[go: up one dir, main page]

WO2009055674A1 - Composés d'alcynyle de pyrrolopyrimidine et leurs procédés de préparation et d'utilisation - Google Patents

Composés d'alcynyle de pyrrolopyrimidine et leurs procédés de préparation et d'utilisation Download PDF

Info

Publication number
WO2009055674A1
WO2009055674A1 PCT/US2008/081119 US2008081119W WO2009055674A1 WO 2009055674 A1 WO2009055674 A1 WO 2009055674A1 US 2008081119 W US2008081119 W US 2008081119W WO 2009055674 A1 WO2009055674 A1 WO 2009055674A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
mmol
group
independently
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2008/081119
Other languages
English (en)
Inventor
Glenn Noronha
Jianguo Cao
Chun Chow
Chi Ching Mak
Moorthy Palanki
Elena Dneprovskaia
Andrew Mcpherson
Ved Prakash Pathak
Joel Renick
Binqi Zeng
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
TargeGen Inc
Original Assignee
TargeGen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by TargeGen Inc filed Critical TargeGen Inc
Publication of WO2009055674A1 publication Critical patent/WO2009055674A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

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, Ha, lib, lie or Hd, 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.
  • 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 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”
  • drug are described in well-known literature references such as the Merck Index, the Physicians Desk Reference, and The Pharmacological Basis of Therapeutics, and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • 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.
  • compositions of the present invention may be administered in a sufficient amount to produce a 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.
  • the term “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. In other embodiments, 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 3 O for straight chain, C3-C30 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 and can be substituted analogous to the alkyls described above;
  • alkenylene denotes an acyclic carbon chain which includes a carbon-to-carbon double bond, and can be optionally substituted analogous to the alkyls as described above.
  • 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 is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "heteroaryl” or “heteroaromatics.”
  • 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, -CF3, -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, aryls and/or heterocyclyls.
  • heterocyclyl or “heterocyclic group” are art-recognized and refer to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be polycycles.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
  • 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, -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,
  • 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.
  • the term "carbocycle” 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 -NO2; the term “halogen” is art- recognized and refers to -F, -Cl, -Br or -I; the term “sulfhydryl” is art-recognized and refers to -SH; the term “hydroxyl” means -OH; and the term “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, 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:
  • R50 is as defined above
  • R54 represents a hydrogen, an alkyl, an alkenyl or - (CH 2 ) 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.
  • ocular 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 of Formula I is an aryl or heteroaryl optionally substituted on a ring carbon by one, two, three, four, or five substituents, ( e.g. when R 1 is monocyclic), or even six, seven or more substitutents (e.g.
  • R 1 when R 1 is multicylic), each independently selected from the group consisting of hydroxyl, carbonyl, nitro, formyl, formamido, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkyl, alkenyl, CF 3 , ureido, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, carbaldehyde oxime, N-alkylsulphamoyl, N-alkylcarbamoyl, -O-alkyl, -S- alkyl, or -R 13 R 11 .
  • Rl can be optionally substituted phenyl, monocyclic heteroaryl, or bicyclic heteroaryl.
  • R 1 can be selected, in some embodiments, from the group consisting of optionally substituted indole, optionally substituted benzoimidazole, and optionally substituted phenyl.
  • R 4 can be H, NH 2 , -NHR 10 or -NH-alkyl.
  • R 4 can be H.
  • R 1O is phenyl or pyridinyl, wherein R 10 is optionally substituted on a ring carbon is optionally substituted on a ring carbon by one, two, or three substituents each independently selected from the group consisting of halo, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, -N-alkyl-amino, carbamoyl, sulphamoyl, CF 3 , ureido, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, -OR 11 , -OR 12 R 11 , or -R 12 R 11 .
  • R 1O is phenyl.
  • 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, hydroxyl, alkyl-hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, CF 3 , ureido, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;
  • R 12 is alkylene or a bond
  • R 13 is alkylene, alkenylene, -C(O)-, or a bond.
  • the pharmaceutically acceptable salts , prodrugs, N-oxides, diastereomers and hydrates of disclosed compounds such as those represented by formula I is also contemplated.
  • R 1 can be selected from:
  • R 5 is selected from H, halo, hydroxyl, nitro, cyano, formyl, formamido, carboxy, amino, amido, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, -O-alkyl, -S-alkyl, or optionally substituted monocyclic aryl or optionally substituted monocyclic heteraryl.
  • Re independently for each occurrence, is selected from H, C 1 - S straight chain alkyl, or C 1 - 5 branched alkyl; and R 7 , independently for each occurrence is selected from H, C 1 - S straight chain alkyl, C 1-4 branched alkyl, cyano, carboxyl, acyl, aldehyde, oxyalkylnitrile, or alkylamine.
  • R 1 can be represented by
  • R 5 is independently, for each occurrence, selected from the group consisting of H, halo, cyano, nitro, C 1 - S straight chain alkyl, C 1 - S branched alkyl, -O-alkyl, -S- alkyl, or -C(O)-alkyl.
  • R 1 can be represented by:
  • Re independently for each occurrence, is selected from H, C 1 - S straight chain alkyl, or C 1 - 5 branched alkyl;
  • R 7 independently for each occurrence is selected from H, C 1 - S straight chain alkyl,
  • R 1 can be represented by:
  • R 6 independently for each occurrence, is selected from H, C 1- 5 straight chain alkyl, or C 1-5 branched alkyl; and R 7 , independently for each occurrence is selected from H, C 1-5 straight chain alkyl, C 1-4 branched alkyl, cyano, carboxyl, acyl, or aldehyde.
  • R 1O for example, can be represented in some embodiments by:
  • X is N or CRg; with, for example,
  • Rg and Rg independently for each occurrence chosen from H, heterocycle, -O- heterocycle, -alkylene-heterocycle, or -O-alkylene-heterocycle, wherein said heterocycle for each occurrence is optionally substituted with one to three substituents each independently selected from halo, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, carbamoyl, sulphamoyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N- alkylsulphamoyl, and N-alkylcarbamoyl.
  • the heterocycle, or the heterocycle of: O-heterocycle, -alkylene-heterocycle, or -O-alkylene-heterocycle can beis substituted with methyl.
  • R 8 can be H and R 9 can be heterocycle or -O-alkylene-heterocycle, wherein said heterocycle is chosen from: pyrrolidinyl, piperazinyl, imidazoyl, piperdinyl, or morpholinyl.
  • Rg is H and Rg is selected from the group consisting of: methylpiperazine, piperazine, or 2-pyrrolidin-lylethoxy. In some embodiments, at least one occurrence of Rg is H.
  • R 4 is H or -NHR 10 , for example, R 4 is H, or R 4 can be -N-phenyl, wherein the phenyl is optionally substituted.
  • R 5 is independently selected for each occurence from the group consisting of H, halo, hydroxyl, carbonyl, nitro, formyl, formamido, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkyl, alkenyl, CF 3 , ureido, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, carbaldehyde oxime, N-alkylsulphamoyl, N-alkylcarbamoyl, -O-alkyl, -S-alkyl, -O-CF 3 , or - R 13 Rn.
  • R 6 independently for each occurrence, is selected from H or alkyl;
  • R 7 independently for each occurrence is selected from H, halo, hydroxyl, carbonyl, nitro, formyl, formamido, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkyl, alkenyl, CF 3 , ureido, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, carbaldehyde oxime, N- alkylsulphamoyl, N-alkylcarbamoyl;
  • R 1O is phenyl or pyridinyl, wherein R 1O is optionally substituted on a ring carbon is optionally substituted on a ring carbon by one, two, or three substituents each independently selected from the group consisting of halo, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, -N-alkyl-amino, carbamoyl, sulphamoyl, CF 3 , ureido, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, -OR 11 , -OR 12 Rn, or -R 12 R 11 ; and
  • 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, hydroxyl, alkyl-hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, CF 3 , ureido, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, aryl, -N-alkyl-, cycloalkyl, heteroaryl, or heterocycloalkyl;
  • R 12 is alkylene or a bond
  • R 13 is alkylene, -SO 2 -, or a bond; or Pharmaceutically acceptable salts , prodrugs, N-oxides, diastereomers and hydrates thereof.
  • R 4 may be, for example, selected from the group consisting of:
  • exemplary compounds can be represented by:
  • R 5 for each occurrence, is selected from the group consisting of: H, halo, alkyl, nitro, -O-alkyl, -S-alkyl, phenyl, or heterocycle, wherein said phenyl or heterocycle is optionally substituted with one to three substituents each independently selected from halo, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, carbamoyl, sulphamoyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, and N- alkylcarbamoyl.
  • Other exemplary compounds can be represented by: H, halo, alkyl, nitro, -O-alkyl, -S-alkyl, phenyl, or heterocycle, wherein said phenyl or heterocycle is optionally substituted with one to three substituents each
  • R 6 independently for each occurrence, is selected from H or branched alkyl.
  • R 7 can be, for example, independently for each occurrence is selected from H or alkyl.
  • Other exemplary compounds can be represented by:
  • R 6 is H or branched alkyl.
  • compositions that include the disclosed compounds and a pharmaceutically acceptable carrier.
  • any 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. [0066] In certain embodiments, 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 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. [0071]
  • the use of the subject 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.
  • compositions of the subject invention may be suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol 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.
  • 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 accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example,
  • 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.
  • 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 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.
  • 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.
  • 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, Ha, lib, Hc, or Hd, 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, Ha, lib, Hc, or Hd 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, 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) 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.
  • MPDs myeloproliferative disorders
  • PV polycythemia vera
  • ET essential thrombocythemia
  • MF myelofibrosis
  • AML acute myeloid leukemia
  • 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, Ha, lib, lie or Hd, 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, Ha, lib, lie or Hd.
  • 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
  • Reverse-phase HPLC chromatography was carried out on Gilson 215 liquid handler equipped with Waters SymmetryShieldTM RP18 7 ⁇ m (40 x 100mm) Prep-Pak cartridge.
  • Mobile phase consisted of standard acetonitrile (ACN) and DI Water, each with 0.1% TFA added. Purification was carried out at a flow rate of 4OmL/ min.
  • NMR spectra 1 H Nuclear magnetic resonance spectra were recorded at 500 MHz.
  • reaction mixture was heated for 2 h at reflux and cooled to room temperature.
  • the resulting mixture was concentrated and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 90:10 gradient) to afford the title compound as yellow oil (0.18 g, 80%).
  • the aqueous was extracted with EtOAc (3 x 30 mL). Combined organic layer was 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 (30 mL) and 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 title compound (12 mg, 4%) was afforded as a yellow solid.
  • the aqueous was extracted with EtOAc (3 x 30 mL). Combined organic layers were 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 (30 mL) and 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 title compound (19 mg, 6%) was afforded as a yellow solid.
  • the aqueous layer was extracted with EtOAc (3 x 20 rnL). Combined organic layers were 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 (30 mL) and 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 title compound (7 mg, 7%) was afforded as a yellow solid.
  • Trifluoromethylsulfonic anhydride was added to a solution of 2-cyclopentylphenol (200 mg, 1.23 mmol), in pyridine (12 rnL) at 0 0 C under constant stirring.
  • the reaction mixture was stirred at room temperature for 1 h, diluted with ethyl acetate (100 mL), washed with water (100 mL), IN hydrochloric acid (2 X 50 mL), brine (100 mL), dried (Na 2 SO 4 ), filtered, concentrated and purified using flash chromatography (SiO 2 , hexanes-ethyl acetate) to afford the title compound as a colorless liquid (342 mg, 94%).
  • Argon was bubbled into a solution of 14 (100 mg, 0.47 mmol), 27 (209 mg, 0.71 mmol), PdCl 2 (PPh 3 ) 2 (63 mg, 0.09 mmol), cuprous iodide (20 mg, 0.1 mmol), diisopropylethylamine (0.7 mL), tetrabutylammoniumfluoride (123 mg, 0.47 mmol) in dimethyl formamide (4 mL) for 5 min.
  • the reaction vessel was sealed, and heated at 150 0 C for 30 min in a microwave reactor.
  • 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 an off white solid (20 mg, 31%).
  • 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). The results, expressed as IC 50 , are presented in Table 1.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés d'alcynyle de pyrrolopyrimidine et leurs procédés de préparation et d'utilisation. De tels composés peuvent être utilisés dans des troubles inflammatoires ou des syndromes myéloprolifératifs. La description concerne également le traitement du cancer.
PCT/US2008/081119 2007-10-26 2008-10-24 Composés d'alcynyle de pyrrolopyrimidine et leurs procédés de préparation et d'utilisation Ceased WO2009055674A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US98282907P 2007-10-26 2007-10-26
US60/982,829 2007-10-26

Publications (1)

Publication Number Publication Date
WO2009055674A1 true WO2009055674A1 (fr) 2009-04-30

Family

ID=40303714

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/081119 Ceased WO2009055674A1 (fr) 2007-10-26 2008-10-24 Composés d'alcynyle de pyrrolopyrimidine et leurs procédés de préparation et d'utilisation

Country Status (1)

Country Link
WO (1) WO2009055674A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110282056A1 (en) * 2008-01-22 2011-11-17 Merck Patent Gmbh Protein kinase inhibitors and use thereof
WO2012045195A1 (fr) * 2010-10-09 2012-04-12 Abbott Laboratories Pyrrolopyrimidines à titre d'inhibiteurs de fak et d'alk pour le traitement des cancers et autres maladies
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
WO2013160387A1 (fr) 2012-04-26 2013-10-31 Bayer Cropscience Ag Procédé pour la préparation de n-(5-chloro-2-isopropylbenzyl)cyclopropanamine
CN108822145A (zh) * 2018-06-11 2018-11-16 广东工业大学 一种磺酰胺类化合物及其制备方法和应用
CN109096178A (zh) * 2017-06-21 2018-12-28 肯塔基大学研究基金会 用于治疗癌症的苯乙炔基取代苯和杂环及其应用
EP4041241A1 (fr) 2019-09-27 2022-08-17 Disc Medicine, Inc. Procédés de traitement de la myélofibrose et d'affections associées
US12365729B2 (en) 2020-05-13 2025-07-22 Disc Medicine, Inc. Anti-hemojuvelin (HJV) antibodies for treating myelofibrosis

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001042246A2 (fr) * 1999-12-10 2001-06-14 Pfizer Products Inc. Composes a base de pyrrolo[2,3-d]pyrimidine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001042246A2 (fr) * 1999-12-10 2001-06-14 Pfizer Products Inc. Composes a base de pyrrolo[2,3-d]pyrimidine

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8481536B2 (en) 2004-04-08 2013-07-09 Targegen, Inc. Benzotriazine inhibitors of kinases
US8372971B2 (en) 2004-08-25 2013-02-12 Targegen, Inc. Heterocyclic compounds and methods of use
US20110282056A1 (en) * 2008-01-22 2011-11-17 Merck Patent Gmbh Protein kinase inhibitors and use thereof
WO2012045195A1 (fr) * 2010-10-09 2012-04-12 Abbott Laboratories Pyrrolopyrimidines à titre d'inhibiteurs de fak et d'alk pour le traitement des cancers et autres maladies
WO2013160387A1 (fr) 2012-04-26 2013-10-31 Bayer Cropscience Ag Procédé pour la préparation de n-(5-chloro-2-isopropylbenzyl)cyclopropanamine
CN109096178A (zh) * 2017-06-21 2018-12-28 肯塔基大学研究基金会 用于治疗癌症的苯乙炔基取代苯和杂环及其应用
CN109096178B (zh) * 2017-06-21 2022-12-16 肯塔基大学研究基金会 用于治疗癌症的苯乙炔基取代苯和杂环及其应用
CN108822145A (zh) * 2018-06-11 2018-11-16 广东工业大学 一种磺酰胺类化合物及其制备方法和应用
CN108822145B (zh) * 2018-06-11 2020-10-23 广东工业大学 一种磺酰胺类化合物及其制备方法和应用
EP4041241A1 (fr) 2019-09-27 2022-08-17 Disc Medicine, Inc. Procédés de traitement de la myélofibrose et d'affections associées
US12365729B2 (en) 2020-05-13 2025-07-22 Disc Medicine, Inc. Anti-hemojuvelin (HJV) antibodies for treating myelofibrosis

Similar Documents

Publication Publication Date Title
CN102574857B (zh) 作为jak受体和蛋白酪氨酸激酶抑制剂的杂环化合物
WO2009055674A1 (fr) Composés d'alcynyle de pyrrolopyrimidine et leurs procédés de préparation et d'utilisation
ES2902198T3 (es) Análogos de piridazina con disustitución 1,4 y métodos para tratar afecciones relacionadas con la deficiencia de SMN
EP3209656B1 (fr) Composés indolecarboxamides utiles comme inhibiteurs de kinase
EP3728207B1 (fr) Quinazolinones en tant qu'inhibiteurs de parp14
CN111315747B (zh) 二氢吡唑酮并嘧啶类化合物及其制备方法和用途
CN107531695B (zh) Jak抑制剂
KR101727264B1 (ko) 이미다조〔2,1-ｂ〕〔1,3,4〕티아디아졸 유도체
CN102471346B (zh) Jak的三环抑制剂
WO2009046416A1 (fr) Anilinopyrimidines en tant qu'inhibiteurs de kinases jak
EA021504B1 (ru) Производные 1-гетероциклил-1,5-дигидропиразоло[3,4-d]пиримидин-4-она и их применение в качестве модуляторов pde9a
KR20170002623A (ko) 피라졸로피리딘 및 피라졸로피리미딘
KR102345381B1 (ko) 키나제 억제제로서 유용한 카르바졸 카르복스아미드 화합물
CN101595110A (zh) 用于免疫抑制的7-取代嘌呤衍生物
JP2009502734A (ja) Ｌｃｋ阻害剤としての縮合複素環
JP2010523522A (ja) Ｊａｋ３阻害剤としてのピロロピリミジン誘導体
WO2009049028A1 (fr) Composés de pyrrolopyrimidine et leur utilisation en tant qu'inhibiteurs des janus kinases
CN107207479B (zh) 作为磷脂酰肌醇3-激酶δ抑制剂的取代嘧啶类化合物及其应用
CA2709710A1 (fr) Pyrazolo[1,5-a]pyrimidines utiles en tant qu'inhibiteurs de jak2
JP2025505882A (ja) Ｐａｒｇの阻害物質
KR20130004342A (ko) 피롤로피라진 유도체 및 jak 및 syk 억제제로서 이의 용도
WO2017000277A1 (fr) Bicyclo-composés de triazole substitués utilisés en tant qu'inhibiteurs de pde2
WO2021099837A1 (fr) Composés antagonistes du récepteur de l'adénosine
JP4484524B2 (ja) １−［アルキル］、１−［（ヘテロアリール）アルキル］および１−［（アリール）アルキル］−７−（ピリミジン−４−イル）−イミダゾ［１，２−ａ］ピリミジン−５（１Ｈ）−オン誘導体
EP2867221A1 (fr) Cyanoguanidines et leur utilisation comme agents antiviraux

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08843254

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08843254

Country of ref document: EP

Kind code of ref document: A1