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WO2009046416A1 - Anilinopyrimidines en tant qu'inhibiteurs de kinases jak - Google Patents

Anilinopyrimidines en tant qu'inhibiteurs de kinases jak Download PDF

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Publication number
WO2009046416A1
WO2009046416A1 PCT/US2008/078932 US2008078932W WO2009046416A1 WO 2009046416 A1 WO2009046416 A1 WO 2009046416A1 US 2008078932 W US2008078932 W US 2008078932W WO 2009046416 A1 WO2009046416 A1 WO 2009046416A1
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Prior art keywords
methyl
pyrimidin
thiophen
phenyl
pyrrolidin
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English (en)
Inventor
Glenn Noronha
Chi Ching Mak
Jianguo Cao
Chun Chow
Elena Daneprovskaia
Joel Renick
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TargeGen Inc
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TargeGen Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • Protein kinases are enzymes that play key roles in signaling pathways since they catalyze the phosphorylation of specific residues leading to the transduction of extra and intra cellular signals, including the action of cytokines on their receptors, growth factors, communication with the nuclei and the triggering of various biological events. In normal cellular physiology, cell cycle control, cell growth, differentiation, apoptosis, mobility, mitogenesis, and various other structural and functional events appear to be mediated by kinases.
  • Aberrant kinase activity has been implicated in many diseases including cancers, in immunological and auto-immune disorders, in diabetes, fibrosis of the liver and kidney, atherosclerosis and in ocular diseases. Inhibition of such kinase activity may be beneficial in e.g., the treatment of such diseases.
  • the Janus kinases are cellular kinases and consist of four members - JAKl, JAK2, JAK3 and TYK2.
  • the JAKs may play a crucial role in regulating cell behavior induced by a number of cytokines.
  • compounds which modulate the activity of the JAKs have potential utility in several indications driven by a dysregulation of signaling pathways normally associated with cytokine regulation. This includes immune and inflammatory diseases in which dysregulated cytokine pathways are thought to play a roles.
  • somatic mutations in the hematopoietic system leading to activation of the JAK pathway has been linked to the myeloproliferative disorders, of cells proliferation and in several cells related to several kinds of immune function.
  • JAK kinases have been implicated in ocular diseases such as Age Related Macular Degeneration (AMD), diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR).
  • AMD Age Related Macular Degeneration
  • DME diabetic macular edema
  • PDR proliferative diabetic retinopathy
  • novel compounds that may inhibit and/or modulate JAK, for example, JAK2.
  • the disclosed compounds may inhibit or modulate one or more of the JAK family, e.g, JAKl, JAK2, JAK3, and/or TYK2, and/or may inhibit or modulate KDR.
  • Treatment or amelioration of disease states and pathological conditions that implicate JAK, e.g. JAK2, pathways are contemplated herein, and such treatment comprises administering one or more of the disclosed compounds, such as those recited in Formulas I, II, or III, or administering a composition as described herein comprising a disclosed compound.
  • disclosed compounds may have a IC 50 against a JAK of less than about 500 nM.
  • myeloproliferative disorders such as polycythemia vera, myelofibrosis, and essential thrombocythemia by administering disclosed compounds.
  • methods of treating afflication such as cancer and/or inflammation are contemplated.
  • the present disclosure is directed in part towards novel compounds and compositions that modulate or inhibit JAK and methods of making and using the same.
  • the disclosed compounds may inhibit or modulate one or more of the JAK family, e.g, JAKl, JAK2, JAK3, and/or TYK2, and/or may inhibit or modulate KDR.
  • JAK family e.g, JAKl, JAK2, JAK3, and/or TYK2
  • KDR KDR
  • therapeutic agent is art-recognized and refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject.
  • therapeutic agents also referred to as “drugs” are described in well-known literature references such as the Merck Index, the Physicians Desk
  • therapeutic effect is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance.
  • the term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and/or conditions in an animal or human.
  • therapeutically-effective amount means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment.
  • the therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • certain compositions of the present invention may be administered in a sufficient amount to produce some desired local or systemic effect at a reasonable benefit/risk ratio applicable to such treatment.
  • modulation is art-recognized and refers to up regulation (i.e., activation or stimulation), down regulation (i.e., inhibition or suppression) of a response, or the two in combination or apart.
  • a "patient,” “subject” or “host” to be treated by the subject method may mean either a human or non-human animal.
  • the term “treating” is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disease.
  • prodrug is art-recognized and is intended to encompass compounds which, under physiological conditions, are converted into the agents of the present invention.
  • a common method for making a prodrug is to select moieties which are hydrolyzed under physiological conditions to provide the desired compound.
  • the prodrug is converted by an enzymatic activity of the host animal or the target organ or cell.
  • alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 3O for straight chain, C 3 -C 30 for branched chain), and alternatively, about 20 or fewer, e.g. from 1 to 6 carbons.
  • cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
  • alkyl is also defined to include halosubstituted alkyls.
  • alkyl (or “lower alkyl”) includes “substituted alkyls”, which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • Such substituents may include, for example, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
  • a carbonyl such as a carboxyl, an alkoxy
  • the moieties substituted on the hydrocarbon chain may themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls may be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CN, and the like.
  • aralkyl is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkylene refers to an organic radical formed from an unsaturated aliphatic hydrocarbon; “alkenylene” denotes an acyclic carbon chain which includes a carbon-to-carbon double bond.
  • lower alkyl refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • heteroatom is art-recognized and refers to an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • aryl refers to a mono-, bi-, or other multi-carbocyclic, aromatic ring system.
  • the aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF 3 , -CN, or the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls.
  • Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7, 8-tetrahydronaphthyl.
  • ortho, meta and para are art- recognized and refer to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively.
  • the names 1,2-dimethylbenzene and ortho- dimethylbenzene are synonymous.
  • heteroaryl or “heteroaromatics” are art-recognized and refer to a 5-15 membered mono-, bi-, or other multi-cyclic, aromatic ring system containing one or more heteroatoms, for example one to four heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can also be fused to non-aromatic rings.
  • the heteroaryl ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy
  • heteroaryl groups include, but are not limited to, acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furazanyl, furyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuryl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazo
  • heterocyclyl or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated 3- to 10-membered ring structures, alternatively 3- to 7- membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur. Heterocycles may also be mono-, bi-, or other multi-cyclic ring systems.
  • a heterocycle may be fused to one or more aryl, partially unsaturated, or saturated rings.
  • Heterocyclyl groups include, for example, biotinyl, chromenyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl, imidazolidinyl, isoquinolyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxolanyl, oxazolidinyl, phenoxanthenyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, thiazolidinyl, th
  • the heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy
  • heterocycloalkyl is art-recognized and refers to a saturated heterocyclyl group as defined above.
  • polycyclyl or “polycyclic group” are art-recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, - CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, sily
  • carrier is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
  • nitro is art-recognized and refers to -NO 2 ;
  • halogen is art- recognized and refers to -F, -Cl, -Br or -I;
  • sulfhydryl is art-recognized and refers to -SH;
  • hydroxyl means -OH;
  • sulfonyl is art-recognized and refers to - SO2 " .
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas: R50
  • R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, - (CH2)m-R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
  • R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and
  • m is zero or an integer in the range of 1 to 8.
  • only one of R50 or R51 may be a carbonyl, e.g., R50, R51 and the nitrogen together do not form an imide.
  • R50 and R51 each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m- R61.
  • alkylamine includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
  • amino is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:
  • acylamino is art-recognized and refers to a moiety that may be represented by the general formula: O
  • R50 is as defined above
  • R54 represents a hydrogen, an alkyl, an alkenyl or -(CH2) m -R61, where m and R61 are as defined above.
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of -S- alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2) m -R61, wherein m and R61 are defined above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • carbonyl is art recognized and includes such moieties as may be represented by the general formulas:
  • X50 is a bond or represents an oxygen or a sulfur
  • R55 and R56 represents a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R61or a pharmaceutically acceptable salt
  • R56 represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R61, where m and R61 are defined above.
  • X50 is an oxygen and R55 or R56 is not hydrogen
  • the formula represents an "ester”.
  • X50 is an oxygen
  • R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid".
  • X50 is an oxygen, and R56 is hydrogen
  • the formula represents a "formate".
  • the oxygen atom of the above formula is replaced by sulfur
  • the formula represents a "thiolcarbonyl” group.
  • X50 is a sulfur and R55 or R56 is not hydrogen
  • the formula represents a "thiolester.”
  • X50 is a sulfur and R55 is hydrogen
  • the formula represents a "thiolcarboxylic acid.”
  • X50 is a sulfur and R56 is hydrogen
  • the formula represents a "thiolformate.”
  • X50 is a bond, and R55 is not hydrogen
  • the above formula represents a "ketone” group.
  • X50 is a bond, and R55 is hydrogen
  • the above formula represents an "aldehyde” group.
  • each expression e.g. alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • substituted is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67 th Ed., 1986-87, inside cover.
  • the term "hydrocarbon” is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom.
  • the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds that may be substituted or unsubstituted.
  • compositions of the present invention refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, including, for example, those contained in compositions of the present invention.
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient.
  • materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • systemic administration refers to the administration of a subject composition, therapeutic or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • eye administration refers to the administration of a subject composition, therapeutic or other material on or into the eye, including topical and parenteral administration.
  • Inhalation administration or “administered by inhalation” refers to administration of a subject composition, therapeutic or other material by a pulmonary route, e.g. aerosol inhalation or nasal administration.
  • parenteral administration and “administered parenterally” are art- recognized and refer to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
  • R 1 may be an heteroaryl optionally substituted on a ring carbon by one or two substituents each independently selected from the group consisting of halo, hydroxyl, nitro, formyl, cyano, formamido, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, ureido, CF 3 , N-alkylsulphamoyl, N- alkylcarbamoyl, -OR 11 , -ORuR 11 , -NRb-R 11 , or -R 14 R 11 .
  • R 1 may be, in some embodiments, an optionally substituted monocyclic or bicyclic heteroaryl.
  • alkyl may be chosen from methyl, ethyl, or propyl.
  • R 1 may contain at least one S atom.
  • R 1 can be selected from the group consisting of optionally substituted thiophene (thienyl) or optionally substituted benzothiophene.
  • R 2 may be a heterocycle, e.g. a phenyl or pyridinyl, wherein R 2 is optionally substituted on a ring carbon by one or two substituents each independently selected from the group consisting of halo, hydroxyl, nitro, formyl, formamido, cyano, carboxy, amino, amido, acylamino, CF 3> carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, -OR 11 , -OR 12 R 11 , or -R 12 R 11 ;
  • R' is alkyl optionally substituted with one, two or three halogens, for example, R' may be methyl;
  • R b is H or alkyl;
  • R 11 is independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein R 11 can be optionally substituted by one to four substituents each independently selected from with halo, alkyl, carbonyl, of halo, hydroxyl, nitro, formyl, formamido, cyano, carboxy, amino, amido, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N,N-dialkylsulphamoyl, N-alkylcarbamoyl, -O-alkylene- Ri 3 , Ri 3 ; or -SO 2 -Ri 3 ,
  • Ri 2 is alkylene, sulfonyl, carbonyl, or a bond
  • Ri 4 is alkylene, alkenylene, sulfonyl, or a bond
  • Ri 3 is independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein Ri 3 can be optionally substituted by one to four substituents each independently selected from with halo, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, cyano, amino, amido, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N,N-dialkylsulphamoy, N-alkylcarbamoyl.
  • R 1 is represented by:
  • R 3 and R 4 may each be independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, formyl, formamido, carboxy, amino, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, - OR 11 , -OR 14 R 11 , -NRbR 11 , or -R 14 R 11 , or R 3 and R 4 taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic or heterocyclic ring, optionally substituted by one to two substituents each independently selected from with halo, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, carbamoyl, sulphamoyl, alkenyl, alkyny
  • R 5 is independently selected from hydrogen, halo, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, acylamino, cyano, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N- alkylcarbamoyl, or -R 14 R 11 and and R 5 ' is selected from the group consisting of H, alkyl, sulphonyl, and carbonyl.
  • R 2 can be represented by
  • X is N or CR 8 ;
  • R 7 and R 8 independently for each occurrence, is chosen from H, heterocycle, heteroaryl, -O-alkylene-heterocycle or -O-heteroaryl, wherein said heterocycle or heteroaryl is optionally substituted with one to three substituents each independently selected from halo, alkyl, carbonyl, cyano, CF 3 , hydroxyl, nitro, formyl, formamido, carboxy, amino, carbamoyl, sulphamoyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, and N- alkylcarbamoyl.
  • R 7 may be a methyl-substituted heterocycle or heteraryl.
  • at least one R 8 is H.
  • R 8 is H and R 7 is a heterocycle (for example a methyl substitituted heterocycle), or -O-alkylene-heterocycle.
  • heterocycles may include pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl.
  • R 8 is H and R 7 is an optionally substituted imidazole.
  • R 8 is H and R 7 is selected from the group consisting of: methylpiperazine, piperazine, N-(4-(2-methyl-lH-imidazol-l-yl), imidazole, or 2-pyrrolidin-lylethoxy.
  • X is CR 8 .
  • R 2 is phenyl
  • meta and/or para substitution of the phenyl, with respect to the 2-position NH on the pyrimidine may be favorable for JAK2 modulation.
  • the phenyl may be substituted at one meta position, or at the para position.
  • this disclosure contemplates compounds of Formula I, wherein when R' is methyl, inhibits JAK2 with an IC 50 at least about ten times lower as compared to a compound represented by Formula I when R' is H, and R 1 , R 2 , R b , Rn and R 13 are as defined above.
  • a 5-methyl substituent (e.g. R' is methyl) on the pyrimidine ring of Formula I may, when interacting with JAK2, "sit" in the JAK2 pocket and may associate with an S -methyl group of a methionine.
  • the R b substituent, e.g. methyl may act to make the pyrimidine portion of Formula I hydrophobic.
  • compound A, where R' is H has a IC 50 against JAK2 of 1360OnM
  • compound B, where R' is methyl has a IC 50 against JAK2 of 105nM:
  • R 1 is thiophene
  • a methyl at the 3-position on the thiophene may result in a loss of JAK2 activity when R' is methyl, e.g. compound C:
  • R 1 of Formula I is a 3-position methyl substituted thiophene, together with a 5-methyl substituted pyrimidine of the Formula I core, the conformation of the thiophene may result in loss of biological activity, such as JAK2 activity.
  • compounds represented by formula II or formula III are compounds represented by formula II or formula III:
  • R 3 and R 4 may each be independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, formyl, formamido, carboxy, cyano, amino, amido, acylamido, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, -OR 11 , -NRbR 11 , or -R 14 R 11 ;
  • R 9 is independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, acylamino, cyano, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, or N- alkylcarbamoyl;
  • X is NR 6 or CR 8 ;
  • R 6 is H or alkyl
  • R 7 and R 8 are each independently chosen from H, -R 12 R 13 , or -OR 12 R 13 wherein at least one R 8 is H;
  • R b is H or alkyl
  • R 11 is independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein R 11 can be optionally substituted by one to four substituents each independently selected from with halo, alkyl, carbonyl, halo, hydroxyl, nitro, formyl, formamido, cyano, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, -O-alkylene-Ri 3 , R 13 or - SO 2 -Ri 3 ;
  • R 13 is independently selected from aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each optionally substituted by one to four substituents each independently selected from with halo, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, cyano, amino, amido, acylamino, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, or N-alkylcarbamoyl,
  • Ri 2 is chosen from: alkylene or a bond
  • Ru is chosen from: alkylene, alkenylene, -SO 2 -, or a bond; or pharmaceutically acceptable salts, prodrugs, N-oxides, distereomers and/or hydrates thereof.
  • R 7 and R 8 of Formula II or III is H.
  • R 3 is H.
  • R 4 is selected from the group consisting of: H, halo, cyano, carboxyl, alkyl, heteroaryl optionally substituted with 1, 2, or 3 substituents each independently selected from halo, alkyl or branched alkyl, -NH-phenyl or -phenyl, wherein said phenyl is optionally substituted with N-alkylsulphamoyl, heterocycle, -S(O) 2 -heterocycle, straight chain alkyl, branched alkyl, or -O-alkylene-heterocycle.
  • Rg may be, for example, selected from H or alkyl.
  • at least one R 9 may be an alkyl, such as methyl.
  • Rg can be H.
  • R 7 or Rg is selected from the group consisting of: and n other embodiments, R 3 is H and R 4 is selected from the group consisting of:
  • Exemplary compounds of this disclosure include: (5-Methyl-4-thiophen-2-yl- pyrimidin-2-yl)-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-amine; (5-Methyl-4-thiophen-2-yl- pyrimidin-2-yl)-phenyl-amine; (5-Methyl-4-thiophen-2-yl-pyrimidin-2-yl)-pyridin-3-yl-amine; [5-Methyl-4-(5-phenyl-thiophen-2-yl)-pyrimidin-2-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]- amine; [5-Methyl-4-(4-methyl-thiophen-2-yl)-pyrimidin-2-yl]-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl] -amine;
  • compositions that include the disclosed compounds and a pharmaceutically acceptable carrier.
  • compositions of the present invention will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the subject composition. Any of the subject formulations may be administered in a single dose or in divided doses. Dosages for the compositions of the present invention may be readily determined by techniques known to those of skill in the art or as taught herein.
  • the dosage of the subject compounds will generally be in the range of about 0.01 ng to about 10 g per kg body weight, specifically in the range of about 1 ng to about 0.1 g per kg, and more specifically in the range of about 100 ng to about 10 mg per kg.
  • An effective dose or amount, and any possible affects on the timing of administration of the formulation may need to be identified for any particular composition of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals (preferably at least 5 animals per group), or in human trials if appropriate.
  • the effectiveness of any subject composition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of the administration by measuring one or more applicable indices, and comparing the post-treatment values of these indices to the values of the same indices prior to treatment.
  • the precise time of administration and amount of any particular subject composition that will yield the most effective treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a subject composition, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), route of administration, and the like.
  • the guidelines presented herein may be used to optimize the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage and/or timing.
  • the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period. Treatment, including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring. The patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters.
  • Adjustments to the amount(s) of subject composition administered and possibly to the time of administration may be made based on these reevaluations.
  • Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained.
  • compositions may reduce the required dosage for any individual agent contained in the compositions because the onset and duration of effect of the different agents may be complimentary.
  • Toxicity and therapeutic efficacy of subject compositions may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 and the ED50.
  • the data obtained from the cell culture assays and animal studies may be used in formulating a range of dosage for use in humans.
  • the dosage of any subject composition lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose may be estimated initially from cell culture assays.
  • compositions of the present invention may be administered by various means, depending on their intended use, as is well known in the art.
  • compositions of the present invention may be formulated as tablets, capsules, granules, powders or syrups.
  • formulations of the present invention may be administered parenterally as injections (intravenous, intramuscular or subcutaneous), drop infusion preparations, suppositories or administration intranasally (for example, to deliver a dosage to the brain via the nose or to deliver a dosage to the nose directly) or by inhalation (e.g. to treat a condition of the respiratory tract or to pretreat or vaccinate via the respiratory tract).
  • compositions of the present invention may be formulated as eyedrops or eye ointments. These formulations may be prepared by conventional means, and, if desired, the compositions may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
  • any conventional additive such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the formulated agents.
  • Subject compositions may be suitable for oral, nasal, topical (including buccal, ocular, and sublingual), rectal, vaginal, aerosol, ocular, and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration.
  • Methods of preparing these formulations include the step of bringing into association compositions of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association agents with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a subject composition thereof as an active ingredient.
  • an inert base such as gelatin and glycerin, or sucrose and acacia
  • compositions of the present invention may also be administered as a bolus, electuary, or paste.
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerator
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing
  • Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Compositions and compounds of the present invention may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • Dosages for administration by nasal delivery e.g. delivered to or via the nasal cavity, can be applied as drops, ointments, gels, mists/sprays (aqueous or nonaqueous), aerosols
  • compositions for inhalation and/or delivery to the nose may contain from 1% to 20% by weight of a penetrator enhancer (for example, surfactants, e.g. sugar esters, sugar ethers, carbohydrate esters) which may allow enhanced nose permeability of the active agent.
  • a penetrator enhancer for example, surfactants, e.g. sugar esters, sugar ethers, carbohydrate esters
  • Dosages for administration by inhalation or by delivered to or via the lung can be applied as mists/sprays (aqueous or nonaqueous), aerosols (liquids, suspensions or dry powders),liquids or suspensions (aqueous or nonaqueous), powders, or combinations thereof.
  • Such delivery can be achieved by commercially available devices such as 1) nebulizers, 2) metered dose inhalers, 3) dry powder inhalers, 4) soft mist inhalers, or by instillation or insufflation, or other mechanisms and/or devices known in the art.
  • compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • compositions of this invention may take the form of solutions, gels, ointments, suspensions or solid inserts, formulated so that a unit dosage comprises a therapeutically effective amount of the active component or some multiple thereof in the case of a combination therapy.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Treatment or amelioration of disease states and pathological conditions that implicate JAK, e.g. JAK2, pathways comprises administering one or more of the disclosed compounds, such as those recited in Formulas I, II, or III, or a composition as described herein comprising a disclosed compound.
  • the disclosed compounds may inhibit or modulate one or more of the JAK family, e.g, JAKl, JAK2, JAK3, and/or TYK2, and/or may inhibit or modulate KDR.
  • the disclosed compounds may for example inhibit JAK2 but may not substantially modulate JAK3 and/or KDR.
  • Methods of treating a patient in need thereof e.g. suffering from a disease where inihibition of kinases are useful, for example, immunological and autoimmune disorders, inflammatory disease, diabetes, fibrosis of the liver and/or kidney, atherosclerosis, and ocular diseases are contemplated.
  • JAKs appear to play a crucial role in regulating cell behavior induced by a number of cytokines
  • treatment of indications driven by a dysregulation of signaling pathways normally associated with cytokine regulation may includecompounds which modulate the activity of the JAKs, such as those recited in Formulas I, II or III is contemplated, such as the treatment of immune and inflammatory diseases, e.g.
  • RA rheumatoid arthritis
  • COPD chronic obstructive pulmonary disease
  • Somatic mutations in the hematopoietic system leading to activation of the JAK pathway has been linked to the myeloproliferative disorders polycythemia vera, essential thrombocythemia and myeloid metaplasia with myelofibrosis.
  • upregulation of the JAK pathway may contribute to the myeloproliferative disorders chronic myelogenous leukemia, chronic myelomomocytic leukemia, thallasemia gravis, hypereosinophilic syndrome, and systemic mast cell disease.
  • methods for treating cancers e.g.
  • cancers are associated with activation of Janus kinases including acute myeloid leukemia, hepatocellular carcinoma, multiple myeloma, prostrate cancer, Hodgkin's lymphomas and T cell leukemia/lymphoma , wherein the method includes administrating a disclosed compounds.
  • ALD Age Related Macular Degeneration
  • DME diabetic macular edema
  • PDR proliferative diabetic retinopathy
  • a method of treating an ocular or other disease includes administration of a disclosed compound that modulates JAK and in some embodiments, inhibits VEGFr. may also be an advantage.
  • Also contemplated herein is a method for treating or ameliorating transplant rejection that includes administering an instantly disclosed compound.
  • a method for treating or ameliorating rheumatoid arthritis that includes administering an instantly disclosed compound is contemplated.
  • Dysregulation in the hematopoietic stem cells of the myeloid compartment may lead to related myeloproliferative disorders (MPDs) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), and to acute myeloid leukemia (AML)
  • MPDs myeloproliferative disorders
  • PV polycythemia vera
  • ET essential thrombocythemia
  • MF myelofibrosis
  • AML acute myeloid leukemia
  • Underlying each of these myeloid diseases may be a cytokine-independent activation of molecular signaling pathways critical for the proliferation and aberrant survival of the cells associated with the disease's pathology.
  • JAK2 V617F Janus kinase 2
  • JAK2 T875N tyrosine kinase mutations
  • JAK2 activation leads to phosphorylation of signal transducer and activator of transcription (STAT) proteins, transcription factors that stimulate the cell's genetic machinery to induce proliferation and prevent apoptosis.
  • STAT signal transducer and activator of transcription
  • AML features ligand-independent activation of the JAK-STAT pathway in the majority of patients. Although there is no predominant known mutation that leads to activation of the JAK-STAT pathway in AML, approximately 30% of AML patients appear to have this activation mediated through mutations in the FMS-like receptor tyrosine kinase 3 (FLT3).
  • FLT3 FMS-like receptor tyrosine kinase 3
  • Methods of treating a patient suffering from acute leukaemias, myeloid and lymphoid malignancies or myeloproliferative disorders such as polycythemia vera, myelofibrosis, and essential thrombocythemia are contemplated and may comprise administering an effective amount of a disclosed compound, such as those recited in Formulas I, II, or III or a composition comprising a disclosed compounds.
  • a method of treatment of AML, PV, ET and MT for example, in patients with mutations in FLT3, comprising administering a disclosed compound, e.g. a compound of Formulas I, II, or III.
  • Treatment of other cancers comprising administering an effective amount of a disclosed compound.
  • the treatment of cancers can include, but are not limited to, an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, leukemia (including acute myelogenous leukemia and chronic myelogenous leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer.
  • Examples of some additional diseases and disorders that can be treated using a disclosed include cell mediated hypersensitivity (allergic contact dermatitis, hypersensitivity pneumonitis), rheumatic diseases (e.g., systemic lupus erythematosus (SLE), juvenile arthritis, Sjogren's Syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis), viral diseases (Epstein Barr Virus, Hepatitis B, Hepatitis C, HIV, HTLVl, Vaicella-Zoster Virus, Human Papilloma Virus), food allergy, cutaneous inflammation, and immune suppression induced by solid tumors.
  • SLE systemic lupus erythematosus
  • rheumatic diseases e.g., systemic lupus erythematosus (SLE), juvenile arthritis, Sjogren's Syndrome, scleroderma, polymyositis, ankylosing spondylitis
  • One embodiment provides for a process for forming a compound of Formula I comprising reacting a compound of formula IV:
  • Another embodiment provides for a process for forming a compound of Formula II comprising reacting a compound of Formula V:
  • Another embodiment provides for a process for forming a compound of Formula III comprising reacting a compound of Formula VII:
  • EXAMPLE 15 Preparation of ⁇ 4-[5-(3-Isopropyl-phenyl)-thiophen-2-yl]-5-methyl- pyrimidin-2-yl ⁇ - [4-(2-pyrrolidin- 1 -yl-ethoxy)-phenyl] -amine
  • the reaction tube was sealed and the suspension irradiated with microwave at 160 0 C for 15 min. After cooling to room temperature, the mixture was filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (20 mg, 17%).
  • the reaction tube was sealed and the suspension irradiated with microwave at 160 0 C for 15 min. After cooling to room temperature, the mixture was filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 rnL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (30 mg, 38%).
  • the impure product was further purified by HPLC and the corrected fractions combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated to afford the title compound as a greenish-yellow solid (14 mg, 1%).
  • EXAMPLE 25 Preparation of ⁇ 4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-5- methyl-pyrimidin-2-yl ⁇ - [4-(2-pyrrolidin- 1 -yl-ethoxy)-phenyl] -amine
  • a suspension of 6 (0.20 g, 0.82 mmol), 4-imidazol-l-yl-phenylamine (0.15 g, 0.94 mmol), Pd 2 (dba) 3 (40 mg, 0.044 mmol), Xantphos (50 mg, 0.086 mmol) and cesium carbonate (0.50 g, 1.53 mmol) in dioxane (6 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 0 C for 20 min. After cooling to room temperature, the resulting mixture was filtered and the filtered solid washed with DCM.
  • the reaction tube was sealed and the suspension irradiated with microwave at 160 0 C for 25 min. After cooling to room temperature, the mixture was filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (10 mg, 14%).
  • the filtrate was concentrated and the residue purified by ⁇ PLC.
  • the fractions were combined and poured into saturated NaHCO 3 solution (30 mL).
  • the combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2 SO 4 and filtered.
  • the filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a brown solid (25 mg, 46%).
  • the reaction tube was sealed and the suspension irradiated with microwave at 160 0 C for 20 min. After cooling to room temperature, the resulting mixture was filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (28 mg, 34%).
  • the organic solution was separated and dried (Na 2 SO 4 ). The solvent was removed in vacuo.
  • the crude product was purified by using ⁇ PLC. The ⁇ PLC fractions containing product were combined and neutralized with saturated NaHCO 3 (20 mL). The free base was extracted with EtOAc (2 x 30 mL). The organic layers were combined and dried (Na 2 SO 4 ). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.2 mL, 0.8 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then the solvent removed in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et 2 O (20 mL) was added. The solid was collected by centrifuging. The title compound (68 mg, 26%) was afforded as a yellow solid.
  • the organic solution was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic layer was dried (Na 2 SO 4 ). The solvent was removed in vacuo.
  • the crude product was purified by using HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO 3 (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na 2 SO 4 ). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then the solvent removed in vacuo.
  • the organic solution was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic layer was dried (Na 2 SO 4 ). The solvent was removed in vacuo.
  • the crude product was purified by using HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO 3 (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na 2 SO 4 ). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then the solvent removed in vacuo.
  • the organic solution was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic layer was dried (Na 2 SO 4 ). The solvent was removed in vacuo.
  • the crude product was purified by using HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO 3 (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na 2 SO 4 ). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then the solvent removed in vacuo.
  • a microwave vial was charged with 16 (0.10 g, 0.25 mmol), thiazolidine-2,4-dione (45 mg, 0.39 mmol), and Cs 2 CO 3 (0.12 g, 0.37 mmol) in a mixture of ethanol/DMF (4/1, 5 mL).
  • the reaction mixture was heated for 30 min at 140 0 C in a Biotage microwave reactor.
  • the resulting reaction mixture was concentrated and the residue triturated in water.
  • the resulting solid was filtered and purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 niL).
  • IC 50 values for compounds were determined using a luminescence -based kinase assay with recombinant JAK2, JAK3 and KDR (VEGF r2 ) obtained from Invitrogen.
  • JAK2, JAK3 and KDR VEGF r2
  • Each well contained 40 ⁇ L of buffer consisting of 40 mM Tris buffer, pH 7.4, containing 50 mM MgCl 2 , 800 ⁇ M EGTA, 350 ⁇ M Triton X-100, 2 mM ⁇ -mercaptoethanol, 250 ⁇ M peptide substrate and an appropriate amount of either JAK2, JAK3 or KDR (75 - 25 ng/well) such that the assay was linear over 60 min.
  • the final concentrations of compounds for IC 50 value determinations ranged from 10 to 0.001 ⁇ M by adding the appropriate amount of compound in 2.5 ⁇ L of DMSO; the DMSO present in each assay was constant at 5%.
  • the reaction was initiated by the addition of 10 ⁇ L of ATP to a final assay concentration of 3 ⁇ M. After the reaction had proceeded for 60 min, 50 ⁇ L of Kinase-Glo reagent (Promega) was added to terminate the reaction. This solution was then allowed to proceed for an additional 10 min to maximize the luminescence reaction. Values were then measured using an Ultra 384 instrument (Tecan) set for luminosity measurements. Two control reactions were also ran: one reaction containing no compound and the second containing neither inhibitor nor peptide substrate. IC 50 values were derived from experimental data using the non-linear curve fitting capabilities of Prism (Version 4; GraphPad Software). Results are reported in Table 1.
  • EXAMPLE 59 Cell Profileration Assay The EC 50 values for compounds (shown below in Table 1) were determined using a colormetric-based cell profileration assay. In clear, flat-bottom, 96-well plates parallel assays were run at 37 0 C and 6.5% CO 2 at a final volume of 100 ⁇ L. Each well contained 99 ⁇ L of RPMI medium containing 10% inactivated fetal calf serum, 2 mM L-glutamine, 1 mM sodium pyruvate, non-essential amino acids and an appropriate amount of human erythroleukemia (HEL) cells that are driven by the V617F mutation of JAK2 and varying amounts of compound in DMSO.
  • HEL human erythroleukemia
  • the final concentrations of compounds for EC 50 value determinations ranged from 10 to 0.001 ⁇ M by adding the appropriate amount of compound in 1 ⁇ L of DMSO; the DMSO present in each assay was constant at 1%.
  • the cells were allowed to proliferate in the presence of the inhibitor for approximately 72 h, XTT (3'-[l-(phenylamino-carbonyl)-3,4-tetrazolium]- bis(4-methoxy-6-nitro)benzene sulfonic acid) was added to a final concentration of 0.3 mg/mL. After the mixture was allowed to proceed for an additional 6 h, the absorbance values at 492 nm were measured to assess the formation of the formazan product. The absorbance at 690 nm was also measured for subtraction of turbidity values.
  • EC 50 values were derived from experimental data using the non-linear curve fitting capabilities of Prism (Version 4; GraphPad Software). Results reported in Table 1.
  • Inhibition of TYK2 by compounds of the invention was assessed using the In vitro gen single point method.
  • the single point TYK2 inhibition data were obtained at a 250 nM concentration of test compound. A higher percent inhibition indicates a more potent compound in this assay.
  • Each data point is the mean of two independent determinations. Inhibition levels of greater than >80% indicate virtually complete inhibition within the limits of experimental determination. For some compounds, IC 50 values were also determined. The results are given in Table 2.
  • Plasma samples were collected by cardiac puncture. Blood was maintained in an ice and water mixture prior to centrifugation to obtain plasma. Plasma samples are transferred to a - 2O 0 C freezer and stored until analysis. Matrix calibration standards and QC samples were prepared by spiking the compound into blank mouse plasma. The final concentrations of a selected compound were 0, 1, 5, 10, 50, 100, 500, 1000, 2500 and 5000 ng/niL for calibration standards, and 2.50, 25.0, 250 and 2500 for QC samples.
  • mice were dosed orally (PO) with 25 mg/kg compound, and the plasma concentration at 1 and 4 hours was measured in triplicate. The results are given in Tables 3 and 4.

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Abstract

L'invention concerne des composés de type pyrimidine et des procédés pour les préparer et les utiliser. Ces composés peuvent être utilisés dans le traitement de troubles inflammatoires ou myéloprolifératifs. L'invention concerne également le traitement du cancer.
PCT/US2008/078932 2007-10-05 2008-10-06 Anilinopyrimidines en tant qu'inhibiteurs de kinases jak Ceased WO2009046416A1 (fr)

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US8133900B2 (en) 2005-11-01 2012-03-13 Targegen, Inc. Use of bi-aryl meta-pyrimidine inhibitors of kinases
US8138199B2 (en) 2005-11-01 2012-03-20 Targegen, Inc. Use of bi-aryl meta-pyrimidine inhibitors of kinases
US8372971B2 (en) 2004-08-25 2013-02-12 Targegen, Inc. Heterocyclic compounds and methods of use
US8481536B2 (en) 2004-04-08 2013-07-09 Targegen, Inc. Benzotriazine inhibitors of kinases
US20130252980A1 (en) * 2010-10-08 2013-09-26 Cadila Healthcare Limited Novel gpr 119 agonists
US8604042B2 (en) 2005-11-01 2013-12-10 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
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US10683282B2 (en) 2018-04-11 2020-06-16 Korea Institute Of Science And Technology Multi-substituted pyrimidine derivatives with excellent kinase inhibitory activities
US10829496B2 (en) 2017-05-11 2020-11-10 Bristol-Myers Squibb Company Thienopyridines and benzothiophenes useful as IRAK4 inhibitors
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WO2023087027A1 (fr) * 2021-11-15 2023-05-19 Erasca, Inc. Inhibiteurs thiophènes de ulk1/2 et leur utilisation
US11685744B2 (en) 2020-09-21 2023-06-27 Prelude Therapeutics Incorporated CDK inhibitors and their use as pharmaceuticals
WO2024233766A1 (fr) * 2023-05-10 2024-11-14 Erasca, Inc. Inhibiteurs d'ulk1/2 macrocycliques et leur utilisation
US12286428B2 (en) 2019-07-18 2025-04-29 Bristol-Myers Squibb Company Tricyclic heteroaryl compounds useful as IRAK4 inhibitors
US12304914B2 (en) 2019-07-18 2025-05-20 Bristol-Myers Squibb Company Pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazinyl compounds useful as IRAK4 inhibitors
US12304916B2 (en) 2019-07-23 2025-05-20 Bristol-Myers Squibb Company Thienopyridinyl and thiazolopyridinyl compounds useful as IRAK4 inhibitors
US12365729B2 (en) 2020-05-13 2025-07-22 Disc Medicine, Inc. Anti-hemojuvelin (HJV) antibodies for treating myelofibrosis
US12391702B2 (en) 2020-02-03 2025-08-19 Bristol-Myers Squibb Company Benzo[5,6][1,4]dioxino[2,3-b]pyridine compounds useful as IRAK4 inhibitors
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083667A2 (fr) * 2001-04-13 2002-10-24 Vertex Pharmaceuticals Incorporated Inhibiteurs de c-jun n-terminal kinases (jnk) et d'autres proteines kinases
WO2002096905A1 (fr) * 2001-06-01 2002-12-05 Vertex Pharmaceuticals Incorporated Composes de thiazole inhibiteurs des proteines kinases
WO2006137658A1 (fr) * 2005-06-20 2006-12-28 Dongbu Hitek Co., Ltd. Nouveaux derives thiazole 1,3 substitues ou sels pharmaceutiquement acceptables de ces derniers presentant une activite d'inhibition de l'immunosuppression ou de l'inflammation, composes intermediaires ou sels pharmaceutiquement acceptables de ces derniers, procede de preparation de ces derniers et compositions pharmaceutiq
WO2007053776A1 (fr) * 2005-11-03 2007-05-10 Sgx Pharmaceuticals, Inc. Modulateurs de kinase de type pyrimidinylthiophène

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083667A2 (fr) * 2001-04-13 2002-10-24 Vertex Pharmaceuticals Incorporated Inhibiteurs de c-jun n-terminal kinases (jnk) et d'autres proteines kinases
US20030096816A1 (en) * 2001-04-13 2003-05-22 Jingrong Cao Inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases
WO2002096905A1 (fr) * 2001-06-01 2002-12-05 Vertex Pharmaceuticals Incorporated Composes de thiazole inhibiteurs des proteines kinases
WO2006137658A1 (fr) * 2005-06-20 2006-12-28 Dongbu Hitek Co., Ltd. Nouveaux derives thiazole 1,3 substitues ou sels pharmaceutiquement acceptables de ces derniers presentant une activite d'inhibition de l'immunosuppression ou de l'inflammation, composes intermediaires ou sels pharmaceutiquement acceptables de ces derniers, procede de preparation de ces derniers et compositions pharmaceutiq
WO2007053776A1 (fr) * 2005-11-03 2007-05-10 Sgx Pharmaceuticals, Inc. Modulateurs de kinase de type pyrimidinylthiophène

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. ZIMMERMANN ET AL.: "Phenylamino-Pyrimidine (PAP) Derivatives: A New Class of Potent and Selective Inhibitors of Protein Kinase C (PKC)", ARCH. PHARM. PHARM. MED. CHEM., vol. 329, 1996, pages 371 - 376, XP000885618 *

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US8372971B2 (en) 2004-08-25 2013-02-12 Targegen, Inc. Heterocyclic compounds and methods of use
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