WO2009013545A2 - Composés chimiques - Google Patents

Composés chimiques Download PDF

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Publication number
WO2009013545A2
WO2009013545A2 PCT/GB2008/050617 GB2008050617W WO2009013545A2 WO 2009013545 A2 WO2009013545 A2 WO 2009013545A2 GB 2008050617 W GB2008050617 W GB 2008050617W WO 2009013545 A2 WO2009013545 A2 WO 2009013545A2
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WIPO (PCT)
Prior art keywords
heterocyclyl
carbocyclyl
occurrence
alkyl
optionally
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PCT/GB2008/050617
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English (en)
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WO2009013545A3 (fr
Inventor
Stephanos Ioannidis
Michelle Lamb
Mei Su
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2009013545A2 publication Critical patent/WO2009013545A2/fr
Publication of WO2009013545A3 publication Critical patent/WO2009013545A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds, their pharmaceutical compositions and methods of use.
  • the present invention relates to therapeutic methods for the treatment and prevention of cancers and to the use of these compounds in the manufacture of medicaments for the treatment and prevention of myeloproliferative disorders and cancers.
  • JAK Janus-associated kinase
  • STAT signal transducers and activators of transcription
  • the JAK family consists of four non-receptor tyrosine kinases Tyk2, JAKl, JAK2, and JAK3, which play a critical role in cytokine- and growth factor mediated signal transduction.
  • Cytokine and/or growth factor binding to cell-surface receptor(s) promotes receptor dimerization and facilitates activation of receptor-associated JAK by autophosphorylation.
  • Activated JAK phosphorylates the receptor, creating docking sites for SH2 domain-containing signalling proteins, in particular the STAT family of proteins (STATl, 2, 3, 4, 5a, 5b and 6).
  • Receptor- bound STATs are themselves phosphorylated by JAKs, promoting their dissociation from the receptor, and subsequent dimerization and translocation to the nucleus.
  • the STATs bind DNA and cooperate with other transcription factors to regulate expression of a number of genes including, but not limited to, genes encoding apoptosis inhibitors (e.g. BcI-XL, McI-I) and cell cycle regulators (e.g. Cyclin D1/D2, c-myc) (Haura et al., Nature Clinical
  • apoptosis inhibitors e.g. BcI-XL, McI-I
  • cell cycle regulators e.g. Cyclin D1/D2, c-myc
  • JAK2 JAK2 kinase domain with an oligomerization domain
  • TEL- JAK2 JAK2 kinase domain with an oligomerization domain
  • Bcr-JAK2 oligomerization domain
  • PCM1-JAK2 PCM1-JAK
  • V617F valine-to- phenylalanine
  • Typical compounds of Formula (I) are believed to possess JAK kinase inhibitory activity and are accordingly useful for their anti-proliferation and/or pro-apoptotic activity and in methods of treatment of the human or animal body.
  • the invention also relates to processes for the manufacture of said compound, or pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing it and to its use in the manufacture of medicaments for use in the production of an anti-proliferation and/or pro-apoptotic effect in warm-blooded animals such as man.
  • the applicants provide methods of using said compound, or pharmaceutically acceptable salts thereof, in the treatment of myeloproliferative disorders, myelodysplastic syndrome and cancer.
  • the properties of the compounds of Formula (I) are expected to be of value in the treatment of myeloproliferative disorders, myelodysplastic syndrome, and cancer by inhibiting the tyrosine kinases, particularly the JAK family and more particularly JAK2.
  • Methods of treatment target tyrosine kinase activity, particularly the JAK family activity and more particularly JAK2 activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndrome and cancer related processes.
  • inhibitors of tyrosine kinases are expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemias, myelomas and lymphomas, tumors of the central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma.
  • Tyrosine kinase inhibitors, particularly the JAK family inhibitors and more particularly JAK2 inhibitors are also expected to be useful for the treatment other proliferative diseases including but not limited to autoimmune
  • the compounds of Formula (I), or pharmaceutically acceptable salts thereof are expected to be of value in the treatment or prophylaxis of against myeloproliferative disorders selected from chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma,
  • the present invention relates to compounds of Formula (I):
  • Ring A is a 5-membered aromatic heterocyclic ring, wherein said 5-membered aromatic heterocyclic ring is optionally substituted on carbon with one or more R 2 , and wherein any -NH- moiety of said 5-membered aromatic heterocyclic ring is optionally substituted with R *;
  • X is selected from -O-, -NH-, and -S-;
  • D is selected from CH and N;
  • R 1 is selected from halo, -CN, Ci_6alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, heterocyclyl, -OR la , -SR la , -N(R la ) 2 , -N(R la )C(O)R lb , -N(R la )N(R la ) 2 , -NO 2 , -N(R la )OR la , -ON(R la ) 2 , -C(O)H
  • R 3 is selected from H, halo, -CN, Ci- ⁇ alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, heterocyclyl, -OR 3a , -SR 3a , -N(R 3a ) 2 , -N(R 3a )C(O)R 3b , -N(R 3a )N(R 3a ) 2 , -NO 2 , -N(R 3a )-OR 3a , -O-N(R 3a ) 2 , -C(O)H, -C(O)R 3b , -C(O) 2 R 3a , -C(O)N(R 3a ) 2 , -C(O)N(R 3a )(OR 3a ), -OC(O)N(R 3a ) 2 , -N(R 3a )C(O) 2 R 3 , -
  • R 3a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ;
  • R 3b in each occurrence is selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 30 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 30* ;
  • R 4 is selected from halo, -CN, Ci_6alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, heterocyclyl, -OR 4a , -SR 4a , -N(R 4a ) 2 , -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2
  • R 4a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ;
  • R 4b in each occurrence is selected from Ci- ⁇ alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ;
  • R 10 in each occurrence is independently selected from halo, -CN, Ci- ⁇ alkyl, C 2 _6alkenyl, C 2 _ 6 alkynyl, carbocyclyl, heterocyclyl, -OR 10a , -SR 1Oa , -N(R 10a ) 2 , -N(R 10a )C(O)R 10b , -N(R 10a )N(R
  • R 1Ob in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C h alky 1, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R a , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R a* ;
  • R 1Oc in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R a , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R a* ;
  • R 20 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 20a , -SR 20a , -N(R 20a ) 2 , -N(R 20a )C(O)R 20b , -N(R 20a )N(R 20a ) 2 , -NO 2 , -N(R 20a )-OR 20a , -O-N(R 20a ) 2 , -C(O)H, -C(O)R 20b , -C(O) 2 R 20a , -C(O)N(R 20a ) 2 , -C(O)N(R 20a )(OR 20a ), -OC(O)N(R 20a ) 2 , -N(R 20a )C(O) 2 R 20a
  • R 20a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ;
  • R 20b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R b , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R b* ;
  • R 20c in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R b* ;
  • R 30 in each occurrence is independently selected from halo, -CN, Ci- ⁇ alkyl, C 2 -6alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 30a , -SR 3Oa , -N(R 30a ) 2 , -N(R 30a )C(O)R 30b , -N(R 3Oa )N(R 3Oa ) 2 , -NO 2 , -N(R 30a )-OR 30a , -O-N(R 30a ) 2 , -C(O)H, -C(O)R 30b , -C(O) 2 R 30a , -C(O)N(R 30a ) 2 , -C(O)N(R 30a )(OR 30a ), -OC(O)N(R 30a ) 2 , -N(R 30a )C(O) 2 R
  • R 30a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R c , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R c ;
  • R 30b in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C h alky 1, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R c , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 0* ;
  • R 30c in each occurrence is independently selected from Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R c , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 0* ;
  • R 40 in each occurrence is
  • R 40b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R d , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R d* ;
  • R 40c in each occurrence is independently selected from Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R d* ;
  • R m in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl; R" in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl; and n is selected from O, 1, 2, 3, and 4.
  • Ci- 4 alkyl includes Cialkyl (methyl), C 2 alkyl (ethyl), Csalkyl (propyl and isopropyl) and C4alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and ⁇ -butyl).
  • alkyl refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only.
  • alkenyl refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon double bond.
  • C 2 _6alkenyl includes, but is not limited to, groups such as C 2 _ 5 alkenyl, C 2 _ 4 alkenyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.
  • alkynyl refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon triple bond.
  • C 2 _6alkynyl includes, but is not limited to, groups such as C 2 - 5 alkynyl, C 2 _ 4 alkynyl, ethynyl, 2-propynyl, 2-methyl-2-propynyl, 3-butynyl, 4-pentynyl, and 5-hexynyl.
  • Halo refers to fluoro, chloro, bromo and iodo. In one aspect, the term “halo” may refer to fluoro, chloro, and bromo. In another aspect, the term “halo” may refer to fluoro and chloro.
  • Carbocyclyl - refers to a saturated, partially saturated, or unsaturated, mono or bicyclic carbon ring that contains 3 to 12 ring atoms, of which one or more -CH 2 - groups may be optionally replaced with a corresponding number of -C(O)- groups.
  • Carbocyclyl include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, indanyl, naphthyl, oxocyclopentyl, 1-oxoindanyl, phenyl, and tetralinyl.
  • Heterocvclyl refers to a saturated, partially saturated, or unsaturated, mono or bicyclic ring containing 4 to 12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and of which a -CH2- group can optionally be replaced by a -C(O)-.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • heterocyclyl include, but are not limited to, 1,3-benzodioxolyl, 3,5-dioxopiperidinyl, furanyl, imidazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholino, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, oxazolyl, 2-oxopyrrolidinyl, 2-oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, quinolyl, tetrahydrofuranyl, tetra
  • heterocyclyl may be “5- or 6-membered heterocyclyl,” which refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 5 or 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -C ⁇ 2- group may be optionally replaced by a -C(O)- group.
  • “5- or 6-membered heterocyclyl” groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • 5- or 6-membered heterocyclyl include, but are not limited to, 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholino, oxazolyl, 2-oxopyrrolidinyl, 2-oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, 2H- pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thiomorpholino, thiophenyl, and pyridine-N-oxid
  • heterocyclyl and “5- or 6-membered heterocyclyl” may be “6-membered heterocyclyl,” which refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH 2 - group may be optionally replaced by a -C(O)- group.
  • “6-membered heterocyclyl” groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Illustrative examples of "6-membered heterocyclyl” include, but are not limited to, 3,5-dioxopiperidinyl, morpholino, piperazinyl, piperidinyl, 2H-pyranyl, pyrazinyl, pyridazinyl, pyridinyl, and pyrimidinyl.
  • heterocyclyl may be “6-membered heteroaryl.”
  • the term “6- membered heteroaryl” is intended to refer to a monocyclic, aromatic heterocyclyl ring containing 6 ring atoms. Unless otherwise specified, "6-membered heteroaryl” groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Illustrative examples of the term “6- membered heteroaryl” include, but are not limited to, pyrazinyl, pyridazinyl, pyrimidinyl, and pyridinyl.
  • Ring A For the purposes of describing Ring A, the term "5-memebered aromatic heterocyclic ring” refers to a monocyclic aromatic ring containing 5 ring atoms of which at least one ring atom is selected from nitrogen, sulfur, and oxygen.
  • the 5-membered aromatic heterocyclic ring and the pyrimidine ring shown in Formula (I) to which it is fused form a bicyclic ring system. It is to be understood that pi electrons of Ring A may be de localized over the whole of the bicyclic ring.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • 5-membered aromatic heterocyclic ring examples include, but are not limited to, imidazole, oxazole, pyrrole, thiazole, and thiophene.
  • Ring A is designated as being, for example, "imidazole,” it should be understood that the imidazole ring is fused, via two adjacent ring carbon atoms, to the pyrimidine ring shown in Formula (I).
  • the -N(R) 2 group is intended to encompass: 1) those -N(R) 2 groups in which both R substituents are the same, such as those in which both R substituents are, for example, Ci_6alkyl; and 2) those -N(R) 2 groups in which each R substituent is different, such as those in which one R substituent is, for example, H, and the other R substituent is, for example, carbocyclyl.
  • the bonding atom of a group may be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl.
  • Effective Amount means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response).
  • the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
  • an effective amount of a compound of Formula (I) for use in the treatment of cancer is an amount sufficient to symptomatically relieve in a warm-blooded animal such as man, the symptoms of cancer and myeloproliferative diseases, to slow the progression of cancer and myeloproliferative diseases, or to reduce in patients with symptoms of cancer and myeloproliferative diseases the risk of getting worse.
  • Leaving Group is intended to refer to groups readily displaceable by a nucleophile such as an amine nucleophile, an alcohol nucleophile, or a thiol nucleophile. Examples of suitable leaving groups include halo, such as chloro and bromo, and sulfonyloxy group, such as methanesulfonyloxy and toluene-4-sulfonyloxy.
  • Optionally substituted indicates that substitution is optional and therefore it is possible for the designated group to be either substituted or unsubstituted. In the event a substitution is desired, any number of hydrogens on the designated group may be replaced with a selection from the indicated substituents, provided that the normal valency of the atoms on a particular substituent is not exceeded, and that the substitution results in a stable compound.
  • a particular group when a particular group is designated as being optionally substituted with "one or more" substituents, the particular may be unsubstituted.
  • the particular group may bear one substituent.
  • the particular substituent may bear two substituents.
  • the particular group may bear three substituents.
  • the particular group may bear four substituents.
  • the particular group may bear one or two substituents.
  • the particular group may be unsubstituted, or may bear one or two substituents.
  • substituent D when D is CH, the hydrogen of the CH moiety is optionally substituted with R 4 when n is at least 1.
  • the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Protecting Group is intended to refer to those groups used to prevent selected reactive groups (such as carboxy, amino, hydroxy, and mercapto groups) from undergoing undesired reactions.
  • suitable protecting groups for a hydroxy group include, but are not limited to, an acyl group; alkanoyl groups such as acetyl; aroyl groups, such as benzoyl; silyl groups, such as trimethylsilyl; and arylmethyl groups, such as benzyl.
  • the deprotection conditions for the above hydroxy protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.
  • suitable protecting groups for an amino group include, but are not limited to, acyl groups; alkanoyl groups such as acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, and ⁇ -butoxycarbonyl; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; and aroyl groups, such benzoyl.
  • alkanoyl groups such as acetyl
  • alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, and ⁇ -butoxycarbonyl
  • arylmethoxycarbonyl groups such as benzyloxycarbonyl
  • aroyl groups such benzoyl.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a ⁇ -butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric, phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid, for example boron trichloride).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.
  • Another suitable protecting group for an amine is, for example, a cyclic ether such as tetrahydrofuran, which may be removed by treatment with a suitable acid such as trifluoroacetic acid.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.
  • Compounds of Formula (I) may form stable pharmaceutically acceptable acid or base salts, and in such cases administration of a compound as a salt may be appropriate.
  • acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethyl- sulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persul
  • base salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as aluminum, calcium and magnesium salts; salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine; and salts with amino acids such as arginine, lysine, ornithine, and so forth.
  • basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide and others.
  • Non-toxic physiologically-acceptable salts are preferred, although other salts may be useful, such as in isolating or purifying the product.
  • the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
  • Some compounds of Formula (I) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers.
  • the invention further relates to any and all tautomeric forms of the compounds of Formula (I).
  • Additional embodiments of the invention are as follows. These additional embodiments relate to compounds of Formula (I) and pharmaceutically acceptable salts thereof. Such specific substituents may be used, where appropriate, with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
  • Ring A is a 5-membered aromatic heterocyclic ring, wherein said 5-membered aromatic heterocyclic ring is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said 5-membered aromatic heterocyclic ring is optionally substituted with R 2 *;
  • R 2 is selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 2a , -SR 2a , -N(R 2a ) 2 , -N(R 2a )C(O)R 2b , -N(R 2a )N(R 2a ) 2 , -NO 2 , -N(R 2a )-OR 2a , -O-N(R 2a ) 2 , -C(O)H, -C(O)R 2b , -C(O) 2 R 2a , -C(O)N(R 2a ) 2 , -C(O)N(R 2a )(OR 2a ) -OC(O)N(R 2a ) 2 ,
  • heterocyclyl is optionally substituted with R ;
  • R 20 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl,
  • R 20* in each occurrence is independently selected from Ci_ 6 alkyl, carbocyclyl, heterocyclyl,
  • R 20a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 20b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl; and R 20c in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl.
  • Ring A together with the pyrimidine to which it is fused, forms a member selected from [l,3]oxazolo[5,4- ⁇ i]pyrimidine, 7H-purine, 5H-pyrrolo[3,2- ⁇ f]pyrimidine, [l,3]thiazolo[5,4- ⁇ f]pyrimidine, thieno[2,3- ⁇ i]pyrimidine, and thieno[3,2- ⁇ f]pyrimidine, wherein said [l,3]oxazolo[5,4- ⁇ i]pyrimidine, 7H-purine, 5H-pyrrolo[3,2- ⁇ i]pyrimidine, [l,3]thiazolo[5,4- ⁇ i]pyrimidine, thieno[2,3- ⁇ i]pyrimidine, and thieno[3,2- ⁇ i]pyrimidine are optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said 7H-purine, 5H-pyrrolo[
  • R 20 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 20a , -SR 20a , -N(R 20a ) 2 , -N(R 20a )C(O)R 20b , -N(R 20a )N(R 20a ) 2 , -NO 2 , -N(R 20a )-OR 20a , -O-N(R 20a ) 2 , -C(O)H, -C(O)R 20b , -C(O) 2 R 20a ,
  • R in each occurrence is independently selected from Ci_6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R 20b , -C(O) 2 R 20c , -C(O)N(R 20a ) 2 , -S(O)R 20b , -S(O) 2 R 20b , -S(O) 2 N(R 20a ) 2 ,
  • R 20a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 20b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl; and R 20c in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl.
  • Ring A together with the pyrimidine to which it is fused, forms a member selected from [l,3]oxazolo[5,4-d]pyrimidine, 7H-purine, 5H-pyrrolo[3,2-d]pyrimidine, [l,3]thiazolo[5,4- ⁇ f]pyrimidine, thieno[2,3- ⁇ i]pyrimidine, and thieno[3,2- ⁇ f]pyrimidine, wherein said [l,3]oxazolo[5,4-d]pyrimidine, 7H-purine, 5H-pyrrolo[3,2-d]pyrimidine, [l,3]thiazolo[5,4- Jjpyrimidine, thieno[2,3-J]pyrimidine, and thieno[3,2-J]pyrimidine are optionally substituted on carbon with one or more R 2 , and wherein any -NH- moiety of said 7H-purine and 5H- pyrrolo[3,2- ⁇ i]
  • Ring A together with the pyrimidine to which it is fused, forms a member selected from [l,3]oxazolo[5,4-d]pyrimidine, 7H-purine, 5H-pyrrolo[3,2-d]pyrimidine, 7H- pyrrolo[2,3-d]pyrimidine, [l,3]thiazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine, and thieno[3,2-J]pyrimidine, wherein said [l,3]oxazolo[5,4-J]pyrimidine, 7H-purine, 5H- pyrrolo[3,2-d]pyrimidine, 7H-pyrrolo[2,3-J]pyrimidine, [l,3]thiazolo[5,4-d]pyrimidine, thieno[2,3-(i]pyrimidine, and thieno[3,2- ⁇ i]pyrimidine are optionally substituted on carbon with one or more R 2
  • Ring A together with the pyrimidine to which it is fused forms [l,3]oxazolo[5,4-d]pyrimidine, wherein said [l,3]oxazolo[5,4-d]pyrimidine is optionally substituted on carbon with one or more R ; and R 2 is C 1-6 alkyl.
  • Ring A, together with the pyrimidine to which it is fused forms 7H- purine, wherein said 7H-purine is optionally substituted on carbon with one or more R 2 , and wherein any -NH- moiety of said 7H-purine is optionally substituted with R u *;
  • R 2 is Ci- 6 alkyl
  • R 2 * is C 1-6 alkyl.
  • Ring A together with the pyrimidine to which it is fused, forms 5H- pyrrolo[3,2- ⁇ i]pyrimidine, wherein said 5H-pyrrolo[3,2- ⁇ i]pyrimidine is optionally substituted on carbon with one ore more R 2 , and wherein any -NH- moiety of said 5H-pyrrolo[3,2- ⁇ i]pyrimidine is optionally substituted with one or more R 2 *; R 2 is C 1-6 alkyl; and
  • R 2 * is C 1-6 alkyl.
  • Ring A together with the pyrimidine to which it is fused, forms [l,3]thiazolo[5,4- Jjpyrimidine, wherein said [l,3]thiazolo[5,4-J]pyrimidine is optionally substituted on carbon with one or more R 2 ; and R 2 is C 1-6 alkyl.
  • Ring A together with the pyrimidine to which it is fused, forms thieno[2,3- ⁇ i]pyrimidine, wherein said thieno[2,3- ⁇ f]pyrimidine is optionally substituted on carbon with one or more R 2 ; and R 2 is C 1-6 alkyl.
  • Ring A together with the pyrimidine to which it is fused, forms thieno[3,2-J]pyrimidine, wherein said thieno[3,2-J]pyrimidine is optionally substituted on carbon with one or more R 2 ; and R 2 is C 1-6 alkyl.
  • Ring A together with the pyrimidine to which it is fused, forms a member selected from [l,3]oxazolo[5,4-d]pyrimidine, 7H-purine, 5H-pyrrolo[3,2- ⁇ f]pyrimidine, [l,3]thiazolo[5,4- ⁇ f]pyrimidine, thieno[2,3- ⁇ i]pyrimidine, and thieno[3,2- ⁇ f]pyrimidine, wherein said [l,3]oxazolo[5,4- ⁇ i]pyrimidine, 7H-purine, 5H-pyrrolo[3,2- ⁇ i]pyrimidine, [l,3]thiazolo[5,4- ⁇ i]pyrimidine, thieno[2,3- ⁇ i]pyrimidine, and thieno[3,2- ⁇ i]pyrimidine are optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said 7H-purine and 5H- pyrrolo
  • Ring A together with the pyrimidine to which it is fused, forms a member selected from [l,3]oxazolo[5,4- ⁇ i]pyrimidine, 7H-purine, 5H-pyrrolo[3,2- ⁇ f]pyrimidine, 7H- pyrrolo[2,3- ⁇ i]pyrimidine, [l,3]thiazolo[5,4- ⁇ i]pyrimidine, thieno[2,3- ⁇ i]pyrimidine, and thieno[3,2- ⁇ i]pyrimidine, wherein said [l,3]oxazolo[5,4- ⁇ i]pyrimidine, 7H-purine, 5H- pyrrolo[3,2- ⁇ i]pyrimidine, 7H-pyrrolo[2,3- ⁇ f]pyrimidine, [l,3]thiazolo[5,4- ⁇ i]pyrimidine, thieno[2,3-J]pyrimidine, and thieno[3,2-J]pyrimidine are optionally substitute
  • Ring A together with the pyrimidine to which it is fused, forms a member selected from 2-methyl[l,3]oxazolo[5,4- ⁇ f]pyrimidine, 7-methyl-7H-purine, 5-methyl- 5H-pyrrolo[3,2- ⁇ f]pyrimidine, 2-methyl[l,3]thiazolo[5,4- ⁇ i]pyrimidine, 7-methylthieno[3,2- ⁇ i]pyrimidine, thieno[2,3- ⁇ i]pyrimidine, and thieno[3,2- ⁇ i]pyrimidine.
  • Ring A together with the pyrimidine to which it is fused, forms a member selected from 2-methyl[l,3]oxazolo[5,4- ⁇ i]pyrimidine, 7-methyl-7H-purine, 5-methyl-5H- pyrrolo[3,2-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, 2-methyl[l,3]thiazolo[5,4-d]pyrimidine, 7-methylthieno[3,2-J]pyrimidine, thieno[2,3-J]pyrimidine, and thieno[3,2-J]pyrimidine.
  • X is -NH-.
  • D is CH.
  • D is N.
  • R 1 is selected from H, halo, -CN, Ci- ⁇ alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, heterocyclyl, -OR la , -SR la , -N(R la ) 2 , -N(R la )C(O)R lb , -N(R la )N(R la ) 2 , -NO 2 , -N(R la )-OR la , -O-N(R la ) 2 , -C(O)H, -C(O)R lb , -C(O) 2 R 13 , -C(O)N(R la ) 2 , -C(O)N(R la )(OR la ), -OC(O)N(R la ) 2 , -N(R la )C(O) 2 R la , -N(R la )C(O)N(O)N
  • C 2 _6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R 10 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 10* ;
  • R la in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 10 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ;
  • R lb in each occurrence is selected from Ci- ⁇ alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 10 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 10* ;
  • R 10 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, heterocyclyl, -OR 10a , -SR 1Oa , -N(R 10a ) 2 , -N(R 10a )C(O)R 10b , -N(R 10a )
  • R 1Ob in each occurrence is independently selected from Ci- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 1Oc in each occurrence is independently selected from H, carbocyclyl, and heterocyclyl.
  • R 1 is selected from Ci_ 6 alkyl and -OR la ; and R la is selected from Ci_ 6 alkyl.
  • R 1 is Ci_ 6 alkyl.
  • R 1 is -OR la ; and R 1 is C 1-6 alkyl.
  • R is selected from methyl, ethoxy, and isopropoxy.
  • R 3 is selected from H, halo, -CN, Ci- ⁇ alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, heterocyclyl, -OR 3a , -SR 3a , -N(R 3a ) 2 , -N(R 3a )C(O)R 3b , -N(R 3a )N(R 3a ) 2 , -NO 2 , -N(R 3a )-OR 3a , -O-N(R 3a ) 2 , -C(O)H, -C(O)R 3b , -C(O) 2 R 33 , -C(O)N(R 3a ) 2 , -C(O)N(R 3a )(OR 3a ), -OC(O)N(R 3a ) 2 , -N(R 3a )C(O) 2 R 3 , -OR 3a
  • R 3b in each occurrence is selected from d- ⁇ alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 30 and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 30* ;
  • R 30 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl,
  • R 30* in each occurrence is independently selected from Ci_ 6 alkyl, carbocyclyl, heterocyclyl,
  • R 30a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 30b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl; and R 30c in each occurrence is independently selected from Ci_6alkyl, carbocyclyl, and heterocyclyl.
  • R 3 is Ci_ 6 alkyl.
  • R 3 is methyl
  • R 4 is selected from halo, -CN, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, heterocyclyl, -OR 4a , -SR 4a , -N(R 4a ) 2 , -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2 , -NO 2 , -N(R 4a )-OR 4a , -O-N(R 4a ) 2 , -C(O)H, -C(O)R 4b , -C(O) 2 R 4a , -C(O)N(R 4a ) 2 , -C(O)N(R 4a )(OR 4a ) -OC(O)N(R 4a ) 2 , -N(R 4a )C(O) 2 R 4a ,
  • R 4a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any -NH-
  • R 4b in each occurrence is selected from Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ;
  • R 40 in each occurrence is independently selected from halo, -CN, Ci- ⁇ alkyl, C 2 -6alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 40a , -SR 40a , -N(R 40a ) 2 , -N(R 40a )C(O)R 40b , -N(R 40a )N(R 40a ) 2
  • R 40b in each occurrence is independently selected from Ci- ⁇ alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl; and R 40c in each occurrence is independently selected from Ci_6alkyl, carbocyclyl, and heterocyclyl.
  • R 4 is halo
  • R 4 is fluoro
  • R 4 is selected from halo, -CN, Ci- ⁇ alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, heterocyclyl, -OR 4a , -SR 4a , -N(R 4a ) 2 , -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2 , -NO 2 , -N(R 4a )-OR 4a , -O-N(R 4a ) 2 , -C(O)H, -C(O)R 4b , -C(O) 2 R 4a , -C(O)N(R 4a ) 2 , -C(O)N(R 4a )(OR 4a ) -OC(O)N(R 4a ) 2 , -N(R 4a )C(O) 2 R 4a ,
  • R 4b in each occurrence is selected from Ci- ⁇ alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 40 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 40a , -SR 40a , -N(R 40a ) 2 , -N(R 40a )C(O)R 40b , -N(R 40a )N(R 40a
  • R 40b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 40c in each occurrence is independently selected from Ci- ⁇ alkyl, carbocyclyl, and heterocyclyl; and n is i .
  • R 4 is halo; and n is 1.
  • R 4 is fluoro; and n is 1.
  • n 1
  • n 1 or 2.
  • Ring A is a 5-membered aromatic heterocyclic ring, wherein said 5-membered aromatic heterocyclic ring is optionally substituted on carbon with one or more R 2 , and wherein any -NH- moiety of said 5-membered aromatic heterocyclic ring is optionally substituted with R 2 *;
  • X is -NH-
  • D is selected from CH and N;
  • R 1 is selected from H, halo, -CN, Ci- ⁇ alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, heterocyclyl, -OR la , -SR la , -N(R la ) 2 , -N(R la )C(O)R lb , -N(R la )N(R la ) 2 , -NO 2 , -N(R la )-OR la , -O-N(R la ) 2 , -C(O)H, -C(O)R lb , -C(O) 2 R 13 , -C(O)N(R la ) 2 , -C(O)N(R la )(OR la ), -OC(O)N(R la ) 2 , -N(R la )C(O) 2 R la , -N(R la
  • R 3 is selected from H, halo, -CN, Ci_6alkyl, C 2- 6alkenyl, C 2- 6alkynyl, carbocyclyl, heterocyclyl, -OR 3a , -SR 3a , -N(R 3a ) 2 , -N(R 3a )C(O)R 3b , -N(R 3a )N(R 3a ) 2 , -NO 2 , -N(R 3a )-OR 3a , -O-N(R 3a ) 2 , -C(O)H, -C(O)R 3b , -C(O) 2 R 3a , -C(O)N(R 3a ) 2 , -C(O)N(R 3a )(OR 3a ), -OC(O)N(R 3a ) 2 , -N(R 3a )C(O) 2 R 3 , -N(R 3
  • R R 3b in each occurrence is selected from Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ;
  • R 4 is selected from halo, -CN, Ci- ⁇ alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, heterocyclyl, -OR 4a , -SR 4a , -N(R 4a ) 2 , -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2 , -NO 2 , -N(R 4a )-OR 4a , -O-N(R 4a ) 2 , -C(O)H, -C(O)R 4b , -C(O) 2 R 43 , -C(O)N(R 4a ) 2 , -C(O)N(R 4a )(OR 4a ) -OC(O)N(R 4a ) 2 , -N(R 4a )C(O) 2 R 4a , -N(R 4
  • C 2 _6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R 40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 4a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ;
  • R 4b in each occurrence is selected from Ci- ⁇ alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 10 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, heterocyclyl, -OR 10a , -SR 1Oa , -N(R 10a ) 2 , -N(R 10a )C(O)R 10b , -N(R 10a )N
  • R 20 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 20a , -SR 20a , -N(R 20a ) 2 , -N(R 20a )C(O)R 20b , -N(R 20a )N(R 20a ) 2 , -NO 2 , -N(R 20a )-OR 20a , -O-N(R 20a ) 2 , -C(O)H, -C(O)R 20b , -C(O) 2 R 20a , -C(O)N(R 20a ) 2 , -C(O)N(R 20a )(OR 20a ), -OC(O)N(R 20a ) 2 , -N(R 20a )C(O) 2 R 20a
  • R 20b in each occurrence is independently selected from d_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 20c in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 30 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, heterocyclyl, -OR 30a , -SR 3Oa , -N(R 30a ) 2 , -N(R 30a )C(O)R 30b , -N(R 3Oa )N(R 3Oa ) 2 , -NO 2 , -N(R 30a )-OR 30a , -O-N(R 30a ) 2 , -C(O)H, -C(O)R 30b , -C(O) 2 R 30a , -C(O)N(R 30a ) 2 , -C(O)N(R 30a )(OR 30a ), -OC(O)N(R 30a ) 2 , -N(R 30a )C(O) 2
  • R 30b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 30c in each occurrence is independently selected from Ci_6alkyl, carbocyclyl, and heterocyclyl;
  • R 40 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 40a , -SR 40a , -N(R 40a ) 2 , -N(R 40a )C(O)R 40b ,
  • R in each occurrence is independently selected from Ci_6alkyl, carbocyclyl, heterocyclyl,
  • R 40a in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 40b in each occurrence is independently selected from Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 40c in each occurrence is independently selected from d_ 6 alkyl, carbocyclyl, and heterocyclyl; n is 1.
  • Ring A together with the pyrimidine to which it is fused, forms a member selected from [l,3]oxazolo[5,4-d]pyrimidine, 7H-purine, 5H-pyrrolo[3,2-d]pyrimidine, [l,3]thiazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine, and thieno[3,2-d]pyrimidine, wherein said [l,3]oxazolo[5,4- ⁇ i]pyrimidine, 7H-purine, 5H-pyrrolo[3,2- ⁇ i]pyrimidine, [l,3]thiazolo[5,4- ⁇ i]pyrimidine, thieno[2,3- ⁇ i]pyrimidine, and thieno[3,2- ⁇ i]pyrimidine are optionally substituted on carbon with one or more R 2 , and wherein any -NH- moiety of said 7H-purine and 5H- pyrrolo[3,2- ⁇
  • D is selected from CH and N; R 1 is selected from Ci_ 6 alkyl and -OR la ; and R la is selected from Ci_ 6 alkyl.
  • R 2 is Ci_ 6 alkyl; R 2 * is Ci_ 6 alkyl; R 3 is Ci_ 6 alkyl; R 4 is halo; and n is i .
  • Ring A together with the pyrimidine to which it is fused, forms a member selected from [l,3]oxazolo[5,4- ⁇ i]pyrimidine, 7H-purine, 5H-pyrrolo[3,2- ⁇ f]pyrimidine, 7H- pyrrolo[2,3-d]pyrimidine, [l,3]thiazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine, and thieno[3,2-J]pyrimidine, wherein said [l,3]oxazolo[5,4-J]pyrimidine, 7H-purine, 5H- pyrrolo[3,2-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, [l,3]thiazolo[5,4-d]pyrimidine, thieno[2,3-J]pyrimidine, and thieno[3,2-J]pyrimidine are optionally substituted on carbon with one or more R
  • R 1 is selected from Ci_6alkyl and -OR la ;
  • R la is selected from Ci_ 6 alkyl.
  • R 2 is Ci_ 6 alkyl
  • R 2 * is C 1-6 alkyl
  • R 3 is C 1-6 alkyl
  • R 4 is halo; and n is 1.
  • Ring A together with the pyrimidine to which it is fused, forms a member selected from [l,3]oxazolo[5,4- ⁇ i]pyrimidine, 7H-purine, 5H-pyrrolo[3,2- ⁇ f]pyrimidine, 7H- pyrrolo[2,3- ⁇ i]pyrimidine, [l,3]thiazolo[5,4- ⁇ i]pyrimidine, thieno[2,3- ⁇ i]pyrimidine, and thieno[3,2- ⁇ i]pyrimidine, wherein said [l,3]oxazolo[5,4- ⁇ i]pyrimidine, 7H-purine, 5H- pyrrolo[3,2-J]pyrimidine, 7H-pyrrolo[2,3-J]pyrimidine, [l,3]thiazolo[5,4-d]pyrimidine, thieno[2,3-J]pyrimidine, and thieno[3,2-J]pyrimidine are optionally substituted on carbon with
  • D is selected from CH and N; R 1 is selected from methyl, ethoxy, and isopropoxy; R 2 is methyl; R 2 * is methyl; R 3 is methyl; R 4 is fluoro; and n is 1.
  • Ring A together with the pyrimidine to which it is fused, forms a member selected from 2-methyl[l,3]oxazolo[5,4-d]pyrimidine, 7-methyl-7H-purine, 5-methyl-5H- pyrrolo[3,2- ⁇ i]pyrimidine, 2-methyl[l,3]thiazolo[5,4- ⁇ i]pyrimidine, 7-methylthieno[3,2-
  • R 1 is selected from methyl, ethoxy, and isopropoxy
  • R 3 is methyl
  • R 4 is fluoro; and n is 1.
  • Ring A together with the pyrimidine to which it is fused, forms a member selected from 2-methyl[l,3]oxazolo[5,4- ⁇ f]pyrimidine, 7-methyl-7H-purine, 5-methyl-
  • X is -NH-
  • D is selected from CH and N;
  • R 1 is selected from methyl, ethoxy, and isopropoxy
  • R 3 is methyl; R 4 is fluoro; and n is 1.
  • the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as illustrated by the Examples, each of which provides a further independent aspect of the invention.
  • Typical compounds of Formula (I) are believed to have utility for the treatment of myeloproliferative disorders, myelodysplastic syndrome and cancer by inhibiting the JAK tyrosine kinases, particularly the JAK2 family.
  • Methods of treatment target tyrosine kinase activity, particularly the JAK family activity and more particularly JAK2 activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndrome and cancer related processes.
  • inhibitors of tyrosine kinase are expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemias, myelomas and lymphomas, tumors of the central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma.
  • Tyrosine kinase inhibitors, particularly the JAK family inhibitors and more particularly JAK2 inhibitors are also expected to be useful for the treatment other proliferative diseases including but not limited to
  • the compounds of Formula (I) have been shown to inhibit tyrosine kinases, particularly the JAK family and more particularly JAK2, as determined by the JAK2 Assay described herein.
  • the compounds of Formula (I) should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit tyrosine kinases, particularly the JAK family and more particularly JAK2. These would be provided in commercial kits comprising a compound of this invention.
  • JAK2 kinase activity may be determined by measuring the kinase's ability to phosphorylate synthetic tyrosine residues within a generic polypeptide substrate using an Amplified Luminescent Proximity Assay (Alphascreen) technology (PerkinElmer, 549 Albany Street, Boston, MA).
  • Amplified Luminescent Proximity Assay Alphascreen
  • a commercially available purified enzyme may be used. The enzyme may be C-terminal His6-tagged, recombinant, human JAK2, amino acids 808-end, (Genbank Accession number NM 004972) expressed by baculovirus in SG 1 cells (Upstate Biotechnology MA).
  • the kinase reaction may be stopped by the addition of 30 mM ethylenediaminetetraacetic acid (EDTA).
  • EDTA ethylenediaminetetraacetic acid
  • the reaction may be performed in 384 well microtitre plates and the reaction products may be detected with the addition of streptavidin coated Donor Beads and phosphotyrosine-specific antibodies coated Acceptor Beads using the EnVision Multilabel Plate Reader after an overnight incubation at room temperature.
  • Teween 20 is a registered trademark of ICI Americas, Inc.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use as a medicament.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of myeloproliferative disorders, myelodysplasia syndrome and cancers (solid and hematologic tumors), f ⁇ broproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma
  • a method for treating myeloproliferative disorders, myelodysplasia syndrome, and cancer, in a warm-blooded animal such as man comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for treating myeloproliferative disorders, myelodysplastic syndrome, and cancers solid and hematologic tumors
  • f ⁇ broproliferative and differentiative disorders psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man
  • said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for producing an anti-proliferative effect in a warm-blooded animal such as man comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for producing a JAK inhibitory effect in a warmblooded animal such as man comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for treating cancer in a warm-blooded animal such as man comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in treating myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in treating myeloproliferative disorders, myelodysplastic syndrome, and cancers (solid and hematologic tumors), f ⁇ broproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the production of an anti -proliferative effect, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the production of a JAK inhibitory effect in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in a warm-blooded animal such as man.
  • the treatment (or prophylaxis) of cancer may particularly refer to the treatment (or prophylaxis) of mesoblastic nephroma, mesothelioma, acute myeloblasts leukemia, acute lymphocytic leukemia, multiple myeloma, oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer including secretory breast cancer, colorectal cancer, prostate cancer including hormone refractory prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma, thyroid cancer including papillary thyroid cancer, mesothelioma, leukaemia, tumors of the central and peripheral nervous
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl />-hydroxybenzoate; and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form or in the form of nano or micronized particles together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexito
  • the aqueous suspensions may also contain one or more preservatives such as ethyl or propyl p_-hydroxybenzoate; anti-oxidants such as ascorbic acid); coloring agents; flavoring agents; and/or sweetening agents such as sucrose, saccharine or aspartame.
  • preservatives such as ethyl or propyl p_-hydroxybenzoate
  • anti-oxidants such as ascorbic acid
  • coloring agents such as ascorbic acid
  • flavoring agents such as ascorbic acid
  • sweetening agents such as sucrose, saccharine or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin.
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally- occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 4 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • a daily dose in the range of 1-50 mg/kg is employed. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • the anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti -tumor agents:
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines including 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (for example anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as tax
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride; (iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor
  • 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family, for example inhibitors or phosphotidylinositol 3-kinase (PI3K) and for example inhibitors of mitogen activated protein kinase (MEK1/2) and for example inhibitors of protein kinase B (PKB/Akt), for example inhibitors of Src tyrosine kinase family and/or Abelson (AbI) tyrosine kinase family such as AZD0530 and dasatinib (BMS-354825) and imatinib mesylate (GleevecTM); and any agents that modify STAT signalling;
  • PI3K phosphotidylinositol 3-kinas
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin);
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM]
  • vastinTM anti-vascular endothelial cell growth factor antibody bevacizumab
  • compounds that work by other mechanisms for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy;
  • GDEPT gene-directed enzyme pro-drug therapy
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine -transfected tumor cell lines and approaches using anti-idiotypic antibodies and approaches using the immunomodulatory drugs thalidomide and lenalidomide [Revlimid R ]; and (x) other treatment regimes including: dexamethasone, proteasome inhibitors (including bortezomib), isotretinoin (13-cis retinoic acid), thalidomide, revemid, Rituxamab, ALIMTA, Cephalon's kinase inhibitors CEP-701 and CEP-2563, anti-Trk or anti-NG
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • compounds of Formula (I) and pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of JAK2 in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • any of the alternate embodiments of the compounds of the invention described herein also apply.
  • the inhibition of JAK activity particularly refers to the inhibition of JAK2 activity.
  • the necessary starting materials for the procedures such as those described herein may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the described procedure or the procedures described in the Examples.
  • Process A - Compounds of Formula (A) and compounds of Formula (B) may be reacted together in the presence of a suitable solvent, examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid- 2-one.
  • a suitable solvent examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid- 2-one.
  • the reaction may advantageously occur in the presence of a suitable base, examples of which include inorganic bases such as potassium carbonate and cesium carbonate, and organic bases such as potassium tert-butoxide and sodium tert-butoxide.
  • the reaction may be advantageously performed at a temperature in a range from 0 0 C to reflux. Heating the reaction may be particularly advantageous.
  • compounds of Formula (A) and compounds of Formula (B) may be reacted together under standard Buchwald conditions (for example see J. Am. Chem. Soc, 118, 7215; J. Am. Chem. Soc, 119, 8451; J. Org. Chem., 62, 1568 and 6066), with a suitable base.
  • suitable bases include inorganic bases such as cesium carbonate, and organic bases such as potassium ⁇ -butoxide.
  • Such a reaction may advantageously occur in the presence of a palladium catalyst such as palladium acetate.
  • solvents suitable for such a reaction include toluene, benzene, dioxane, and xylene.
  • the -NH- moiety of the compound of Formula (B) may advantageously be protected with a suitable protecting group, examples of which include protecting groups such as tert-butoxycarbonyl.
  • Process B - Compounds of Formula (D) and compounds of Formula (B) may be reacted together under conditions similar to those described for the reaction of compounds of Formula (A) with compounds of Formula (B).
  • Formula (A) wherein L in each occurrence may be the same or different, and is a leaving group as described hereinabove.
  • Compounds of Formula (D) and compounds of Formula (E) may be reacted together under conditions similar to those described for the reaction of compounds of Formula (A) with compounds of Formula (B).
  • L in each occurrence may be the same or different, and is a leaving group as described hereinabove.
  • Compounds of Formula (B) and compounds of Formula (E) may be reacted together in the presence of a suitable solvent, examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid-2-one.
  • a suitable solvent examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid-2-one.
  • the reaction advantageously will take place in the presence of a suitable base, examples of which include inorganic bases such as potassium carbonate and cesium carbonate, and organic bases such as potassium tert-butoxide and sodium tert-butoxide.
  • the reaction is advantageously performed at a temperature in a range from 0 C to reflux.
  • temperatures are given in degrees Celsius ( 0 C); operations are carried out at room temperature or ambient temperature, that is, in a range of 18-25 0 C;
  • organic solutions were dried over anhydrous magnesium sulfate unless other wise stated; evaporation of organic solvent was carried out using a rotary evaporator under reduced pressure (4.5 - 30 mmHg) with a bath temperature of up to 60 0 C;
  • chromatography means flash chromatography on silica gel; thin layer chromatography
  • NMR data when given, NMR data is in the form of delta values for major diagnostic protons, given in part per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz in DMSO-d ⁇ unless otherwise stated;
  • Biotage refers to normal phase flash column chromatography using pre-packed silica gel cartridges (12 g, 40 g, 80 g etc.) used according to the manufacturers instruction obtained from Biotage Inc, 1725 Discovery Drive Charlotteville, Virginia 22911, USA.
  • "Gilson” refers to a YMC-AQC 18 reverse phase HPLC Column with dimension 20 mm/100 and 50 mm/250 in H 2 OMeCN with 0.1% TFA as mobile phase unless otherwise stated and used according to the manufacturers instruction obtained from Gilson, Inc. 3000 Parmenter Street, Middleton, WI 53562-0027, U.S.A.
  • SFC super critical fluid chromatography
  • ASFC Analytical SFC (ASC- 1000 Analytical SFC System with Diode Array Detector) and/or Preparative SFC (APS- 1000 AutoPrep Preparative SFC) and used according to the manufacturers instruction obtained from SFC Mettler Toledo AutoChem, Inc. 7075 Samuel Morse Drive Columbia MD 21046, U.S.A.
  • DIPEA N, N-diisopropylethylamine N-diisopropylethylamine.
  • a 10 ml microwave vial was charged with 2-chloro-5-fluoropyrimidine (2.0 g, 15.09 mmol), Pd 2 (dba) 3 (0.549 g, 0.6 mmol), dppf (0.67 g, 1.21 mmol), zinc cyanide (1.15 g, 9.81 mmol), and zinc dust (0.237 mg, 3.62 mmol).
  • the flask was evacuated and backfilled with N 2 , and anhydrous DMAc.
  • the vial was mounted onto a Personal Chemistry microwave reactor and heated at 100 0 C for 10 hours.
  • the reaction mixture was diluted with EtOAc and then washed with brine three times. The organic layer was obtained and evaporated to dryness.
  • N-( 1 -(5-Fluoropyrimidin-2-yl)vinyl)acetamide 5-Fluoropyrimidine-2-carbonitrile (Intermediate 4, 1.0 g, 8.1 mmol) in THF (10 ml) was added a solution of MeMgBr (3.3 ml, 9.75 mmol) in ether drop wise at 0 0 C. After addition, the reaction was warmed to room temperature, stirred at room temperature for 1 hour and then diluted with DCM (10 ml). Acetic anhydride (1.23 ml, 13.0 mmol) was added in one portion. The reaction was stirred at room temperature for 1 hour and 40 0 C for 1 hour.
  • N-(l-(5-Fluoropyrimidin-2-yl)vinyl)acetamide (Intermediate 5, 0.10 g, 0.55 mmol) in MeOH (5 ml) under N2 was added (+)-l,2-bis((2 J 5, 5.S)-2,5-dietliylpliospliolano)benzene (cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.04 g, 0.0055 mmol).
  • the solution was transferred to a high pressure bomb and charged 150 psi H2. The reaction was stirred at room temperature for 4 hours.
  • N-( 1 -(5-Fluoropyridin-2-yl)vinyl)acetamide A solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrous THF and cooled to 0 0 C. 5-Fluoropyridine-2-carbonitrile (Intermediate 9, 53.6 g, 425.82 mmol) in THF (170 ml) was added drop wise. The reaction was stirred at 0 0 C for 30 minutes, then diluted with DCM (170 ml).
  • N- ⁇ ( IS)- 1 -(5-fluoropyridin-2-vP)ethyll acetamide To a solution of N-(l-(5-fluoropyridin-2-yl)vinyl)acetamide (Intermediate 10, 11.0 g, 61.1 mmol) in MeOH (120 ml) under N 2 was added (+)-l,2-bis((2S,5 ( S)-2,5- diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.441 g, 0.611 mmol). The solution was transferred to a high pressure bomb and charged 150 psi H 2 .
  • the hydrochloride may be prepared by dissolving the title compound in MeOH and adding HCl/dioxane solution. Evaporation of the solvents provides the hydrochloride salt of the title compound as a tan solid.
  • a microwave vessel was charged with 6-chloro-N 2 -[(l.S ⁇ )-l-(5-fluoropyrimidin-2-yl)ethyl]- ⁇ /4 -(5- methyl-lH-pyrazol-3-yl)pyrimidine-2,4-diamine (Intermediate 32, 155 mg, 0.44 mmol) and 2,2- dimethoxyethanamine (1402 mg, 13.33 mmol).
  • the resulting solution was heated in a microwave for Ih at 140 0 C.
  • the reaction was not complete, so it was heated for an extra hour at 160 0 C.
  • a microwave reaction vessel was charged with 5-chloro-2-methyl-N-(5-methyl-lH-pyrazol-3- yl)[l,3]thiazolo[5,4-d]pyrimidin-7-amine (Intermediate 19, 150 mg, 0.53 mmol), (15)-l-(5- fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 8, 104 mg, 0.59 mmol) and DIPEA (0.28 mL, 1.59 mmol). Isoamyl alcohol (2 ml) was added, and the tube was sealed and heated in a microwave reactor at 160 0 C for 4 hours. The reaction mixture was concentrated in vacuo leaving a pink/brown solid.
  • a microwave vessel was charged with a solution of fS / )- ⁇ /4 -(2,2-dimethoxyethyl)-N 2 -(l-(5- fluoropyrimidin-2-yl)ethyl)- ⁇ /6 -(5-methyl-lH-pyrazol-3-yl)pyrimidine-2,4,6-triamine (Intermediate 34, 0.184 g, 0.44mmol) in p-toluenesulfonic acid (2.5 ml, 15.53 mmol) in acetic acid (12%). The solution was heated to 160 0 C for 1.5 hours. Evaporation of the volatiles afforded a dark oil.

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Abstract

Cette invention se rapporte à des composés de formule (I) et à leurs sels, à des compositions pharmaceutiques, à leurs procédés d'utilisation et à leurs procédés de préparation. Ces composés sont utilisés dans le traitement du syndrome myéloprolifératif et du cancer.
PCT/GB2008/050617 2007-07-26 2008-07-23 Composés chimiques WO2009013545A2 (fr)

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Cited By (11)

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WO2010103130A3 (fr) * 2009-03-13 2010-12-23 Katholieke Universiteit Leuven, K.U.Leuven R&D Nouveaux hétérocycles bicycliques
WO2011093672A2 (fr) * 2010-01-29 2011-08-04 Hanmi Pharm. Co., Ltd. Dérivés hétéroaryle bicyclique ayant une activité inhibitrice de protéine kinase
WO2012030894A1 (fr) * 2010-09-01 2012-03-08 Ambit Biosciences Corporation Composés thiénopyridines et thiénopyrimidines et leurs procédés d'utilisation
JP2013517243A (ja) * 2010-01-14 2013-05-16 サノフイ ２，５−置換されたオキサゾロピリミジン誘導体
WO2013113715A1 (fr) 2012-02-03 2013-08-08 Basf Se Composés de pyrimidine fongicides
CN103242341A (zh) * 2013-04-19 2013-08-14 中国科学院广州生物医药与健康研究院 噻吩并2，4取代嘧啶类化合物及其药物组合物与应用
WO2013135671A1 (fr) 2012-03-13 2013-09-19 Basf Se Composés de pyrimidine fongicides
WO2015036059A1 (fr) 2013-09-16 2015-03-19 Basf Se Composés fongicides de pyrimidine
WO2015036058A1 (fr) 2013-09-16 2015-03-19 Basf Se Composés pyrimidines fongicides
US9708272B2 (en) 2014-08-29 2017-07-18 Tes Pharma S.R.L. Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase
WO2018137036A1 (fr) 2017-01-26 2018-08-02 The Royal Institution For The Advancement Of Learning / Mcgill University Composés bicycliques substitués à base de pyrimidine, compositions et utilisations associées

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WO2005049033A1 (fr) * 2003-11-17 2005-06-02 Astrazeneca Ab Derives de pyrazole en tant qu'inhibiteurs de recepteur tyrosine kinases
WO2006123113A2 (fr) * 2005-05-16 2006-11-23 Astrazeneca Ab Composes chimiques
WO2007049041A1 (fr) * 2005-10-28 2007-05-03 Astrazeneca Ab Derives 4-(3-aminopyrazole)pyrimidine et leur utilisation en tant qu’inhibiteurs de tyrosine kinases dans le cadre d’un traitement anticancereux

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WO2002050065A2 (fr) * 2000-12-21 2002-06-27 Vertex Pharmaceuticals Incorporated Composes de pyrazole presentant une grande utilite comme inhibiteurs de proteine kinase
WO2005049033A1 (fr) * 2003-11-17 2005-06-02 Astrazeneca Ab Derives de pyrazole en tant qu'inhibiteurs de recepteur tyrosine kinases
WO2006123113A2 (fr) * 2005-05-16 2006-11-23 Astrazeneca Ab Composes chimiques
WO2007049041A1 (fr) * 2005-10-28 2007-05-03 Astrazeneca Ab Derives 4-(3-aminopyrazole)pyrimidine et leur utilisation en tant qu’inhibiteurs de tyrosine kinases dans le cadre d’un traitement anticancereux

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9221822B2 (en) 2009-03-13 2015-12-29 Katholieke Universiteit Leuven, K. U. Leuven R&D Thiazolopyrimidine modulators as immunosuppressive agents
WO2010103130A3 (fr) * 2009-03-13 2010-12-23 Katholieke Universiteit Leuven, K.U.Leuven R&D Nouveaux hétérocycles bicycliques
US8901132B2 (en) 2009-03-13 2014-12-02 Katholieke Universiteit Leuven, K.U. Leuven R&D Thiazolopyrimidine modulators as immunosuppressive agents
JP2013517243A (ja) * 2010-01-14 2013-05-16 サノフイ ２，５−置換されたオキサゾロピリミジン誘導体
US9040544B2 (en) 2010-01-14 2015-05-26 Sanofi 2,5-substituted oxazolopyrimidine derivatives
CN102741256B (zh) * 2010-01-29 2015-12-02 韩美药品株式会社 对于蛋白激酶具有抑制活性的双环杂芳基衍生物
EP2528920A4 (fr) * 2010-01-29 2013-08-07 Hanmi Pharm Ind Co Ltd Dérivés hétéroaryle bicyclique ayant une activité inhibitrice de protéine kinase
US10112954B2 (en) 2010-01-29 2018-10-30 Hanmi Pharm. Co., Ltd. Bicyclic heteroaryl derivatives having inhibitory activity for protein kinase
EP2528920A2 (fr) * 2010-01-29 2012-12-05 Hanmi Pharm. Co., Ltd. Dérivés hétéroaryle bicyclique ayant une activité inhibitrice de protéine kinase
CN102741256A (zh) * 2010-01-29 2012-10-17 韩美药品株式会社 对于蛋白激酶具有抑制活性的双环杂芳基衍生物
WO2011093672A2 (fr) * 2010-01-29 2011-08-04 Hanmi Pharm. Co., Ltd. Dérivés hétéroaryle bicyclique ayant une activité inhibitrice de protéine kinase
WO2011093672A3 (fr) * 2010-01-29 2012-01-05 Hanmi Pharm. Co., Ltd. Dérivés hétéroaryle bicyclique ayant une activité inhibitrice de protéine kinase
WO2012030894A1 (fr) * 2010-09-01 2012-03-08 Ambit Biosciences Corporation Composés thiénopyridines et thiénopyrimidines et leurs procédés d'utilisation
WO2013113715A1 (fr) 2012-02-03 2013-08-08 Basf Se Composés de pyrimidine fongicides
WO2013135671A1 (fr) 2012-03-13 2013-09-19 Basf Se Composés de pyrimidine fongicides
CN103242341A (zh) * 2013-04-19 2013-08-14 中国科学院广州生物医药与健康研究院 噻吩并2，4取代嘧啶类化合物及其药物组合物与应用
WO2015036058A1 (fr) 2013-09-16 2015-03-19 Basf Se Composés pyrimidines fongicides
WO2015036059A1 (fr) 2013-09-16 2015-03-19 Basf Se Composés fongicides de pyrimidine
US9708272B2 (en) 2014-08-29 2017-07-18 Tes Pharma S.R.L. Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase
US10513499B2 (en) 2014-08-29 2019-12-24 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
US11254644B2 (en) 2014-08-29 2022-02-22 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
WO2018137036A1 (fr) 2017-01-26 2018-08-02 The Royal Institution For The Advancement Of Learning / Mcgill University Composés bicycliques substitués à base de pyrimidine, compositions et utilisations associées
US11279719B2 (en) 2017-01-26 2022-03-22 Youla S. Tsantrizos Substituted bicyclic pyrimidine-based compounds and compositions and uses thereof

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