selected from Table 1.
  • Some embodiments further comprise the administration of one or more additional therapies to the patient.
  • the corticosteroid is hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisone, prednisolone, methylprednisone, methylprednisolone, or any combination thereof.
  • the corticosteroid is prednisone, prednisolone,
  • methylprednisone or methylprednisolone.
  • the corticosteroid is methylprednisone or
  • the corticosteroid is orally administered to the patient in need thereof.
  • at least about 5 mg of corticosteroid is administered at least once per week.
  • methylprednisone, or methylprednisolone is administered at least once per week. In some instances, from about 8 mg to about 15 mg of prednisone or prednisolone is orally administered at least once per week. In other instances, from about 6 mg to about 12 mg of methylprednisone or methylprednisolone is orally administered at least once per week.
  • At least about 8 mg of corticosteroid is administered at least once per week.
  • At least about 5 mg of corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • from about 8 mg to about 15 mg of prednisone or prednisolone is orally administered at least twice per week.
  • from about 6 mg to about 12 mg of methylprednisone or methylprednisolone is orally administered at least twice per week.
  • the corticosteroid is prednisone or methylprednisone.
  • the corticosteroid is administered concurrently with the compound of Formula I. In other embodiments, the corticosteroid is administered prior to or subsequent to the administration of the compound of Formula I.
  • Another aspect of the present invention provides a method of treating or reducing the severity of rheumatoid arthritis comprising administering to a patient once daily or twice daily a pharmaceutical composition comprising a compound of Formula I, wherein the pharmaceutical composition is as described herein, and a corticosteroid (e.g., prednisone or methylprednisone) .
  • a corticosteroid e.g., prednisone or methylprednisone
  • Some embodiments further comprise the administration of one or more additional therapies to the patient.
  • the pharmaceutical composition comprising a JAK inhibitor API (e.g., a compound of Formula I) and optionally other excipients (e.g., a diluent, a disintegrant, a wetting agent, a binder, a glidant, a colorant, a lubricant, or any combination thereof).
  • a JAK inhibitor API e.g., a compound of Formula I
  • other excipients e.g., a diluent, a disintegrant, a wetting agent, a binder, a glidant, a colorant, a lubricant, or any combination thereof.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises about 25 mg of a compound of Formula I, a diluent, a disintegrant, a surfactant, a binder, a glidant, and a lubricant.
  • the pharmaceutical composition comprises about 50 mg of a compound of Formula I, a diluent, a disintegrant, a surfactant, a binder, a glidant, and a lubricant.
  • the corticosteroid is prednisone or methylprednisone.
  • the pharmaceutical composition comprises about 20 mg or less of the corticosteroid.
  • the pharmaceutical compositions of the present invention also comprise one or more excipients such as diluents, disintegrants, surfactants, binders, glidants, lubricants, colorants, or fragrances, such as any of those described below.
  • excipients such as diluents, disintegrants, surfactants, binders, glidants, lubricants, colorants, or fragrances, such as any of those described below.
  • the pharmaceutical composition can comprise tablets and the tablets can be coated with a colorant and optionally labeled with a logo, other image and/or text using a suitable ink.
  • the pharmaceutical composition can be made into tablets and the tablets can be coated with a colorant, waxed, and optionally labeled with a logo, other image and/or text using a suitable ink.
  • Suitable colorants and inks are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition.
  • the suitable colorants and inks can be any color and are water based or solvent based.
  • tablets made from the pharmaceutical composition are coated with a colorant and then labeled with a logo, other image, and/or text using a suitable ink. For example, tablets comprising a
  • composition as described herein can be coated with about 3 wt% (e.g., less than about 6 wt% or less than about 4 wt%) of film coating comprising a colorant.
  • the colored tablets can be labeled with a logo and text indicating the strength of the active ingredient in the tablet using a suitable ink.
  • the colored tablets can be labeled with a logo and text indicating the strength and/or mass of the active ingredient in the tablet using a black ink (e.g., Opacode® WB, commercially available from Colorcon, Inc. of West Point, PA.).
  • tablets made from the pharmaceutical composition are coated with a colorant, waxed, and then labeled with a logo, other image, and/or text using a suitable ink.
  • the colored tablets can be waxed with Carnauba wax powder weighed out in the amount of about 0.01 % w/w of the starting tablet core weight.
  • the waxed tablets can be labeled with a logo and text indicating the strength of the active ingredient in the tablet using a suitable ink.
  • the pharmaceutical composition comprises from about 5 wt% to about 50 wt% of a compound of Formula V, by weight of the composition; from about 25 wt% to about 50 wt% of a diluent; from about 1 wt% to about 10 wt% of a disintegrant; from about 2 wt% to about 0.3 wt% of a wetting agent (e.g., surfactant); from about 5 wt% to about 50 wt% of a binder; from about 2 wt% to about 0.05 wt% of a glidant; and from about 2 wt% to about 0.1 wt% of a lubricant.
  • a wetting agent e.g., surfactant
  • the pharmaceutical composition comprises from about 35 wt% to about 50 wt% of a compound of Formula I; from about 25 wt% to about 50 wt% of a diluent; from about 1 wt% to about 10 wt% of a disintegrant; from about 2 wt% to about 0.3 wt% of a wetting agent (e.g., surfactant); from about 5 wt% to about 50 wt% of a binder; from about 2 wt% to about 0.05 wt% of a glidant; and from about 2 wt% to about 0.1 wt% of a lubricant.
  • a wetting agent e.g., surfactant
  • the pharmaceutical composition comprises from about 30 wt% to about 50 wt% of a compound of Formula I; from about 35 wt% to about 55 wt% of microcrystalline cellulose by weight of the composition; from about 35 wt% to about 55 wt% of lactose by weight of the composition; from about 1 wt% to about 5 wt% of sodium croscarmellose by weight of the composition; from about 0.5 wt% to about 1.5 wt% of SLS by weight of the composition; from about 0.5 wt% to about 1.5 wt% of colloidal silicon dioxide by weight of the composition; and from about 0.5 wt% to about 1.0 wt% of magnesium stearate by weight of the composition.
  • the pharmaceutical composition of the present invention comprises about 20 wt% of a compound of Formula I, about 37 wt% of microcrystalline cellulose by weight of the composition, about 37 wt% of lactose by weight of the composition, about 3 wt% of sodium croscarmellose by weight of the composition, about 1 wt% of SLS by weight of the composition, about 1 wt% of colloidal silicon dioxide by weight of the composition, and about 0.75 wt% of magnesium stearate by weight of the composition.
  • the pharmaceutical composition of the present invention comprises about 10 wt% of a compound of Formula I; about 42 wt% of microcrystalline cellulose by weight of the composition; about 42 wt% of lactose by weight of the
  • composition comprising: about 3 wt% of sodium croscarmellose by weight of the composition; about 1 wt% of SLS by weight of the composition; about 1 wt% of colloidal silicon dioxide by weight of the composition; and about 0.75 wt% of magnesium stearate by weight of the composition.
  • the pharmaceutical composition consists of a tablet that comprises a protein kinase inhibitor API (e.g., a compound of Formula I) and other excipients (e.g., a filler, a disintegrant, a surfactant, a binder, a glidant, a colorant, a lubricant, or any combination thereof), each of which is described above and in the Examples below, wherein the tablet has a hardness of about 5 Kp or greater.
  • a protein kinase inhibitor API e.g., a compound of Formula I
  • other excipients e.g., a filler, a disintegrant, a surfactant, a binder, a glidant, a colorant, a lubricant, or any combination thereof
  • the pharmaceutical composition consists of a tablet that comprises a JAK inhibitor API (e.g., a compound of Formula I) and other excipients (e.g., a filler, a disintegrant, a surfactant, a binder, a glidant, a colorant, a lubricant, or any combination thereof), each of which is described above and in the Examples below, wherein the tablet has a hardness of about 5 Kp or greater (e.g., about 5.5 Kp or greater, about 6 Kp or greater, or about 7 Kp or greater).
  • a JAK inhibitor API e.g., a compound of Formula I
  • other excipients e.g., a filler, a disintegrant, a surfactant, a binder, a glidant, a colorant, a lubricant, or any combination thereof
  • the pharmaceutical composition comprises a compound of Formula I; a diluent; a disintegrant; a wetting agent; a binder; a glidant; and a lubricant.
  • the diluent is lactose, sorbitol, cellulose, calcium phosphate, starch, sugar, or any combination thereof.
  • the diluent is lactose and has a concentration of about 10 wt% or greater by weight of the composition.
  • the disintegrant is sodium croscarmellose, sodium starch glycolate, or a combination thereof.
  • the disintegrant is sodium croscarmellose and has a concentration of about 10 wt% or less by weight of the composition.
  • the wetting agent is sodium lauryl sulfate, sodium stearyl fumarate, polyoxyethylene 20 sorbitan mono-oleate, or any combination thereof.
  • the wetting agent is sodium lauryl sulfate and has a concentration of about 10 wt% or less by weight of the composition.
  • the binder is microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, modified cellulose, or any combination thereof.
  • the binder is microcrystalline cellulose and has a concentration of about 1 wt% or greater by weight of the composition.
  • the glidant is colloidal silicon dioxide, talc, or a combination thereof.
  • the glidant is colloidal silicon dioxide and has a concentration of 2 wt% or less by weight of the composition.
  • the lubricant is magnesium stearate, stearic acid,
  • the lubricant is magnesium stearate and has a concentration of less than about 2 wt% by weight of the composition.
  • the pharmaceutical composition further comprises a colorant.
  • the pharmaceutical composition comprises a tablet having a hardness of about 5 Kp or greater (e.g., about 5.5 Kp or greater, about 6 Kp or greater, or about 7 Kp or greater).
  • the tablet has a dissolution of about 50% or greater in about 30 minutes.
  • the pharmaceutical composition consists of a tablet that comprises a compound of Formula I, a diluent, a disintegrant, a surfactant, a binder, a glidant, and a lubricant, wherein the tablet has a dissolution of about 50% or greater in about 30 minutes.
  • dissolution can be measured with a standard USP Type II apparatus that employs a dissolution media of 0.6% sodium lauryl sulfate dissolved in 900 mL of DI water, stirring at about 50-75 rpm at a temperature of about 37 °C. A single experimental tablet is tested in each test vessel of the apparatus. Dissolution can also be measured with a standard USP Type II apparatus that employs a dissolution media of 0.7% sodium lauryl sulfate dissolved in 900 mL of 50 mM sodium phosphate buffer (pH 6.8), stirring at about 65 rpm at a temperature of about 37 °C. A single experimental tablet is tested in each test vessel of the apparatus.
  • Dissolution can also be measured with a standard USP Type II apparatus that ' employs a dissolution media of 0.5% sodium lauryl sulfate dissolved in 900 mL of 50 mM sodium phosphate buffer (pH 6.8), stirring at about 65 rpm at a temperature of about 37 °C, wherein a single experimental tablet is tested in each test vessel of the apparatus.
  • the pharmaceutical composition comprises a compound of Formula I, a binder, a glidant, a surfactant, a lubricant, a disintegrant, and a filler, wherein each of these ingredients comprises a powder (e.g., provided as particles having a mean diameter, measured by light scattering, of about 250 ⁇ or less (e.g., about 150 ⁇ or less, about 100 ⁇ or less, about 50 ⁇ or less, about 45 ⁇ or less, about 40 ⁇ or less, or about 35 ⁇ or less)).
  • a powder e.g., provided as particles having a mean diameter, measured by light scattering, of about 250 ⁇ or less (e.g., about 150 ⁇ or less, about 100 ⁇ or less, about 50 ⁇ or less, about 45 ⁇ or less, about 40 ⁇ or less, or about 35 ⁇ or less)).
  • the pharmaceutical composition comprises a compound of Formula I, wherein the compound of Formula I comprises a powder having a mean diameter of about 250 ⁇ or less (e.g., about 150 ⁇ or less, about 100 ⁇ or less, about 50 ⁇ or less, about 45 ⁇ or less, about 40 ⁇ or less, or about 35 ⁇ or less).
  • the compound of Formula I comprises a powder having a mean diameter of about 250 ⁇ or less (e.g., about 150 ⁇ or less, about 100 ⁇ or less, about 50 ⁇ or less, about 45 ⁇ or less, about 40 ⁇ or less, or about 35 ⁇ or less).
  • the pharmaceutical composition comprises one or more excipients selected from a binder, a glidant, a surfactant, a lubricant, a disintegrant, and a filler, wherein the excipient comprises a powder having a mean particle diameter of about 250 ⁇ or less (e.g., about 150 ⁇ or less, about 100 ⁇ or less, about 50 ⁇ or less, about 45 ⁇ or less, about 40 ⁇ or less, or about 35 ⁇ or less)).
  • the excipient comprises a powder having a mean particle diameter of about 250 ⁇ or less (e.g., about 150 ⁇ or less, about 100 ⁇ or less, about 50 ⁇ or less, about 45 ⁇ or less, about 40 ⁇ or less, or about 35 ⁇ or less)).
  • the pharmaceutical composition comprises a tablet, a capsule, or a suspension.
  • the pharmaceutical composition comprises: a. about 20 wt% of a compound of Formula I by weight of the composition; b. about 37 wt% of microcrystalline cellulose by weight of the composition; c. about 37 wt% of lactose by weight of the composition;
  • the pharmaceutical composition comprises:
  • Another aspect of the present invention provides a method for treating or lessening the severity of rheumatoid arthritis comprising administering to a patient in need thereof a corticosteroid and a compound of F
  • X 1 is N or CR 4 ;
  • R 2 is H or halo
  • R 3 is H or halo
  • R 4 is H or halo
  • R" is H or an unsubstituted Ci -2 aliphatic; R is an unsubstituted CM aliphatic;
  • R 9 is an unsubstituted C 1-4 aliphatic
  • R is a Ci-3 aliphatic optionally substituted with up to 3 occurrences of F.
  • R 14 is H or unsubstituted Ci -2 alkyl
  • Some embodiments further comprise administering the compound of Formula I from 1 to 4 times per day.
  • from about 20 mg to about 250 mg e.g., from about 25 mg to about 200 mg, from about 50 mg to about 175 mg, or from about 75 mg to about 150 mg
  • the compound of formula I is administered to the patient at least once per day (e.g., from 1 to 4 times per day).
  • about 25 mg of the compound of formula I is administered to the patient once per day.
  • about 50 mg of the compound of formula I is administered to the patient once per day.
  • about 75 mg of the compound of formula I is administered to the patient once per day.
  • about 100 mg of the compound of formula I is administered to the patient once per day.
  • about 150 mg of the compound of formula I is administered to the patient once per day.
  • from about 20 mg to about 250 mg e.g., from about 25 mg to about 200 mg, from about 50 mg to about 175 mg, or from about 75 mg to about 150 mg
  • from about 20 mg to about 250 mg e.g., from about 25 mg to about 200 mg, from about 50 mg to about 175 mg, or from about 75 mg to about 150 mg
  • from about 20 mg to about 250 mg e.g., from about 25 mg to about 200 mg, from about 50 mg to about 175 mg, or from about 75 mg to about 150 mg
  • from about 20 mg to about 250 mg e.g., from about 25 mg to about 200 mg, from about 50 mg to about 175 mg, or from about 75 mg to about 150 mg
  • the corticosteroid is hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisone, prednisolone, methylprednisone, methylprednisolone, or any combination thereof.
  • the corticosteroid is prednisone, prednisolone,
  • the corticosteroid is methylprednisone or
  • the corticosteroid is orally administered to the patient in need thereof.
  • At least about 5 mg of corticosteroid is administered at least once per week.
  • methylprednisone, or methylprednisolone is administered at least once per week. In some instances, from about 8 mg to about 15 mg of prednisone or prednisolone is orally administered at least once per week. In other instances, from about 6 mg to about 12 mg of methylprednisone or methylprednisolone is orally administered at least once per week.
  • At least about 8 mg of corticosteroid is administered at least once per week.
  • At least about 5 mg of corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • from about 8 mg to about 15 mg of prednisone or prednisolone is orally administered at least twice per week.
  • from about 6 mg to about 12 mg of methylprednisone or methylprednisolone is orally administered at least twice per week.
  • the corticosteroid is prednisone or methylprednisone.
  • the corticosteroid is administered concurrently with the compound of Formula I. In other embodiments, the corticosteroid is administered prior to or subsequent to the administration of the compound of Formula I.
  • R is H or F.
  • each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R and R is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R and R is
  • R 14 is H or methyl.
  • R is an unsubstituted Ci -3 aliphatic.
  • R is a Ci -3 aliphatic substituted with 1-3 occurrences of F.
  • R is a group selected from -CH 2 CH 3 , -CH 2 CF 3 ,
  • the compound of Formula I is a compound selected from Table 1.
  • the compound of Formula I is administered to the patient in the form of an oral tablet.
  • the tablet comprises 50 mg of the compound of Formula I (e.g., Tablet 1, described below).
  • 100 mg of the compound of Formula I is administered, either once per day (q.d.) or twice per day (b.i.d.), and the administration may further include the oral administration of two 50 mg tablets.
  • the administration may further include the oral administration of three of the 50 mg tablets (e.g., 3 x Tablet 1) once per day or twice per day depending on the dosage regime.
  • 200 mg of the compound of Formula I is administered, either once per day (q.d.) or twice per day (b.i.d.), the
  • administration may further include the oral administration of four 50 mg tablets
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a corticosteroid and a co
  • X 1 is N or CR 4 ;
  • R 2 is H or halo;
  • R 3 is
  • R 4 is H or halo
  • R 1 is R" is H or an unsubstituted Cj.2 aliphatic
  • R' is H or halo
  • R is an unsubstituted C 1-4 aliphatic; R is an unsubstituted C 1-4 aliphatic; R is a Ci -3 aliphatic optionally substituted with up to 3 occurrences of F; and R 14 is H or unsubstituted C 1-2 alkyl
  • R 2 is H or F.
  • R is H or CI.
  • each of R 8 and R 9 is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R 8 and R 9 is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R 8 and R 9 is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
  • each of R 8 and R 9 is
  • R 14 is H or methyl.
  • R 7 is an unsubstituted C 1-3 aliphatic.
  • R 7 is a C 1-3 aliphatic substituted with 1-3 occurrences of F.
  • R is a group selected from -CH 2 CH 3 , -CH 2 CF3, -CH2CH2CH3, or -CHCH 3 CH 3 .
  • the compound of Formula I is selected from Table 1 , above.
  • the corticosteroid is hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisone, prednisolone, methylprednisone, methylprednisolone, or any combination thereof.
  • the pharmaceutical composition comprises a tablet.
  • the tablet comprises from about 20 mg to about 250 mg (e.g., from about 25 mg to about 200 mg, from about 50 mg to about 175 mg, or from about 75 mg to about 150 mg) of the compound of formula I.
  • the tablet comprises from about 1 mg to about 25 mg (e.g., from about 2.5 mg to about 8 mg) of the corticosteroid.
  • the tablet comprises tablet comprises from about 20 mg to about 250 mg (e.g., from about 25 mg to about 200 mg, from about 50 mg to about 175 mg, or from about 75 mg to about 150 mg) of the compound of formula I and from about 1 mg to about 25 mg (e.g., from about 2.5 mg to about 8 mg) of the corticosteroid.
  • Tablets and other pharmaceutical compositions of the present invention may optionally comprise one or more excipients selected from fillers or diluents, wetting agents (e.g., surfactants), binders, glidants, lubricants, disintegrants, or any combination thereof.
  • wetting agents e.g., surfactants
  • binders e.g., glidants, lubricants, disintegrants, or any combination thereof.
  • suitable excipients are provided in PCT publication no. WO 2013/070606, which is incorporated herein by reference in its entirety.
  • the pharmaceutical composition of the present invention comprises one or more excipients selected from diluents, disintegrants, surfactants, binders, glidants, lubricants, colorants, fragrances, or any combination thereof.
  • Diluents suitable for the present invention are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition.
  • exemplary diluents include lactose, sorbitol, celluloses, calcium phosphates, starches, sugars (e.g., mannitol, sucrose, or the like), or any combination thereof.
  • the pharmaceutical composition comprises at least one diluent in an amount of about 10 wt% or greater (e.g., about 20 wt% or greater, about 25 wt% or greater, or about
  • the pharmaceutical composition comprises from about 30 wt% to about 50 wt% (e.g., from about 35 wt% to about 45 wt%), by weight of the composition, of at least one diluent.
  • the pharmaceutical composition comprises from about 40 wt% to about 60 wt% (e.g., from about 45 wt% to about 55 wt%), by weight of the composition, of at least one diluent.
  • the pharmaceutical composition comprises about 20 wt% or greater (e.g., about 25 wt% or greater, or about 30 wt% or greater) of lactose, by weight of the composition.
  • the pharmaceutical composition comprises from about 20 wt% to about 60 wt% (e.g., from about 25 wt% to about 55 wt% or from about 27 wt% to about 45 wt%) of lactose, by weight of the composition.
  • Disintegrants suitable for the present invention enhance the dispersal of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition.
  • Exemplary disintegrants include sodium croscarmellose, sodium starch glycolate, or a combination thereof.
  • the pharmaceutical composition comprises disintegrant in an amount of about 10 wt% or less (e.g., about 9 wt% or less, about 8.5 wt% or less, about 8 wt% or less, or about 7.5 wt% or less) by weight of the composition.
  • the pharmaceutical composition comprises from about 1 wt% to about 10 wt% (e.g., from about 1 wt% to about 9 wt% or from about 2 wt% to about 8 wt%) of disintegrant, by weight of the composition.
  • the pharmaceutical composition comprises about 10 wt% or less (e.g., about 9 wt% or less, about 8 wt% or less, or about 7.5 wt% or less) of sodium croscarmellose, by weight of the composition. In some examples, the pharmaceutical composition comprises from about 0.1% to about 10 wt% (e.g., from about
  • the pharmaceutical composition comprises from about 0.5% to about 10 wt% (e.g., from about 1.5 wt% to about 7.5 wt% or from about
  • disintegrant 2.5 wt% to about 6 wt%) of disintegrant, by weight of the composition.
  • wetting agents e.g., surfactants
  • wetting agents suitable for the present invention enhance the solubility of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition.
  • the pharmaceutical composition comprises a surfactant in an amount of about 10 wt% or less (e.g., about 5 wt% or less, about 2 wt% or less, or about
  • the pharmaceutical composition includes from about 10 wt% to about 0.1 wt% (e.g., from about 5 wt% to about 0.2 wt% or from about 2 wt% to about 0.3 wt%) of surfactant, by weight of the composition.
  • the pharmaceutical composition comprises 10 wt% or less (e.g., about 5 wt% or less, about 2 wt% or less, about 1 wt% or less, about 0.8 wt% or less, or about 0.6 wt% or less) of sodium lauryl sulfate, by weight of the composition.
  • the pharmaceutical composition comprises from about 10 wt% to about 0.1 wt% (e.g., from about 5 wt% to about 0.2 wt% or from about 2 wt% to about 0.3 wt%) of sodium lauryl sulfate, by weight of the composition.
  • Binders suitable for the present invention enhance the tablet strength of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition.
  • exemplary binders include microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn (maize) starch, modified cellulose (e.g., hydroxymethyl cellulose), or any combination thereof.
  • the pharmaceutical composition comprises a binder in an amount of about
  • the pharmaceutical composition comprises from about 5 wt% to about 50 wt% (e.g., from about 10 wt% to about 45 wt% or from about 20 wt% to about 45 wt%) of binder, by weight of the composition.
  • the pharmaceutical composition comprises about 1 wt% or greater (e.g., about 10 wt% or greater, about 15 wt% or greater, about 20 wt% or greater, or about 22 wt% or greater) of microcrystalline cellulose, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 5 wt% to about
  • microcrystalline cellulose by weight of the composition.
  • Glidants suitable for the present invention enhance the flow properties of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition.
  • exemplary glidants include colloidal silicon dioxide, talc, or a combination thereof.
  • the pharmaceutical composition comprises a glidant in an amount of about
  • the pharmaceutical composition comprises from about 2 wt% to about 0.05 wt% (e.g., from about 1.5 wt% to about 0.07 wt% or from about 1.0 wt% to about 0.09 wt%) of glidant, by weight of the composition.
  • the pharmaceutical composition comprises about 2 wt% or less (e.g., about
  • the pharmaceutical composition comprises from about 2 wt% to about 0.05 wt% (e.g., from about 1.5 wt% to about 0.07 wt% or from about 1.0 wt% to about 0.09 wt%) of colloidal silicon dioxide, by weight of the composition.
  • Lubricants suitable for the present invention improve the compression and ejection of compressed pharmaceutical compositions from a die press and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, or the biological activity of the pharmaceutical composition.
  • Exemplary lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, or any combination thereof.
  • the stearic acid stearin
  • hydrogenated oil sodium stearyl fumarate, or any combination thereof.
  • composition comprises a lubricant in an amount of about 2 wt% or less (e.g., about 1.75 wt% or less, about 1.25 wt% or less, or about 1.00 wt% or less) by weight of the composition.
  • the pharmaceutical composition comprises from about 2 wt% to about 0.10 wt% (e.g., from about 1.5 wt% to about 0.15 wt% or from about 1.3 wt% to about
  • composition comprises about 2 wt% or less (e.g., about 1.75 wt% or less, about 1.25 wt% or less, or about 1.00 wt% or less) of magnesium stearate, by weight of the composition.
  • pharmaceutical composition comprises from about
  • magnesium stearate 2 wt% to about 0.10 wt% (e.g., from about 1.5 wt% to about 0.15 wt% or from about 1.3 wt% to about 0.30 wt%) of magnesium stearate, by weight of the composition.
  • the pharmaceutical composition can optionally comprise one or more colorants, flavors, and/or fragrances to enhance the visual appeal, taste, and/or scent of the composition.
  • Suitable colorants, flavors, or fragrances are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition.
  • the pharmaceutical composition comprises a colorant, a flavor, and/or a fragrance.
  • the pharmaceutical composition comprises less than about 1 wt% (e.g., less than about 0.75 wt% or less than about 0.5 wt%) of each optionally ingredient, i.e., colorant, flavor and/or fragrance, by weight of the composition.
  • the pharmaceutical composition comprises less than about 1 wt% (e.g., less than about 0.75 wt% or less than about 0.5 wt%) of a colorant.
  • the pharmaceutical composition can comprise tablets and the tablets can be coated with a colorant and optionally labeled with a logo, other image and/or text using a suitable ink.
  • the pharmaceutical composition can be made into tablets and the tablets can be coated with a colorant, waxed, and optionally labeled with a logo, other image and/or text using a suitable ink.
  • Suitable colorants and inks are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition.
  • the suitable colorants and inks can be any color and are water based or solvent based.
  • tablets made from the pharmaceutical composition are coated with a colorant and then labeled with a logo, other image, and/or text using a suitable ink. For example, tablets comprising a
  • composition as described herein can be coated with about 3 wt% (e.g., less than about 6 wt% or less than about 4 wt%) of film coating comprising a colorant.
  • the colored tablets can be labeled with a logo and text indicating the strength of the active ingredient in the tablet using a suitable ink.
  • the colored tablets can be labeled with a logo and text indicating the strength and/or mass of the active ingredient in the tablet using a black ink (e.g., Opacode® WB, commercially available from Colorcon, Inc. of West Point, PA.).
  • tablets made from the pharmaceutical composition are coated with a colorant, waxed, and then labeled with a logo, other image, and/or text using a suitable ink.
  • the colored tablets can be waxed with Carnauba wax powder weighed out in the amount of about 0.01 % w/w of the starting tablet core weight.
  • the waxed tablets can be labeled with a logo and text indicating the strength of the active ingredient in the tablet using a suitable ink.
  • the invention also provides a method of treating or lessening the severity of rheumatoid arthritis comprising administering to said patient one of the compositions as defined herein and a corticosteroid.
  • the corticosteroid is hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisone, prednisolone, methylprednisone, methylprednisolone, or any combination thereof.
  • the corticosteroid is prednisone, prednisolone,
  • methylprednisone or methylprednisolone.
  • the corticosteroid is methylprednisone or
  • the corticosteroid is orally administered to the patient in need thereof.
  • At least about 5 mg of corticosteroid is administered at least once per week.
  • methylprednisone, or methylprednisolone is administered at least once per week. In some instances, from about 8 mg to about 15 mg of prednisone or prednisolone is orally administered at least once per week. In other instances, from about 6 mg to about 12 mg of methylprednisone or methylprednisolone is orally administered at least once per week.
  • At least about 8 mg of corticosteroid is administered at least once per week.
  • At least about 5 mg of corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • corticosteroid e.g., prednisone, prednisolone, methylprednisone, or methylprednisolone
  • from about 8 mg to about 15 mg of prednisone or prednisolone is orally administered at least twice per week.
  • from about 6 mg to about 12 mg of methylprednisone or methylprednisolone is orally administered at least twice per week.
  • the corticosteroid is prednisone or methylprednisone.
  • the corticosteroid is administered concurrently with the compound of Formula I. In other embodiments, the corticosteroid is administered prior to or subsequent to the administration of the compound of Formula I.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient a pharmaceutical
  • composition comprising about 20 mg or greater (e.g., about 25 mg) of a compound of Formula I at least once per day and orally administering to the patient at least about 5 mg of a corticosteroid at least once per week.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient a pharmaceutical
  • composition comprising about 45 mg or greater (e.g., about 50 mg) of a compound of Formula I at least once per day and orally administering to the patient at least about 5 mg of a corticosteroid at least once per week.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient a pharmaceutical
  • composition comprising about 150 mg or greater (e.g., about 200 mg) of a compound of Formula I at least once per day and orally administering to the patient at least about 5 mg of a corticosteroid at least once per week.
  • Another aspect of the present invention provides a method of administering a corticosteroid and a pharmaceutical composition comprising orally administering to a patient at least once per day at least one tablet comprising a pharmaceutical composition comprising:
  • a binder d. a glidant
  • the tablet comprising the pharmaceutical composition comprising a compound of Formula I, the diluent, the binder, the glidant, the disintegrant, the surfactant, and the lubricant is orally administered to the patient once per day or twice per day (e.g., about every 12 hours). In other embodiments, the tablet comprising the
  • composition comprising a compound of Formula I, the diluent, the binder, the glidant, the disintegrant, the surfactant, and the lubricant is orally administered to the patient twice per day.
  • the tablet comprises about 25 mg or greater of a compound of Formula I.
  • the tablet comprises about 25 mg of a compound of Formula I. In other instances, the tablet comprises about 50 mg of a compound of Formula I.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient at least once per day the composition comprising about 20 mg or greater of a compound of Formula I.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient at least once per day the composition comprising about 25 mg of a compound of Formula I.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient at least once per day the composition comprising about 50 mg of a compound of Formula I.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient twice per day the
  • composition comprising a compound of Formula I.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient twice per day the
  • composition comprising about 25 mg of a compound of Formula I.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient twice per day the
  • composition comprising about 50 mg of a compound of Formula I.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient twice per day the composition comprising about 100 mg of a compound of Formula I.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient twice per day the composition comprising about 150 mg of a compound of Formula I.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient a pharmaceutical composition once every 12 hours.
  • the composition comprises about 25 mg or greater of a compound of Formula I.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours, about 50 mg or greater of a compound of Formula I.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours, about 100 mg or greater of a compound of Formula I.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient once every 12 hours, about 150 mg or greater of a compound of Formula I.
  • a pharmaceutical composition as described herein is orally administered to a patient once every 24 hours.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition
  • a pharmaceutical composition comprising orally administering to a patient at least once per day at least one tablet comprising a pharmaceutical composition comprising a compound of Formula I, a diluent, a binder, a glidant, a disintegrant, a surfactant, and a lubricant, each of which is described above and in the Examples below, wherein the composition comprises about 25 mg or greater (e.g., at least 35 mg, at least 40 mg, or at least 45 mg) of a compound of Formula I.
  • the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient at least one tablet comprising:
  • a wetting agent e. a binder
  • the present invention provides a method of administering a pharmaceutical composition comprising orally administering to a patient at least one tablet comprising:
  • the present invention provides for a method of orally administering the pharmaceutical composition described herein once a day. In other embodiments, the present invention provides for a method of orally administering the pharmaceutical composition described herein twice a day.
  • Another aspect of the present invention provides a method of administering a pharmaceutical composition by orally administering to a patient at least once per day at least one tablet comprising about 25 mg or greater of a compound of Formula I, a diluent, a binder, a glidant, a disintegrant, a surfactant, and a lubricant.
  • the tablet is orally administered to the patient once per day.
  • the administration comprises orally administering to a patient twice per day at least one tablet comprising about 25 mg or greater of a compound of Formula I, a diluent, a binder, a glidant, a disintegrant, a surfactant, and a lubricant.
  • Some tablets useful in this method comprise about 50 mg of a compound of Formula I.
  • the administration includes orally administering to a patient twice per day at least one tablet comprising about 50 mg or greater of a compound of Formula I, a diluent, a binder, a glidant, a disintegrant, a surfactant, and a lubricant.
  • the method of administering a pharmaceutical composition includes orally administering to a patient at least once per day at least one tablet comprising a pharmaceutical composition containing from about 20 mg to about 55 mg of a compound of
  • Formula I and a diluent, a binder, a glidant, a disintegrant, a surfactant, and a lubricant.
  • the method of administering a pharmaceutical composition includes orally administering to a patient once per day at least one tablet comprising a pharmaceutical composition containing a compound of Formula I, a filler, a binder, a glidant, a disintegrant, a surfactant, and a lubricant, each of which is described above and in the
  • the compound of Formula I is present in an amount of about 25 mg or greater (e.g., about 35 mg or greater, about 40 mg or greater, about 45 mg or greater, about
  • the method of administering a pharmaceutical composition includes orally administering to a patient once per day a plurality of tablets (e.g., two tablets, three tablets, four or five tablets), wherein each tablet comprises a pharmaceutical
  • composition comprising a compound of Formula I, a filler, a binder, a glidant, a disintegrant, a surfactant, and a lubricant, wherein the compound of Formula I is present in an amount of about 25 mg or greater (e.g., about 35 mg or greater, about 40 mg or greater, about 45 mg or greater, about 75 mg or greater, about 150 mg or greater, or about 250 mg or greater).
  • the method of administering a pharmaceutical composition includes orally administering to a patient twice per day at least one tablet comprising a pharmaceutical composition containing a compound of Formula I, a filler, a binder, a glidant, a disintegrant, a surfactant, and a lubricant, each of which is described above and in the
  • the compound of Formula I is present in an amount of about 25 mg or greater (e.g., about 35 mg or greater, about 40 mg or greater, about 45 mg or greater, about
  • the method of administering a pharmaceutical composition includes orally administering to a patient twice per day a plurality of tablets (e.g., two tablets, three tablets, four tablets or five tablets), wherein each tablet comprises a pharmaceutical composition comprising a compound of Formula I, a filler, a binder, a glidant, a disintegrant, a surfactant, and a lubricant, wherein the compound of Formula I is present in an amount of about 20 mg or greater (e.g., about 25 mg or greater, about 30 mg or greater, about 35 mg or greater, about 45 mg or greater, about 75 mg or greater, about 150 mg or greater, or about
  • each of the tablets may comprise about the same amount of a compound of Formula I or at least two of the tablets may comprise different amounts of the compound of Formula I.
  • compositions of the present invention can be employed in combination therapies, that is, the compound and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated".
  • the additional agent is a nutritional agent.
  • exemplary agents include vitamin a, vitamin b, vitamin c, vitamin e, pancrelipase (pancreating enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation.
  • the additional nutritional agent is pancrelipase.
  • the Boc-protected amino acid starting material (1) undergoes amidation in the presence of an activating agent, a coupling reagent, and the acid salt of the amine HNR 7 R 17 to generate the Boc-protected amide intermediate (2).
  • the amide intermediate (2) is
  • 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine was less than 4%.
  • Typical retention time for l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid was 4.6 minutes.
  • Extra triisopropyl borate and n-BuLi was added to lower the peak area of 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine.
  • HC1 acid 28L was added into the aqueous phase to adjust the pH to between 3 and 4 while maintaining the temperature of about 10-20 °C.
  • the mixture was stirred at about 10-15 °C for 1 hour.
  • the mixture was transferred into a centrifuge and filtered.
  • the resultant cake after filtering was washed with water (5 kg) and petroleum ether (5 kg).
  • the cake was dried at 35-45 °C until the LOD (loss on drying) was less than 3%.
  • An off-white solid resulted (2.5 kg and 98.8% purity as measured by HPLC analysis (method A), 69.4% yield of l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid).
  • Typical retention times are 6.2 minutes for (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid hydrochloride and 10.6 minutes for (R)-2-methyl-2-(2-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4- ylamino)butanoic acid.
  • Additional catalyst and 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine (900 g, 2.26 moles, 0.2 equiv.) were then added to the reaction mixture and the mixture was stirred.
  • reaction was shown to be 99.7% complete as measured by HPLC analysis (method C) of a 1.0 mL aliquot.
  • the additional catalyst added above was prepared by dissolving 37.5 g Palladium(II) acetate in 1 volume of acetonitrile (which was de-gassed for 20 minutes), and then adding 133.5 g of triphenylphosphine.
  • Typical retention times are 10.6 minutes for (R)-2- methyl-2-(2-( 1 -tosyl- 1 H-pyrrolo [2,3 -b]pyridin-3 -yl)pyrimidin-4-ylamino)butanoic acid and 5.5 minutes for (R)-2-(2-(l H-pyrrolo [2,3 -b]pyridin-3-y l)pyrimidin-4-ylamino)-2- methylbutanoic acid.
  • the pH of the mixture was adjusted to less than 1.0 with concentrated HCl solution at 25 ⁇ 10 °C and held for at least 4 hours. If necessary, the pH was readjusted with 6N NaOH.
  • the mixture was then filtered through a Nutshce filter, which was equipped with a filter cloth, and the solids were rinsed with 6.0 kg (2 volumes) of IN HCl. The filter cake was maintained under positive pressure of nitrogen for at least 30 minutes.
  • the HCl filtrate was agitated and heated to 25 ⁇ 5 °C. 0.9 kg of Darco G-60 activated carbon was added to the HCl filtrate and the mixture was stirred for at least 4 hours.
  • the mixture was then filtered through a Nutshce filter, which was equipped with a filter cloth, and the solids were washed with 6.0 kg (2 volumes) of IN HC1.
  • the second filter cake was maintained under positive pressure of nitrogen for at least 30 minutes.
  • the HC1 filtrate was again agitated and heated, charcoal was added and filtering step was repeated with a Nutshce filter, which was equipped with a 0.45 um in-line filter between the Nutsche filter and the receiver flask, to yield a third filter cake and a final filtrate.
  • the solids were washed with 6.0 kg of IN HC1.
  • the third filter cake was maintained under positive pressure of nitrogen for at least 30 minutes.
  • the pH of the final filtrate was adjusted to between 4.5 and 5.0 using 6N NaOH while the temperature was maintained between 25 ⁇ 5 °C. If necessary, the pH was readjusted using IN HC1.
  • the final filtrate was then cooled to 5 ⁇ 5 °C and agitated for at least 2 hours.
  • the mixture was filtered was filtered with a Nutshce filter, which was equipped with a filter cloth. The solids were rinsed with 6.0 kg (2 volumes) of water.
  • the final filter cake was maintained under positive pressure of nitrogen for at least 30 minutes.
  • DIEA Diisopropylethylamine
  • the mixture was concentrated under vacuum with a rotary evaporator at a temperature ⁇ 45 °C.
  • Isopropylacetate (1.55 kg, 0.5 volumes) was added to the concentrated aqueous solution, and the pH of the solution was adjusted to 7.5-8.0 using 6N NaOH solution at ⁇ 35 °C.
  • the mixture was cooled to 10 ⁇ 5 °C and stirred at for at least one hour. If necessary, 6N HC1 was added to readjust the pH of mixture to 7.5-8.0.
  • the resultant slurry was filtered and washed with water (10.5 kg, 3 volumes). The filter cake was maintained under positive pressure of nitrogen for at least 30 minutes.
  • the wet cake was dissolved in methanol (44.7 kg, 12 volumes) by agitation, and the solution was treated with PL-BnSH MP- Resin (BNSHMP) polymer resin (0.235 kg of 5 % wt of resin) at 25 ⁇ 5 °C. After agitating at 25 ⁇ 5 °C for at least 12 hours, the mixture was filtered. The solids were washed with methanol (2.77 kg, 1 volume). The filtrate was concentrated under vacuum in a rotary evaporator at a temperature ⁇ 50 °C. The filtrate was not concentrated to dryness. The concentrated filtrate was allowed to sit at room temperature for about 2.5 days.
  • BNSHMP PL-BnSH MP- Resin
  • the mixture was then stirred until homogeneous and heated to 40 °C, followed by slow addition of preheated water (56.1 kg at 45 °C) while maintaining a temperature of 45 ⁇ 5 °C. After the mixture was spun for 1 hour, the remaining methanol was concentrated further, but not concentrated to dryness. The resultant mixture was cooled down to at least 5 ⁇ 5 °C and agitated for at least 2 hours. The product was filtered, and the solids were washed with water (10.5 kg, 3 volumes). The filter cake was maintained under positive pressure of nitrogen for at least 30 minutes.
  • the isolated product was dried to a constant weight under vacuum in a drying oven at a temperature of ⁇ 70 °C with a nitrogen purge to yield 2-(2-(lH-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (4.182 kg, white powder, 0.18% water content, 98.6% AUC using HPLC (method D)).
  • Typical retention times are 4.4 minutes for (R)-2-(2-(lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4- ylamino)-2-methylbutanoic acid and 6.2 minutes for 2-(2-(lH-pyrrolo[2,3-b]pyridin-3- yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide.
  • Example 4a 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lH- pyrrolo[2, 3-bJpyridine
  • 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine was less than 4%.
  • HC1 (28L) was added into the aqueous phase to adjust the pH to between 3 and 4 while maintaining the temperature of about 10-20 °C.
  • the mixture was stirred at about 10-15 °C for 1 hour.
  • the mixture was transferred into a centrifuge and filtered.
  • the resultant cake after filtering was washed with water (5 kg) and petroleum ether (5 kg).
  • the cake was dried at 35-45 °C until the LOD (loss on drying) was less than 3%.
  • An off-white solid resulted (2.5 kg and 98.8% purity as measured by HPLC analysis (method A), 69.4% yield of l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid).
  • Example 4b (R)-2-methyl-2-(2-(l-tosyl-lH ⁇ yrrolo[2,3-b]pyridin-3-yl)pyrimidin-4- ylamino)butanoic acid
  • reaction was shown to be 99.7% complete as measured by HPLC analysis (method C) of a 1.0 mL aliquot.
  • the additional catalyst added above was prepared by dissolving 37.5 g palladium(II) acetate in 1 volume of acetonitrile (which was de-gassed for 20 minutes), and then adding 133.5 g of triphenylphosphine.
  • Example 4c (R)-2-methyl-2-(2-(l-tosyl-lH ⁇ yrrolo[2 -b]pyridin-3-yl)pyrimidin-4- ylamino)butanoic acid
  • the pH of the final filtrate was adjusted to between 4.5 and 5.0 using 6N NaOH while the temperature was maintained between 25 ⁇ 5 °C. If necessary, the pH was readjusted using IN HCl.
  • the final filtrate was then cooled to 5 ⁇ 5 °C and agitated for at least 2 hours.
  • the mixture was filtered was filtered with a Nutshce filter, which was equipped with a filter cloth. The solids were rinsed with 6.0 kg (2 volumes) of water.
  • the final filter cake was maintained under positive pressure of nitrogen for at least 30 minutes.
  • Example 4b To the reaction mixture in Example 4b, charge a solution of KOH (8.8 eq) in water (7.3 vol) and agitate the batch at a temperature of from 70-75 °C until HPLC analysis shows conversion from the intermediate to (R)-2-(2-(lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4- ylamino)-2-methylbutanoic acid reaches > 99%. Cool the batch to 20-25 °C then charge Darco G-60 activated carbon (30wt% based on (R)-2-((2-chloropyrimidin-4-yl)amino)-2- methylbutanoic acid) and agitate the batch for 12-24 hrs at 20-25 °C. Filter the slurry, rinsing the solids with water (2 x 1 vol). Cool the batch to 15-20 °C then adjust the pH of the batch to ⁇ 5 with cone. HCl while maintaining a batch temperature no more than 20-25 °C.
  • Example 4b To the reaction mixture in Example 4b, charge a solution of KOH (8.8 eq) in water (7.3 vol) and agitate the batch at a temperature of from 70-75 °C until HPLC analysis shows conversion from the intermediate to (R)-2-(2-(lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4- ylamino)-2-methylbutanoic acid reaches > 99%. Cool the batch to 15-25 °C and adjust the pH to ⁇ 5 with cone. HC1. Perform a fine adjustment of the pH to 5.5 - 6 using 6M NaOH.
  • DIEA Diisopropylethylamine
  • the mixture was concentrated under vacuum with a rotary evaporator at a temperature ⁇ 45 °C.
  • Isopropylacetate (1.55 kg, 0.5 volumes) was added to the concentrated aqueous solution, and the pH of the solution was adjusted to 7.5-8.0 using 6N NaOH solution at ⁇ 35 °C.
  • the mixture was cooled to 10 ⁇ 5 °C and stirred at for at least one hour. If necessary, 6N HC1 was added to readjust the pH of mixture to 7.5-8.0.
  • the resultant slurry was filtered and washed with water (10.5 kg, 3 volumes). The filter cake was maintained under positive pressure of nitrogen for at least 30 minutes.
  • the wet cake was dissolved in methanol (44.7 kg, 12 volumes) by agitation, and the solution was treated with PL-BnSH MP- Resin (BNSHMP) polymer resin (0.235 kg of 5% wt of resin) at 25 ⁇ 5 °C. After agitating at 25 ⁇ 5 °C for at least 12 hours, the mixture was filtered. The solids were washed with methanol (2.77 kg, 1 volume). The filtrate was concentrated under vacuum in a rotary evaporator at a temperature ⁇ 50 °C. The filtrate was not concentrated to dryness. The concentrated filtrate was allowed to sit at room temperature for about 2.5 days.
  • BNSHMP PL-BnSH MP- Resin
  • the mixture was then stirred until homogeneous and heated to 40 °C, followed by slow addition of preheated water (56.1 kg at 45 °C) while maintaining a temperature of 45 ⁇ 5 °C. After the mixture was spun for 1 hour, the remaining methanol was concentrated further, but not concentrated to dryness. The resultant mixture was cooled down to at least 5 ⁇ 5 °C and agitated for at least 2 hours. The product was filtered, and the solids were washed with water (10.5 kg, 3 volumes). The filter cake was maintained under positive pressure of nitrogen for at least 30 minutes.
  • reaction mixture was cooled to 25 °C and adjusted to have a pH of 0.4-0.6 using 11M HC1 (3.146 mL).
  • Activated charcoal 0.3 g, 30 wt%) was charged into the reactor, and the resulting mixture was stirred for > 12 Hr.
  • the reaction mixture was filtered to remove the charcoal, and water (50 mL) was added to the filtrate after returning it to the cleaned reactor.
  • the pH of the reaction mixture was adjusted to 5.5-6.0 using 6M NaOH (6.263 mL).
  • the reaction mixture was heated to 64 °C under stirring.
  • the reaction mixture was maintained under stirring at 64 °C for a period of 60 min. after the formation of a solution.
  • the reactor was cooled at a rate of 20 °C/hr until reaching a temperature of 25 °C.
  • the reaction mixture was continuously stirred at 25 °C for at least 4 hr.
  • the batch was then filtered and washed with water (10 mL) followed by heptane (20 mL). The solids were collected at dried under vacuum at 60 °C.
  • Table 2 Inhibition data for selected compounds of Formula I.
  • HT-2 clone A5E cells (ATCC Cat. # CRL- 1841 ) were grown and maintained at 37 °C in a humidified incubator in cell culture medium (RPMI 1640 supplemented with 2 mM L-glutamine adjusted to contain 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10 mM HEPES, 1.0 mM sodium pyruvate, 0.05 mM 2-mercaptoethanol, 10% fetal bovine serum, and 10% by volume rat T-STIM factor [Fisher Scientific Cat # CB40115] with Con A).
  • RPMI 1640 supplemented with 2 mM L-glutamine adjusted to contain 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10 mM HEPES, 1.0 mM sodium pyruvate, 0.05 mM 2-mercaptoethanol, 10% fetal bovine serum, and 10% by volume rat T-STIM factor [Fisher Scientific Cat # CB40115] with Con A
  • HT-2 cells were washed, resuspended at a density of 5 x 10 6 cells per ml in fresh cell culture medium without T-STIM and incubated for 4 hours without T-STIM. After four hours, 50 ⁇ (0.25 x 10 6 cells) of the resuspended cells were added to each well of a 96 well plate. Serial dilutions of compounds were made in DMSO and then added to RPMI. 100 ⁇ of the diluted compounds were added to each well and the plates were incubated for 1 hour at 37 °C. 50 ⁇ of recombinant murine interleukin-2 (rmIL-2) at
  • the plates were then centrifuged for 5 minutes at 1000 rpm, the supernatant was aspirated and 50 ⁇ of 3.7% formaldehyde in phosphate buffered saline (PBS) was added per well. The plates were incubated for 5 minutes at room temperature on a plate shaker. The plates were again centrifuged at 1000 rpm for 5 minutes. The supernatant was aspirated, 50 ⁇ of 90% methanol was added to each well, and the plate was incubated on ice for 30 minutes. The supernatant was aspirated and the plate washed with PBS.
  • PBS phosphate buffered saline
  • TF-1 cells (ATCC Cat. # CRL-2003) were grown and maintained at 37 °C in a humidified incubator in cell culture medium (RPMI 1640 supplemented with 2 mM
  • HEPES HEPES, 1.0 mM sodium pyruvate, 10% fetal bovine serum and recombinant human granulocyte-macrophage colony stimulating factor [rhGMCSF, R&D Systems Inc. Cat. # 215-GM]).
  • rhGMCSF human granulocyte-macrophage colony stimulating factor
  • TF-1 cells were washed, resuspended at a density of 5 x l0 6 cells per ml in fresh cell culture medium without rhGMCSF and incubated for 4 hours without rhGMCSF. After four hours, 50 ⁇ (0.25 * 10 6 cells) of the resuspended cells were added to each well of a 96 well plate. Serial dilutions of compounds were made in DMSO and then added to RPMI.
  • a formulation is provided in Table 3 for Exemplary Tablet 1 comprising 50 mg of API, i.e., a compound of Formula I.
  • Table 3 Exemplary Tablet 1
  • a formulation is provided in Table 4 for Exemplary Tablet 2 comprising 25 mg of API, i.e., a compound of Formula I.
  • Example 10 Exemplary Tablet 1 (Formulated to have 50 mg of a Compound of Formula I)
  • a batch of 250 mg total weight tablets can be formulated to have approximately 50 mg of compound of Formula I per tablet using the amounts of ingredients recited in Table 3, above.
  • Sieve magnesium stearate (commercially available from Mallinckrodt, Inc.) through a 20 mesh screen to remove lumps, and add to the blended mixture. Blend the second mixture containing the newly added magnesium stearate for another 4 minutes at a speed of about 10 to 24 rpm.
  • Example 11 Exemplary Tablet 2 (Formulated to have 25 mg of a Compound of Formula I)
  • a batch of 250 mg total weight tablets can be formulated to have approximately 25 mg of a compound of Formula I per tablet using the amounts of ingredients recited in Table B, above.
  • Sieve magnesium stearate (commercially available from Mallinckrodt, Inc.) through a 20 mesh screen to remove lumps, and add to the blended mixture. Blend the second mixture containing the newly added magnesium stearate for another 4 minutes at a speed of about 10 to 24 rpm.
  • Example 12 Exemplary Capsule (Formulated to have 25 mg of the compound of Formula I)
  • Example 14 Exemplary Capsule (Formulated to have 75 mg of a compound of Formula I)
  • Example 15 A Exemplary Administration A
  • Table 5 Exemplary administration of pharmaceutical formulations of the present invention.
  • compositions may be administered to subjects anytime during the day, and in some administrations, the pharmaceutical formulation is given at
  • the tablets may be administered with or without a fluid (e.g., water or other beverage).
  • a fluid e.g., water or other beverage.
  • human patients being administered the tablet(s) may fast for a period of time prior to or after the administration.
  • the administration of the tablet(s) may last for a period of about
  • Example 15B Exemplary Administration B
  • the pharmaceutical formulations may be administered to subjects in the morning, e.g., between 5:00 AM and 12:00 PM, and evening, e.g., between 5:00 PM and 12:00 AM, and in some administrations, the pharmaceutical formulation is given at approximately the same time (within a 1-hour window) on each dosing occasion.
  • the tablet(s) may be administered with or without a fluid (e.g., water or other beverage).
  • a fluid e.g., water or other beverage.
  • human patients being administered the tablet may fast for a period of time prior to or after the administration.
  • the administration of the tablet(s) lasts for a period of about 12 weeks.
  • Example 15C Exemplary Administration C
  • the pharmaceutical formulations may be administered to subjects in the morning, e.g., between 5:00 AM and 12:00 PM, and evening, e.g., between 5:00 PM and 12:00 AM, and in some administrations, the pharmaceutical formulation is given at approximately the same time (within a 1 -hour window) on each dosing occasion.
  • the tablet(s) e.g., Tablet 1 and/or Tablet 2
  • a fluid e.g., water or other beverage
  • human patients being administered the tablet may fast for a period of time prior to or after the administration.
  • the administration of the tablet(s) lasts for a period of about 12 weeks.
  • Example 16 Administration of Pharmaceutical Formulations
  • Example 16 A Exemplary Administration A
  • Table 8 Exemplary administration of pharmaceutical formulations of the present invention.
  • the pharmaceutical formulations may be administered to subjects in the morning, e.g., between 6:00 AM and 12:00 PM, and evening, e.g., between 5:00 PM and 11 :00 PM, and in some administrations, the pharmaceutical formulation is given at approximately the same time (within a 1-hour window) on each dosing occasion.
  • the pharmaceutical formulation may be given anytime during the day, and in some administrations, the pharmaceutical formulation is given at approximately the same time (within a 1-hour window) on each dosing occasion.
  • the tablets may be administered with or without a fluid (e.g., water or other beverage).
  • a fluid e.g., water or other beverage.
  • human patients being administered the tablet(s) may fast for a period of time prior to or after the administration.
  • the administration of the tablet(s) may last for a period of about 12 weeks.
  • Example 16B Exemplary Administration B
  • the pharmaceutical formulations may be administered to subjects anytime during the 24 hr. interval, and in some administrations, the pharmaceutical formulation is given at approximately the same time (within a 1-hour window) on each dosing occasion.
  • the tablet(s) may be administered with or without a fluid (e.g., water or other beverage). Also, human patients being administered the tablet may fast for a period of time prior to or after the administration.
  • a fluid e.g., water or other beverage
  • the administration of the tablet(s) lasts for a period of about 12 weeks.
  • Example 17 A Exemplary Administration A
  • Table 10 Exemplary administration of pharmaceutical formulations of the present invention.
  • the pharmaceutical formulations may be administered to subjects in the morning, e.g., between 6:00 AM and 12:00 PM, and evening, e.g., between 5:00 PM and 1 1 :00 PM, and in some administrations, the pharmaceutical formulation is given at approximately the same time (within a 1-hour window) on each dosing occasion.
  • the tablets e.g., Tablet 1
  • a fluid e.g., water or other beverage
  • human patients being administered the tablet(s) may fast for a period of time prior to or after the administration.
  • the administration of the tablet(s) may last for a period of about 12 weeks.
  • Some embodiments further comprise administering to the patient a co-therapy.
  • Co- therapies that are useful in the methods of the present invention may be administered concurrently with the compound of Formula I or sequentially.
  • Some embodiments further comprise administering to the patient an additional agent selected from a corticosteroid, cyclosporine, methotrexate, an oral retinoid, mycophenolate mofetil, thioguanine, hydroxyurea, sirolimus, azathioprine, or any combination thereof.
  • an additional agent selected from a corticosteroid, cyclosporine, methotrexate, an oral retinoid, mycophenolate mofetil, thioguanine, hydroxyurea, sirolimus, azathioprine, or any combination thereof.
  • Some embodiments further comprise administering a chemotherapy agent to the patient.
  • the chemotherapy agent comprises methotrexate, azathioprine (e.g., Imuran), cyclophosphamide (e.g., Cytoxan), cyclosporine,
  • 6-mercaptopurine or any combination thereof.
  • the chemotherapy agent comprises an injectable formulation or an oral formulation. And, in some instances, the patient is administered from about 5 mg to about 100 mg of the chemotherapy agent per month.
  • a drug-drug interaction study in healthy male subjects was conducted. The study was designed to evaluate the effect of Compound 1 200 mg daily (qd) on the PK of a single dose of a corticosteroid (prednisone or methylprednisolone) and the effect of a single dose of a corticosteroid (prednisone or methylprednisolone) and the effect of a single dose of a corticosteroid on the PK of Compound 1.
  • methylprednisolone one 8-mg tablet.
  • subjects in Cohort 1 received a single oral dose of 10 mg prednisone, and subjects in Cohort 2 received a single oral dose of 8 mg methylprednisolone.
  • the dosing schedule is shown in Table 1 1. [0530] Table 11 : Dosing schedule for Compound 1.
  • Blood samples for prednisone and prednisolone PK analysis (in Cohort 1) or methylprednisolone PK analysis (in Cohort 2) were collected over Days 1 and 2 and over Days 7 and 8 at 0 (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after the steroid dose.
  • Blood samples for Compound 1 PK analysis were collected on Day 2 at 0 (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose; on Days 3 through 6 at predose only; and over Days 7 through 10 at 0 (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours postdose.
  • Methylprednisolone GLSM C max increased approximately 1.7-fold in the presence of Compound 1 (90% CI: 1.54, 1.95) and GLSM AUC 0- oo increased approximately 4.3-fold (90% CI:3.98, 4.72) in the presence of Compound 1.
  • Safety results Drug exposure levels [0540] Safety evaluations included adverse events, clinical laboratory assessments, clinical evaluation of vital signs and physical examinations, and 12-lead electrocardiograms (ECGs). Compound 1 was safe and well tolerated when co-administered with prednisone and methylprednisolone in healthy male subjects. There were no death or other serious adverse events and no adverse events leading to discontinuation of study drug.

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Abstract

La présente invention concerne une méthode de traitement ou d'atténuation de la gravité d'une maladie ou d'un trouble médié par une réponse immunitaire anormale (par exemple, la polyarthrite rhumatoïde) qui consiste à administrer un composé de formule (I) et un corticostéroïde.
PCT/US2014/042275 2013-06-14 2014-06-13 Combinaisons pharmaceutiques utiles pour traiter la polyarthrite rhumatoïde WO2014201332A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9345708B2 (en) 2009-06-17 2016-05-24 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9771361B2 (en) 2013-11-13 2017-09-26 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10023569B2 (en) 2013-11-13 2018-07-17 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
JP2018524271A (ja) * 2015-05-13 2018-08-30 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ インフルエンザウイルスの複製の阻害剤を調製する方法
US10273233B2 (en) 2015-05-13 2019-04-30 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000054780A2 (fr) * 1999-03-15 2000-09-21 Arakis Ltd. Formulation corticosteroidienne
WO2005095400A1 (fr) 2004-03-30 2005-10-13 Vertex Pharmaceuticals Incorporated Azaindoles utiles comme inhibiteurs de janus kinases et d'autres proteines kinases
WO2007084557A2 (fr) 2006-01-17 2007-07-26 Vertex Pharmaceuticals Incorporated Azaindoles utiles comme inhibiteurs de janus kinases
WO2013006634A2 (fr) 2011-07-05 2013-01-10 Vertex Pharmaceuticals Incorporated Procédés et intermédiaires pour produire des azaindoles
WO2013070606A1 (fr) 2011-11-07 2013-05-16 Vertex Pharmaceuticals Incorporated Méthodes pour le traitement de maladies inflammatoires et combinaisons pharmaceutiques utiles pour celles-ci

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000054780A2 (fr) * 1999-03-15 2000-09-21 Arakis Ltd. Formulation corticosteroidienne
WO2005095400A1 (fr) 2004-03-30 2005-10-13 Vertex Pharmaceuticals Incorporated Azaindoles utiles comme inhibiteurs de janus kinases et d'autres proteines kinases
WO2007084557A2 (fr) 2006-01-17 2007-07-26 Vertex Pharmaceuticals Incorporated Azaindoles utiles comme inhibiteurs de janus kinases
US20070203142A1 (en) * 2006-01-17 2007-08-30 Luc Farmer Azaindoles useful as inhibitors of janus kinases
WO2013006634A2 (fr) 2011-07-05 2013-01-10 Vertex Pharmaceuticals Incorporated Procédés et intermédiaires pour produire des azaindoles
WO2013070606A1 (fr) 2011-11-07 2013-05-16 Vertex Pharmaceuticals Incorporated Méthodes pour le traitement de maladies inflammatoires et combinaisons pharmaceutiques utiles pour celles-ci

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
"March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS
"Scientific Tables, Geigy Pharmaceuticals", 1970, ARDSLEY, pages: 537
"Tofacitinib", DRUGS IN R & D, vol. 10, no. 4, 2010, pages 271 - 84
FREIREICH ET AL., CANCER CHEMOTHER. REP., vol. 50, 1966, pages 219
FRIDMAN J.S. ET AL., J IMMUNOL., vol. 184, 2010, pages 5298 - 5307
KREMER J. M. ET AL., ARTHRITIS RHEUMATISM, vol. 60, no. 7, 2009, pages 1895 - 1905
PANES, J. ET AL., 19TH ANN. EUR. GASTROENTEROLOGY WEEK, 22 October 2011 (2011-10-22)
STUMP K. L. ET AL., ARTHRITIS RES. THER., vol. 13, 2011, pages R68
THOMAS SORRELL: "Organic Chemistry", 1999, UNIVERSITY SCIENCE BOOKS
WEST K., CURR. OP. INVESTIG. DRUGS, vol. 10, 2009, pages 491 - 504
XIONG, W. ET AL., THER ADV MUSCULOSKELET DIS., vol. 3, no. 5, 2011, pages 255 - 266

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9345708B2 (en) 2009-06-17 2016-05-24 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9518056B2 (en) 2009-06-17 2016-12-13 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9808459B2 (en) 2009-06-17 2017-11-07 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10039762B2 (en) 2009-06-17 2018-08-07 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10874673B2 (en) 2009-06-17 2020-12-29 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9771361B2 (en) 2013-11-13 2017-09-26 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10023569B2 (en) 2013-11-13 2018-07-17 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US10640501B2 (en) 2013-11-13 2020-05-05 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US11345700B2 (en) 2013-11-13 2022-05-31 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
JP2018524271A (ja) * 2015-05-13 2018-08-30 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ インフルエンザウイルスの複製の阻害剤を調製する方法
US10273233B2 (en) 2015-05-13 2019-04-30 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10533004B2 (en) 2015-05-13 2020-01-14 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication

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