WO2014075318A1 - Composés de pyrimidine et utilisation associée - Google Patents

Composés de pyrimidine et utilisation associée Download PDF

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WO2014075318A1
WO2014075318A1 PCT/CN2012/084846 CN2012084846W WO2014075318A1 WO 2014075318 A1 WO2014075318 A1 WO 2014075318A1 CN 2012084846 W CN2012084846 W CN 2012084846W WO 2014075318 A1 WO2014075318 A1 WO 2014075318A1
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Prior art keywords
piperidine
pyrimidinyl
substituted
furo
group
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PCT/CN2012/084846
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English (en)
Chinese (zh)
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刘飞
沈晗
丛欣
朱新荣
吴刚
赵鑫鑫
陈盼
王佳
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江苏先声药业有限公司
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Priority to PCT/CN2012/084846 priority Critical patent/WO2014075318A1/fr
Publication of WO2014075318A1 publication Critical patent/WO2014075318A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of biomedicine, and in particular to pyrimidine compounds and pharmaceutically acceptable equivalents or salts, and processes for their preparation and use as Janus kinase inhibitors. Background technique:
  • Protein kinases are composed of a series of structurally related enzymes that are primarily responsible for the control of intracellular signal transduction processes. In general, protein kinases mediate intracellular signals by affecting the phosphoryl transfer from nucleoside triphosphates to protein receptors involved in signaling pathways. These phosphorylation events act as molecular switches that modulate or regulate the biological function of the target protein. Many diseases are associated with abnormal cellular responses elicited by the above protein kinase-mediated events.
  • Janus kinase is a cytoplasmic protein kinase that acts with type I and type II cytokine receptors to regulate cytokine signaling. JAK1, JAK2 and TYK2 inhibit multiple gene expression, whereas JAK3 only plays a role in granulocytes.
  • the typical function of cytokine receptors exists as a heterodimeric form and is therefore generally not a JAK kinase acting as a cytokine receptor.
  • the downstream substrates of the JAK family include signal transduction agents and activators (STAT) of transcriptional proteins.
  • JAK/STAT signaling involves many abnormal immune responses, such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and solid and hematological malignancies such as leukemia. Lymphoma.
  • JAK1 acts through cytokine receptors such as IFNalpha, IFNgamma, IL-2, and IL-6, and JAK1 knockout mice die due to loss of LIF receptor signaling. Observation of the characteristic tissues of JAK1 knockout mice revealed that JAK1 plays an important role in cellular pathways such as IFN, IL-10, IL-2/IL-4, and IL-6.
  • JAK2 knockout mice died of anemia.
  • Kinase-mediated JAK2 variants are associated with human myeloproliferative disorders, including true erythrocytosis, spontaneous thrombocytosis, chronic idiopathic myelofibrosis, bone marrow transformation with myelofibrosis, chronic endemic leukemia, chronic bone marrow Monocytic leukemia and the like.
  • JAK3 specifically acts on the gamma cytokine receptor chain, which is present in cytokine receptors such as IL-2, IL-4, IL-7, IL-9, IL-15, IL-21. JAK3 plays an important role in lymphocyte growth, proliferation, and mutation, and abnormalities can lead to severe immunodeficiency. Based on its role in regulating lymphocytes, JAK3 and JAK3 mediated The pathway is used to regulate the indications of immunosuppression.
  • JAK3 is implicated in the mediation of many abnormal immune responses, such as allergies, asthma, autoimmune diseases such as inhibition of transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and solid and hematological malignancies such as Leukemia, lymphoma.
  • TYK2 acts on cytokine receptor complexes such as type I interferon, IL-6, IL-10, IL-12, and IL-23. Consistent with this, primary cells derived from humans deficient in TYK2 have barriers in the signaling of type I interferons, IL-6, IL-10, IL-12, and IL-23.
  • novel compounds of the invention may inhibit one or more JAK kinases and are therefore contemplated for use in the treatment of diseases associated therewith.
  • the object of the invention can be achieved by the following measures:
  • a class of pyrimidine compounds such as structural formula (I) compounds and pharmaceutically acceptable equivalents or salts thereof:
  • R 1 is an optionally substituted alkyl group, a cycloalkyl group, an acyl group or a sulfonyl group;
  • R 2 is hydrogen, halogen, C1-C6 straight or branched alkyl, cycloalkyl, halogenated C1-C6 straight or branched alkyl;
  • R 3 is hydrogen, halogen;
  • R 2 and R 3 together with the carbon atom to which they are attached form a 5-membered heteroaryl ring
  • Z is independently selected from N, CR 4 ;
  • n is an integer of 0-3;
  • R 4 is independently selected from the group consisting of hydrogen, halogen, R 5 , OR 5 , OH, R 6 , CN, CF 3 , (CH 2 ) n N(R 5 ) 2 , N0 2 , R 5 R 6 OR 5 R 6 or Two R 4 substituents together with the carbon atom to which they are attached form a saturated or unsaturated 5 or 6 membered heterocyclic group;
  • R 5 is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, or substituted or unsubstituted C 1 -C 4 alkylene, wherein up to two carbon atoms may be optionally replaced by CO, S, S0 2 , or 0 ;
  • R 6 is NH 2 , NHR 5 , N(R 5 ) 2 , N(R 4 ) 2 , substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperazine a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted pyrrolidinyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted oxazolyl group, a substituted or unsubstituted imidazolyl group;
  • Alkyl represents an unsubstituted or substituted straight or branched saturated hydrocarbon group having the stated number of carbon atoms.
  • Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl , isohexyl, 3-methylheptyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.
  • Cycloalkyl represents a ring of monocyclic, fused, spiro or bridged rings which are all carbon. Typically, it is cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, spiro[3.4]octane, bicyclo[3.1.1]hexane.
  • alkylene group denotes itself or as a moiety of another substituent, and refers to a linear saturated or unsaturated alkanediyl group having two terminal monovalent group centers, which are derived from two terminal carbon atoms of a linear parent alkane, alkene or a block. Each removes a hydrogen atom.
  • Typical alkylene groups include, but are not limited to, methylene, ethylene, vinylidene, ethylene block, propylene, butylene, and the like.
  • a saturated heterocyclic group i.e., a heterocycloalkyl group, means a monocyclic or fused ring containing one or more heteroatoms of N, 0 or S. Typically, it is a 5-6 membered heterocyclic group containing one or more heteroatoms of N, 0 or S, such as piperazino, morpholino, piperidino, pyrrolidinyl and derivatives thereof.
  • Piperazinolide refers to a group having the following chemical structure.
  • Morpholino group refers to a group having the following chemical structure.
  • Piperidino group refers to a group having the following chemical structure.
  • Pyrrolidinyl refers to a group having the following chemical structure.
  • heteroaryl a monocyclic or fused ring group of 5 to 12 ring atoms, containing one, two, three or four rings of selected N, 0 or S Heteroatoms, the remaining ring atoms are C, and have a fully conjugated ⁇ -electron system.
  • Typical heteroaryl groups (but not limited to) pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, pyridine.
  • Halogen or halogen groups are fluorine, chlorine, bromine or iodine. Preferred are fluorine, chlorine, and bromine.
  • the Cr3 alkyl group substituted by halogen means an alkyl group in which one or more hydrogens are replaced by a halogen, and preferably contains one, two or three halogen groups.
  • R 1 is: Wherein R 7 is a C1-6 straight or branched alkyl group, -CN, -NHS0 2 R 12 , -NHOH, -NHCOR 12 , -CON(R 12 ) 2 , -N(R 12 ) 2 , -OR 12 ,
  • -CF, ; 1 ⁇ is a straight or branched alkyl group, a C3-C7 cycloalkyl group, or R 9 , R 1U or R 11 which are the same or different and each independently selected from halogen, hydrogen, C1-C6 straight Chain or branched alkyl group, C3-C7 cycloalkyl, R 12 is selected from the group consisting of hydrogen, -CN, -NHS0 2 R 5 , halogen, -N(R 5 ) 2 ,
  • R 1 is, wherein R' is a C1-C4 linear or branched alkyl group, -CN, a branched alkyl group;
  • R 9 , R 1Q or R 11 are the same or different, each The halogen is selected from halogen, hydrogen or R 12 is selected from -CN or hydrogen; X is S; m is 0 or 1.
  • R 7 is -CN, or ⁇ ;
  • R 8 is a methyl group; R 9 or R 1Q is hydrogen; R 11 is ; R 12 is -CN or hydrogen; X is S; m is 0 or 1.
  • R 2 is hydrogen, halogen, C1-C4 straight or branched alkyl or halogenated C1-C4 straight or branched alkane 3 is hydrogen; or R 2 , R 3 are attached to them
  • the present invention provides a structure of the compound represented by the formula (I), R 2 hydrogen, -F, -CH 3 ,
  • R 3 is hydrogen; or R 2 , R 3 together with the carbon atom to which they are attached constitute the following heterocyclic ring: ;
  • Z is CR 4 .
  • R 4 is hydrogen, halogen, -N0 2 , -OH, C1-C6 linear or branched alkoxy, substituted or unsubstituted saturated or unsaturated 5 or 6-membered saturated Or an unsaturated heterocyclic group or -OR 5 R 6 ;
  • R 5 is a substituted or unsubstituted C1-C3 alkylene group;
  • R 6 is NH 2 , a C1-C6 linear or branched alkylamino group, substituted or unsubstituted Morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, a substituted or unsubstituted oxazolyl, substituted or unsubstituted imidazo
  • R 4 is hydrogen, -F, -N0 2 , -OH, C1-C4 linear or branched alkoxy, pyrrolidinyl, C1-C6 alkyl substituted pyrrolidinyl, piperidinyl , C1-C6 alkyl-substituted piperidinyl, piperazinyl, C1-C6 alkyl-substituted piperazinyl, morpholinyl, C1-C6 alkyl-substituted morpholinyl, imidazolyl, C1-C6 alkyl Substituted imidazolyl or
  • R 4 is further hydrogen, -F, -N0 2 , -OH, -OCH 3 , .
  • R 5 is ⁇ ⁇ or
  • R 6 is a substituted or unsubstituted morpholinyl group, a substituted or unsubstituted thiomorpholinyl group, a substituted or unsubstituted piperazinyl group, a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted pyrrolidinyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted oxazolyl group, a substituted or unsubstituted imidazolyl group; the substituent is a hydroxyl group, a C1-C6 straight chain or a branched alkyl group a hydroxy-substituted C1-C6 straight or branched alkyl group, a C1-C6 alkyl acyl group, a C3-C7 cycloalkanoyl group or a piperidinyl group.
  • n 0, 1 or 2.
  • R 4 is a para-substituent of the amino group on the phenyl ring; when n is 2, R 4 is a meta and para substituent of the amino group on the phenyl ring.
  • Specific examples of the pyrimidine compound of the formula (I) include those listed in the following table:
  • the present invention also provides a pharmaceutical composition for treating a JAK kinase-associated disease in an organism, comprising the above respective compounds provided by the present invention and a pharmaceutically acceptable carrier, excipient or diluent.
  • salts represent those salts which retain the biological effectiveness and properties of the parent compound.
  • the salt formation with an acid means that it is obtained by a reaction of a free base of a parent compound with an inorganic acid or an organic acid.
  • Inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid and the like.
  • Organic acids include acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid , methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or malonic acid.
  • compositions refer to one or more compounds of the invention or their pharmaceutically acceptable salts and prodrugs with other chemical ingredients, including mixtures of pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to facilitate administration of the compound to the organism.
  • a pharmaceutically acceptable carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound.
  • excipients include, without limitation, calcium carbonate, calcium phosphate, various sugars, and various types of starch, cellulose derivatives, and Gum, vegetable oil and polyethylene glycol.
  • the invention further relates to a process for the preparation of the general formula (I), characterized in that it comprises
  • the preparation method is characterized in that, in the preparation process, the solvent Si is selected from an organic solvent such as dichloromethane or ethyl acetate, preferably Is a dichloromethane; the base is selected from an organic base such as triethylamine, N-ethyldiisopropylamine, preferably triethylamine; the catalyst may be p-dimethylaminopyridine, 4-pyrrolidinyl Pyridine, 1-hydroxybenzotriazole, tributylphosphine, preferably 1-hydroxybenzotriazole; condensing agent 1 is carbonyldiimidazole, dicyclohexylcarbodiimide, 1-ethyl- (3 -Dimethylaminopropyl)carbodiimide, preferably 1-ethyl-(3-dimethylaminopropyl)carbodiimide; temperature is -15-15 °,
  • the invention also provides for the use of novel pyrimidine derivatives, in particular as Janus kinase inhibitors.
  • novel pyrimidine derivatives include, but are not limited to, true erythrocytosis, spontaneous thrombocytosis, chronic idiopathic myelofibrosis, bone marrow transformation with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, metamorphosis Response, asthma, autoimmune diseases such as inhibition of transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and solid and hematological malignancies such as leukemia, lymphoma, and the like.
  • the invention also provides the use of each of the above compounds for the manufacture of a medicament for the treatment of JAK2, JAK3 mediated disorders, comprising administering to a system or individual in need of such treatment an effective amount of a compound as defined in any one of the invention or a pharmaceutical composition thereof Thereby treating the condition.
  • JAK kinase To test the level of action of the compounds provided by the present invention on JAK kinase, a biochemical level enzyme activity test was used. The level of activity and effect of various compounds of the invention on one or more PKs is determined. Similar experiments can be designed in the same manner for any kinase using methods well known in the art.
  • HTRF Homogeneous Time-Resolved Fluorescence
  • FRET fluorescence resonance energy transfer
  • TR time-resolved
  • the avidin-labeled XL-665 and the substrate-phosphorylated Eu-labeled antibody are added as the substrate.
  • the Eu-labeled antibody recognizes the phosphorylated product and forms a time-resolved fluorescence resonance energy transfer (FRET) with avidin-labeled XL665, while the unphosphorylated substrate is not recognized by the antibody.
  • FRET fluorescence resonance energy transfer
  • the FRET signal could not be formed, and the inhibitory activity of the test substance on JAK2, JAK3 kinase at different concentrations was determined by measuring the difference of fluorescence signals at 665 nm and 620 nm.
  • the activity of the compounds of the present invention against the biochemical levels of the above tyrosine kinases can be determined by this method, and similar assays can be used for other protein kinases using methods well known in the art.
  • the invention discloses a compound, a preparation method thereof, an intermediate of the compound and a preparation method thereof, and the use of the compound as a JAK kinase inhibitor, and those skilled in the art can learn from the contents of the present invention and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the method and the application of the present invention have been described in the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
  • the preparation method is the same as that in Example 1.
  • 1-cyanoacyl-4-(3-(3,5-difluoro-4-morpholinanilinyl)-6-methyl)pyrimidinyl-furo[3,2- c] Synthesis of piperidine, except that 4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c Piperidine was changed to 4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • 1-benzyl-4-(3-(4-N-methylpiperazinylanilide)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine is prepared in the same manner as in Example 3. Synthesis of 1-benzyl-4-(3-(4-morpholinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine, the difference is that 4-? The phenylaniline was changed to N-methylpiperazinyl aniline.
  • the preparation method is the same as that of Example 1 in 1-nitrile acyl-4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl- Synthesis of furo[3,2-c]piperidine, except that 4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furan And [3,2-c] piperidine was changed to 4-(3-(4-(2-pyrrolidine-1-ethoxy)anilino)-6-methyl)pyrimidinyl-furo[3,2 -c] piperidine.
  • the preparation method is the same as the synthesis of 1-benzyl-4-(3-(4-morpholinylanilino)pyrimidinyl-furo[3,2-c]piperidine in Example 6, except that 4 -Morolinylaniline was changed to N-methylpiperazinylaniline.
  • the preparation method is the same as the synthesis of 4-(3-(4-morpholinylanilino))pyrimidinyl-furo[3,2-c]piperidine in Example 6, except that 1-benzyl-4 is used.
  • - (3-(4-morpholinylanilino))pyrimidinyl-furo[3,2-c] piperidine was changed to 1-benzyl-4-(3-(4-N-methylpiperazinyl) Anilino)) pyrimidinyl-furo[3,2-c] piperidine.
  • the preparation method is the same as that in Example 1.
  • 1-cyanoacyl-4-(3-(3,5-difluoro-4-morpholinanilinyl)-6-methyl)pyrimidinyl-furo[3,2- c] Synthesis of piperidine, except that 4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c Piperidine was changed to 4-(3-(4-N-methylpiperazinylphenyl))pyrimidinyl-furo[3,2-c]piperidine.
  • 1-cyanoacetyl-4-(3-(4-morpholinoanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] piperidine is prepared in the same manner as in Example 1. Synthesis of 1-cyanoyl-4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine, The difference is that 4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine is changed to 4- (3-(4-Morpholinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as the synthesis of 1-benzyl-4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in Example 3.
  • the procedure was to change 4-morpholinylaniline to N-ethylpiperazinylaniline.
  • the preparation method is the same as the synthesis of 4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in Example 3, except that 1 -benzyl-4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine was changed to 1-benzyl-4-(3- (4-N-Ethylpiperazinylanilide)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as the synthesis of 1-benzyl-4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in Example 3.
  • the place was changed to 4-morpholinylaniline to 3,4,5-trimethoxyaniline.
  • the preparation method is the same as the synthesis of 4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in Example 3, except that 1 -benzyl-4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine was changed to 1-benzyl-4-(3- (3,4,5-Trimethoxyanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as the synthesis of 1-benzyl-4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in Example 3. The difference is that 4-morpholinylaniline is changed to aniline.
  • the preparation method is the same as the synthesis of 4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in Example 3, except that 1 -benzyl-4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine was changed to 1-benzyl-4-(3- Anilino-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as that in Example 1.
  • 1-cyanoacyl-4-(3-(3,5-difluoro-4-morpholinanilinyl)-6-methyl)pyrimidinyl-furo[3,2- c] Synthesis of piperidine, except that 4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c Piperidine was changed to 4-(3-(anilino-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as the synthesis of 1-benzyl-4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in Example 3. The difference is that 4-morpholinylaniline is changed to 4-nitroaniline.
  • the preparation method is the same as the synthesis of 4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in Example 3, except that 1 -benzyl-4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine was changed to 1-benzyl-4-(3- (4-Nitro-anilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as that in Example 1.
  • 1-cyanoacyl-4-(3-(3,5-difluoro-4-morpholinanilinyl)-6-methyl)pyrimidinyl-furo[3,2- c] Synthesis of piperidine, except that 4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c Piperidine was changed to 4-(3-(4-nitroanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as the synthesis of 1-benzyl-4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in Example 3. The difference is that 4-morpholinylaniline is changed to 4-fluoroaniline.
  • the preparation method is the same as the synthesis of 4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in Example 3, except that 1 -benzyl-4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine was changed to 1-benzyl-4-(3- (4-Fluoro-anilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as that in Example 1.
  • 1-cyanoacyl-4-(3-(3,5-difluoro-4-morpholinanilinyl)-6-methyl)pyrimidinyl-furo[3,2- c] Synthesis of piperidine, except that 4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c Piperidine was changed to 4-(3-(4-fluoroanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as 2-(4-morpholinylanilino)-4-chloro-5-trifluoromethylpyrimidine in Example 8, except that 4-morpholinanilide is changed to N-Boc-piperazinyl. aniline.
  • the preparation method is the same as that in Example 8, 1-p-methoxybenzyl-4-(3-(4-morpholinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] Piperidine, except that 2-(4-morpholinoanilino)-4-chloro-5-trifluoromethylpyrimidine was changed to
  • 1-Nitrile acetyl-4-(4-N-ethylpiperazinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] piperidine is prepared in the same manner as in Example 1. Synthesis of 1-Nitrileacyl-4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine , except that 4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine was changed to 4 - (4-N-ethylpiperazinylanilide)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine
  • the preparation method was the same as the synthesis of 2-(4-morpholinylanilino)-4-chloro-5-trifluoromethylpyrimidine in Example 8, except that 4-morpholinanilide was changed to 2-chloro-1. - ethoxyaniline.
  • the preparation method is the same as that in Example 1.
  • 1-cyanoacyl-4-(3-(3,5-difluoro-4-morpholinanilinyl)-6-methyl)pyrimidinyl-furo[3,2- c] Synthesis of piperidine, except that 4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c Piperidine was changed to 4-(3-(4-(2-chloro-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as the synthesis of 1-methanesulfonyl-4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine in Example 16. The difference is that 4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine is changed to -(3-(anilino-6-) Pyrimidinyl-furo[3,2-c] piperidine.
  • MS: [M+H] ten 385.1.
  • the preparation method is the same as the synthesis of 1-methanesulfonyl-4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine in Example 16. The difference is that 4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine is changed to 4-(3-(4-morpholinyl) Anilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • 1-Methanesulfonyl-4-(3-(4-N-methylpiperazinylanilide)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine was prepared in the same manner as in Example 16 Synthesis of 1-methylsulfonyl-4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine, except that 4- ((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine was changed to 4-(3-(4-N-methylpiperazinylanilide) -6-Methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as the synthesis of 1-methanesulfonyl-4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine in Example 16. The difference is that 4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c] piperidine is changed to 4- (3- (4- (2-) Pyrrolidin-1-ethoxy)anilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as the synthesis of 1-benzyl-4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in Example 3. The difference is that 4-morpholinylaniline is changed to 4-imidazolylaniline.
  • the preparation method is the same as the synthesis of 4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in Example 3, except that 1 -benzyl-4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine was changed to 1-benzyl-4-(3- (4-imidazolidinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as that in Example 19, 1-methylsulfonyl-4-(3-(4-(2-pyrrolidin-1-ethoxy)anilinyl)-6-methyl) Pyrimidinyl-furo[3,2-c]piperidine, except 4-(3-(4-(2-pyrrolidin-1-ethoxy)anilino)-6-methyl)pyrimidine
  • the benzyl-furo[3,2-c]piperidine is replaced by 4-(3-(4-imidazolidinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • 1-Methanesulfonyl-4-(3-(3,4,5-trimethoxyanilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine is prepared in the same manner as in Example 10 Synthesis of 1-cyanoacetyl-4-(3-(3,4,5-trimethoxyanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine The point is to change the cyanoacetic acid to methanesulfonic acid.
  • the preparation method is the same as the synthesis of 1-methanesulfonyl-4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine in Example 16. The difference is that 4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c] piperidine is changed to 4-(3-(4-N-A) Piperazinylanilino))pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as the synthesis of 1-benzyl-4-(3-chloro-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in Example 1, except that 2,4- Dichloro-5-methyl-pyrimidine was changed to 2,4-dichloro-5-fluoro-pyrimidine.
  • the preparation method is the same as in Example 10, 1-benzyl-4-(3-(3,4,5-trimethoxyanilino)-6-methyl)pyrimidinyl-furan.
  • the preparation method is the same as the synthesis of 4-(3-(3,4,5-trimethoxyanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in Example 10.
  • 1-benzyl-4-(3-(3,4,5-trimethoxyanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine is changed to 1- Benzyl-4-(3-(3,4,5-trimethoxyanilino)-6-fluoro)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as the synthesis of 1-methanesulfonyl-4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine in Example 16. The difference is that 4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c] piperidine is changed to 4-(3-(4-nitroaniline). Base) -6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as the synthesis of 1-methanesulfonyl-4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine in Example 16.
  • the procedure is to change 4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine to 4-(3-(4-fluoroanilinyl) -6-Methyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as that in Example 15 of 1-cyanoacetyl-4-(3-(4-(2-pyrrolidinyl-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furan.
  • [3,2-c] Synthesis of piperidine, except that 1-cyanoacetyl-4-(3-(4-(2-chloro-1-ethoxy)anilino)-6-three Fluoromethyl)pyrimidinyl-furo[3,2-c]piperidine is changed to 1-methanesulfonyl-4-(3-(4-(2-chloro-1-ethoxy)anilino)-6 -Trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as the synthesis of 1-methanesulfonyl-4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine in Example 16. The difference is that 4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine is changed to 4-(3-(4-morpholinyl) Anilino)) pyrimidinyl-furo[3,2-c] piperidine.
  • 1-benzyl-4-(3-((4-(2-pyrrole-1-ethoxy)anilino)-6-fluoro-)pyrimidinyl-furo[3,2-c]piperidine The preparation method is the same as that in Example 23, 1-benzyl-4-(3-((4-(2-pyrrolidin-1-ethoxy)anilinyl))pyrimidinyl-furo[3,2-c]piperidin Synthesis of a pyridine, except that 1-benzyl-4-(3-(4-(2-chloro)-pyrimidinyl-furo[3,2-c]piperidine is changed to 1-benzyl- 4-(3-(4-(2-Chloro-6-fluoro)-pyrimidinyl-furo[3,2-c] piperidine.
  • the preparation method is the same as the synthesis of 4-(3-(4-(2-pyrrolidin-1-ethoxy)anilinyl))pyrimidinyl-furo[3,2-c]piperidine in Example 23, Is based on 1-benzyl-4-(3-((4-(2-pyrrolidin-1-ethoxy)anilinyl)pyrimidinyl)
  • the preparation method is the same as in Example 23, 1-methylsulfonyl-4-(3-(4-(2-pyrrolidin-1-ethoxy)anilino)pyrimidinyl-furo[3,2-c]piperidin Synthesis of a pyridine, except that 4-(3-(4-(2-pyrrolidin-1-ethoxy)anilino))pyrimidinyl-furo[3,2-c]piperidine was changed to 4 - (3-(4-(2-Pyrrolidin-1-ethoxy)anilino)-6-fluoro)pyrimidinyl-furo[3,2-c]piperidine.
  • 1-isobutyryl-4-(3-(4-morpholinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] piperidine is prepared in the same manner as in Example 8 Synthesis of cyanoacetyl-4-(3-(4-morpholinoanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine, except that The cyanoacetic acid was changed to isobutyric acid.
  • the preparation method is the same as in Example 8, 1-cyanoacetyl-4-(3-(4-morpholinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the synthesis was carried out except that the cyanoacetic acid was changed to 4-nitrile benzoic acid.
  • the preparation method is the same as in Example 8, 1-cyanoacetyl-4-(3-(4-morpholinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine. Synthesis, the difference is that the cyanoacetic acid is changed to 3-nitrile benzoic acid
  • the preparation method is the same as in Example 8, 1-cyanoacetyl-4-(3-(4-morpholinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine. Synthesis, the difference is that the cyanoacetic acid is changed to thiophene-2-carboxylic acid
  • the preparation method is the same as that of Example 32, wherein 1-methylsulfonyl-4-(3-(4-morpholinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine Synthesis, except that methanesulfonyl chloride was changed to propionyl chloride.
  • the preparation method is the same as that in Example 15 of 1-cyanoacetyl-4-(3-(4-(2-pyrrolidinyl-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furan.
  • [3,2-c] Synthesis of piperidine, except that 1-cyanoacetyl-4-(3-(4-(2-chloro-1-ethoxy)anilino)-6-three Fluoromethyl)pyrimidinyl-furo[3,2-c] piperidine was changed to 1-(3-cyanobenzoyl)-4-(3-(4-(2-chloro-1-ethoxy) Anilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as that in Example 15 of 1-cyanoacetyl-4-(3-(4-(2-pyrrolidinyl-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furan.
  • [3,2-c] Synthesis of piperidine, except that 1-cyanoacetyl-4-(3-(4-(2-chloro-1-ethoxy)anilino)-6-three Fluoromethyl)pyrimidinyl-furo[3,2-c] piperidine was changed to 1-(4-cyanobenzoyl)-4-(3-(4-(2-chloro-1-ethoxy) Anilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine.
  • the preparation method is the same as that in Example 1.
  • 1-cyanoacyl-4-(3-(3,5-difluoro-4-morpholinanilinyl)-6-methyl)pyrimidinyl-furo[3,2- c] Synthesis of piperidine, except that 4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c Piperidine was changed to 4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine.
  • Example 52 In vitro biochemical inhibition JAK kinase (PK) activity assay
  • JAK2, JAK3 kinase from Invitrogen; 384-well plate (Greiner); HTRF KinEASE; MgCl 2 (sigma); DTT (Sunshine); PHERAstar FS multi-function microplate reader (BMG); Type 1 low speed centrifuge (StaiteXiangyi); TD25-W5 type incubator (Binder); YG020524/oscillator (Linbel); ATP (sigma);
  • the selected positive drug is CP-690550, the structure is as follows:
  • test compound was formulated into 0.5-10 mmol/L mother liquor in DMSO, after dispensing -20
  • Enzyme reaction step 4 ⁇ l of kinase was added to each well of a 384-well plate, and Enzymatic buffer of 4 was added as a negative control; 2 ⁇ of the compound working solution was added to the well, and 2 of the compound-free solution was added.
  • Buffer as a control ie positive control, Positive
  • 2 ATP and TK Substrate-biotin mixture to the wells to initiate the enzymatic reaction at 25 ° C (or 30 ° C) Oscillating reaction for 15-60 min
  • Add 4 uL of TK-Ab-cryptate to the well; incubate at 25 °C (or 30 °C) for 5-10 min
  • PHERAstar FS instrument reads HTRF signal.
  • the ratio 665 nm / 620 nm
  • Inhibition rate % ( 1- ) l 00 %
  • the present invention provides a half-inhibitory concentration (IC 5Q ) of a compound of formula I for JAK kinase activity as shown in Table 1:

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Abstract

La présente invention concerne des composés de formule générale (I) et leurs équivalents ou sels pharmaceutiquement acceptables, ainsi que l'utilisation des composés comme inhibiteurs de la Janus kinase dans une variété d'applications médicales.
PCT/CN2012/084846 2012-11-19 2012-11-19 Composés de pyrimidine et utilisation associée WO2014075318A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110724137A (zh) * 2019-11-13 2020-01-24 广东工业大学 一种噻吩类衍生物及其制备方法与应用
EP3697787A4 (fr) * 2017-10-18 2022-12-14 HK inno.N Corporation Composé hétérocyclique à utiliser en tant qu'inhibiteur de protéine kinase

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101516860A (zh) * 2006-09-15 2009-08-26 诺瓦提斯公司 可用作janus激酶抑制剂的苯并唑和唑并吡啶
CN101861313A (zh) * 2007-03-12 2010-10-13 西托匹亚研究有限公司 苯基氨基嘧啶化合物及其用途
CN101910152A (zh) * 2007-11-16 2010-12-08 因塞特公司 作为janus激酶抑制剂的4-吡唑基-n-芳基嘧啶-2-胺和4-吡唑基-n-杂芳基嘧啶-2-胺

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101516860A (zh) * 2006-09-15 2009-08-26 诺瓦提斯公司 可用作janus激酶抑制剂的苯并唑和唑并吡啶
CN101861313A (zh) * 2007-03-12 2010-10-13 西托匹亚研究有限公司 苯基氨基嘧啶化合物及其用途
CN101910152A (zh) * 2007-11-16 2010-12-08 因塞特公司 作为janus激酶抑制剂的4-吡唑基-n-芳基嘧啶-2-胺和4-吡唑基-n-杂芳基嘧啶-2-胺

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3697787A4 (fr) * 2017-10-18 2022-12-14 HK inno.N Corporation Composé hétérocyclique à utiliser en tant qu'inhibiteur de protéine kinase
CN110724137A (zh) * 2019-11-13 2020-01-24 广东工业大学 一种噻吩类衍生物及其制备方法与应用

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