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WO2014075318A1 - Pyrimidine compounds and use thereof - Google Patents

Pyrimidine compounds and use thereof Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
piperidine
pyrimidinyl
substituted
furo
group
Prior art date
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PCT/CN2012/084846
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French (fr)
Chinese (zh)
Inventor
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/en
Publication of WO2014075318A1 publication Critical patent/WO2014075318A1/en

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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

Disclosed in the present invention are compounds of general formula (I) and pharmaceutically acceptable equivalents or salts thereof, and the use of the compounds as a Janus kinase inhibitor for application in a variety of medicinal uses.

Description

嘧啶类化合物及其应用 技术领域：  Pyrimidine compounds and their applications
本发明涉及生物医药领域， 具体涉及嘧啶类化合物和药学上可接受的等价物或盐， 及 其制备方法和作为 Janus激酶抑制剂的用途。 背景技术：  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:
蛋白激酶由一系列结构上相关的酶组成，主要负责细胞内信号转导过程的控制。通常， 蛋白激酶通过影响从核苷三磷酸向参与信号传导途径的蛋白受体的磷酰基转移，而介导胞 内信号。这些磷酸化事件起到调制或调节目标蛋白生物功能的分子开关作用。很多疾病都 与通过上述蛋白激酶介导的事件所引发的异常细胞反应有关。  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激酶 (JAK)， 包括 JAK1， JAK2, JAK3和 TYK2属于细胞质蛋白激酶， 与 I型 和 II型细胞因子受体作用， 调节细胞因子信号转导。 JAK1， JAK2和 TYK2可以抑制多种 基因表达， 然而 JAK3仅在粒细胞中发挥作用。细胞因子受体的典型功能是作为异二聚体 形式存在， 因此通常不是一种 JAK激酶与细胞因子受体作用。  Janus kinase (JAK), including JAK1, JAK2, JAK3 and TYK2, 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.
JAK家族的下游底物包括转录蛋白的信号转导剂和激活剂 (STAT)。 JAK/STAT信号转 导涉及很多异常免疫反应，如变态反应，哮喘， 自身免疫病如移植排斥，类风湿性关节炎， 肌肉縮性侧索硬化和多发性硬化以及实体和血液恶性肿瘤如白血病， 淋巴瘤。  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.
遗传生物学研究表明， JAK1通过与 IFNalpha, IFNgamma, IL-2, IL-6等细胞因子受 体作用而发挥作用， JAK1敲除小鼠由于 LIF受体信号缺失而死亡。 观察 JAK1敲除小鼠 的特征组织， 发现 JAK1在 IFN， IL-10, IL-2/IL-4, 和 IL-6等细胞通路中起重要作用。  Genetic biology studies have shown that 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.
遗传生物学研究表明， JAK2与单链， IL-3和干扰素 γ细胞因子受体家族之间存在联 系。 与此相对应， JAK2敲除小鼠死于贫血。 激酶介导的 JAK2变异与人体骨髓增生紊乱 相关， 包括真性红细胞增多， 自发性血小板增多， 慢性特发性骨髓纤维化， 伴有骨髓纤维 化的骨髓性组织转化， 慢性特骨髓性白血病， 慢性骨髓单核细胞性白血病等。  Genetic biology studies have shown a link between JAK2 and the single-stranded, IL-3 and interferon gamma cytokine receptor families. Correspondingly, 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特异性的作用于 γ细胞因子受体链， 它在 IL-2， IL-4, IL-7, IL-9, IL-15, IL-21 等细胞因子受体中存在。 JAK3在淋巴细胞生长， 增生， 变异过程中起到重要作用， 发生 异常可以导致严重的免疫缺失。 基于其调节淋巴细胞的作用， JAK3以及 JAK3介导的通 路用于调节免疫抑制的适应症。 JAK3在很多异常免疫应答的介导中有牵连，如变态反应， 哮喘， 自身免疫疾病如抑制移植排斥， 类风湿性关节炎， 肌肉縮性侧索硬化和多发性硬化 以及实体和血液恶性肿瘤如白血病， 淋巴瘤。 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作用于 I型干扰素， IL-6， IL-10, IL-12, IL-23等细胞因子受体复合物。 与之 相一致的是， 衍生于 TYK2缺失的人的初级细胞， 在 I型干扰素， IL-6， IL-10, IL-12, IL-23的信号传导中存在障碍。  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.
综上所述， 迫切需要开发出可用于蛋白激酶抑制剂的化合物， 确切的说， 需要开发可 用于 JAK家族激酶抑制剂的化合物。 本发明的新化合物可以抑制一种或多种 JAK激酶， 因此预期可用于治疗与之相关的疾病。 发明内容： 本发明的目的在于提供一类新的嘧啶类化合物。  In summary, there is an urgent need to develop compounds that can be used for protein kinase inhibitors, and more specifically, to develop compounds that can be used in JAK family kinase inhibitors. The 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. SUMMARY OF THE INVENTION It is an object of the present invention to provide a new class of pyrimidine compounds.
本发明的目的可以通过以下措施达到：  The object of the invention can be achieved by the following measures:
一类嘧啶类化合物， 如结构通式 （I) 化合物及其药学上可接受的等价物或盐：  A class of pyrimidine compounds, such as structural formula (I) compounds and pharmaceutically acceptable equivalents or salts thereof:
Figure imgf000003_0001
Figure imgf000003_0001
式 （I )  Formula (I)
其巾 : Its towel :
R1为任意取代的烷基、 环烷基、 酰基、 磺酰基； R 1 is an optionally substituted alkyl group, a cycloalkyl group, an acyl group or a sulfonyl group;
R2为氢、 卤素、 C1-C6直链或支链烷基、 环烷基、 卤代 C1-C6直链或支链烷基； R3为氢、 卤素； R 2 is hydrogen, halogen, C1-C6 straight or branched alkyl, cycloalkyl, halogenated C1-C6 straight or branched alkyl; R 3 is hydrogen, halogen;
或者 R2与 R3以及与连接它们的碳原子一起形成一个 5元的杂芳环； Or R 2 and R 3 together with the carbon atom to which they are attached form a 5-membered heteroaryl ring;
Z独立的选自 N、 CR4; Z is independently selected from N, CR 4 ;
n为 0-3整数；  n is an integer of 0-3;
R4独立地选自氢、 卤素、 R5、 OR5、 OH、 R6、 CN、 CF3、 （CH2)nN(R5)2、 N02、 R5R6 OR5R6或者两个 R4取代基与它们连接的碳原子共同形成饱和或不饱和的 5或 6 元杂环基； R5是氢、取代或未取代的 C1-C4烷基、或者取代或未取代的 C1-C4亚烷基、其中 至多两个碳原子可以任选地被 CO、 S、 S02、 或 0替代； 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 ;
R6是 NH2、 NHR5、 N(R5)2、 N(R4)2、 取代或未取代的吗啉基、 取代或未取代的硫 代吗啉基、 取代或未取代的哌嗪基、 取代或未取代的哌啶基、 取代或未取代的吡咯烷 基、 取代或未取代的吡咯基、 取代或未取代的噁唑基， 取代或未取代的咪唑基； 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;
本发明的目的还在于提供新的嘧啶类化合物的用途，具体地说是作为 Janus激酶抑制 剂的用途。 It is also an object of the present invention to provide the use of novel pyrimidine compounds, in particular as Janus kinase inhibitors.
发明详述 Detailed description of the invention
烷基表示具有所述数目之碳原子的未经取代或经取代的直链或支链饱和烃基。典型的 烷基包括（但不限于） 甲基、 乙基、 正丙基、异丙基、 正丁基、异丁基、 叔丁基、 正戊基、 异戊基、 新戊基、 正己基、 异己基、 3-甲基庚基、 2，2-二甲基丁基和 2，3-二甲基丁基。  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.
环烷基表示全部为碳的单环、 稠合、 螺环或桥环的环。 典型地为环丙烷、 环丁烷、 环 戊烷、 环戊烯、 环己烷、 螺 [3.4]辛烷、 二环 [3.1.1]己烷。  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.
亚烷基表示本身或作为另一取代基的部分，系指具有两个终端单价基中心之直链饱和 或不饱和烷二基， 其从直链母烷、 烯或块的两个终端碳原子各移除一个氢原子而得。 典型 的亚烷基包括（但不局限于）亚甲基、 亚乙基、 亚乙烯基、 亚乙块基、 亚丙基、 亚丁基等。  An 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.
饱和的杂环基即杂环烷基，表示含 1个或多个N、 0或 S的杂原子的单环或稠合的环。 典型地为含 1个或多个N、 0或 S的杂原子的 5-6元杂环基， 例如哌嗪子基、 吗啉代基、 哌啶子基、 吡咯烷基及其衍生物。  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.
哌嗪子基指的是具有以下化学结构的基 。  Piperazinolide refers to a group having the following chemical structure.
Figure imgf000004_0001
Figure imgf000004_0001
吗啉代基指的是具有以下化学结构的基 。
Figure imgf000004_0002
哌啶子基指的是具有以下化学结构的基团。
Figure imgf000005_0001
吡咯烷基指的是具有以下化学结构的基团。 Morpholino group refers to a group having the following chemical structure.
Figure imgf000004_0002
Piperidino group refers to a group having the following chemical structure.
Figure imgf000005_0001
Pyrrolidinyl refers to a group having the following chemical structure.
0 N 不饱和的杂环基即杂芳基， 表示 5至 12个环原子的单环或稠合环基团， 含有一个、 两个、 三个或四个选 g N、 0或 S的环杂原子， 其余环原子是 C， 另外具有完全共轭的 π 电子系统。 典型的杂芳基 （但不局限于） 吡咯、 呋喃、 噻吩、 咪唑、 噁唑、 噻唑、 吡唑、 嘧啶、 吡啶。  0 N Unsaturated heterocyclic group, ie 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 π-electron system. Typical heteroaryl groups (but not limited to) pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, pyridine.
卤素或卤素基团为氟、 氯、 溴或碘。 优选为氟、 氯、 溴。 被卤素取代的 Cr3烷基基团 表示其中 1个或多个氢被卤素置换的烷基， 优选含一个、 两个或三个卤素基团。 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.
在一种优选方案中， R1为：
Figure imgf000005_0002
， 其中 R7为 C1-6直 链或支链烷基、 -CN、 -NHS02R12、 -NHOH、 -NHCOR12、 -CON(R12)2、 -N(R12)2、 -OR12、 In a preferred embodiment, R 1 is:
Figure imgf000005_0002
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^为^-6直链或支链烷基、 C3-C7环烷基、 或 R9、 R1U或 R11相同或不同， 各自独立选自卤素、 氢、 C1-C6直链或支链烷 基、
Figure imgf000005_0003
C3-C7环烷基、 ； R12选自氢、 -CN、 -NHS02R5、卤素、 -N(R5)2、-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,
Figure imgf000005_0003
C3-C7 cycloalkyl, R 12 is selected from the group consisting of hydrogen, -CN, -NHS0 2 R 5 , halogen, -N(R 5 ) 2 ,
-OR5、 -CF3或 C1-C3直链或支链烷基； X选自 S、 NH或 0; m为 0-3整数, -OR 5 , -CF 3 or C1-C3 straight or branched alkyl; X is selected from S, NH or 0; m is 0-3 integer,
种优选方案中， R1为 ， 其中 R' 为 C1-C4直链或支链烷基、 -CN、 支链烷基; In a preferred embodiment, R 1 is, wherein R' is a C1-C4 linear or branched alkyl group, -CN, a branched alkyl group;
R9、 R1Q或 R11相同或不同， 各自独
Figure imgf000005_0004
立选自卤素、 氢或 R12选自 -CN或氢； X 为 S; m 为 0或 1。 作为一种优选， 在上述方案中， R7为 -CN、 或~^； R 9 , R 1Q or R 11 are the same or different, each
Figure imgf000005_0004
The halogen is selected from halogen, hydrogen or R 12 is selected from -CN or hydrogen; X is S; m is 0 or 1. As a preferred example, in the above scheme, R 7 is -CN, or ~^;
R8为甲基； R9或 R1Q为氢； R11为
Figure imgf000006_0001
； R12为 -CN或氢； X为 S; m为 0或 1。 R 8 is a methyl group; R 9 or R 1Q is hydrogen; R 11 is
Figure imgf000006_0001
; R 12 is -CN or hydrogen; X is S; m is 0 or 1.
在一种技术方案中， R2为氢、 卤素、 C1-C4直链或支链烷基或卤代 C1-C4直链或支 链烷 3为氢； 或者 R2、 R3 与连接它们的碳原子一起组成以下杂环：
Figure imgf000006_0002
In one embodiment, 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 carbon atoms together make up the following heterocycles:
Figure imgf000006_0002
作为一种优选， 本发明提供的结构如式 （ I ) 所示的化合物中， R2 氢、 -F、 -CH3、 As a preferred embodiment, the present invention provides a structure of the compound represented by the formula (I), R 2 hydrogen, -F, -CH 3 ,
-CF3、 R3为氢； 或者 R2、 R3与连接它们的碳原子一起组成以下杂环：
Figure imgf000006_0003
; -CF 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:
Figure imgf000006_0003
;
在一种优选的技术方案中， Z为 CR4。 In a preferred embodiment, Z is CR 4 .
在一种优选的技术方案中， R4为氢、 卤素、 -N02、 -OH、 C1-C6直链或支链烷氧基、 取代或非取代的饱和或不饱和的 5或 6元饱和或不饱和杂环基或 -OR5R6 ; R5是取代或未 取代的 C1-C3亚烷基； R6是 NH2、 C1-C6直链或支链烷氨基、 取代或未取代的吗啉基、 取代或未取代的硫代吗啉基、取代或未取代的哌嗪基、取代或未取代的哌啶基、取代或未 取代的吡咯烷基、取代或未取代的吡咯基、取代或未取代的噁唑基、取代或未取代的咪唑 基； R4、 R5和 R6中的取代基分别独立地为卤素、 羟基、 C1-C6直链或支链烷基、 羟基取 代的 C1-C6直链或支链烷基、 C3-C7环烷基、 C3-C7环烷甲酰基、 二恶烷基或哌啶基。 In a preferred embodiment, 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 imidazolyl group; the substituents in R 4 , R 5 and R 6 are each independently halogen, hydroxy, C1-C6 straight or branched alkyl, hydroxy substituted A C1-C6 linear or branched alkyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkylene group, a dioxoalkyl group or a piperidinyl group.
作为一种优选， R4为氢、 -F、 -N02、 -OH、 C1-C4 直链或支链烷氧基、 吡咯烷基、 C1-C6烷基取代的吡咯烷基、 哌啶基、 C1-C6烷基取代的哌啶基、 哌嗪基、 C1-C6烷基取 代的哌嗪基、 吗啉基、 C1-C6 烷基取代的吗啉基、 咪唑基、 C1-C6 烷基取代的咪唑基或Preferably, 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
-OR'R' -OR'R'
作为一种优选， R4进一步为氢、 -F、 -N02、 -OH、 -OCH3、
Figure imgf000006_0004
Figure imgf000006_0005
。 在一种优选的技术方案中， R5为 ^^ ^或 Preferably, R 4 is further hydrogen, -F, -N0 2 , -OH, -OCH 3 ,
Figure imgf000006_0004
Figure imgf000006_0005
. In a preferred technical solution, R 5 is ^^ ^ or
在一种优选的技术方案中， R6是取代或未取代的吗啉基、 取代或未取代的硫代吗啉 基、取代或未取代的哌嗪基、取代或未取代的哌啶基、取代或未取代的吡咯烷基、取代或 未取代的吡咯基、 取代或未取代的噁唑基、 取代或未取代的咪唑基； 所述取代基为羟基、 C1-C6直链或支链烷基、 羟基取代的 C1-C6直链或支链烷基、 C1-C6烷基酰基、 C3-C7 环烷甲酰基或哌啶基 In a preferred embodiment, 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.
Figure imgf000007_0001
Figure imgf000007_0001
在一种优选的技术方案中， n为 0、 1或 2。 其中优选当 n为 1时， R4为苯环上氨基 的对位取代基； 当 n为 2时， R4为苯环上氨基的间位和对位取代基。 式 (I) 的嘧啶类化合物的具体实例包括下表所列的那些化合物: In a preferred embodiment, n is 0, 1 or 2. Preferably, when n is 1, 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:
- I - - I -
Figure imgf000008_0001
t8丽 ZIOZXD/工：) d 8TCS.0/M0Z OAV
Figure imgf000008_0001
T8丽ZIOZXD/工:) d 8TCS.0/M0Z OAV
Figure imgf000009_0001
Figure imgf000009_0001
本发明还提供了一种用于治疗有机体中 JAK激酶相关疾病的药用组合物， 包括本发 明提供的上述各化合物和药学上可接受的载体、 赋形剂或稀释剂。  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.
药学上可接受的盐表示保留母体化合物的生物有效性和性质的那些盐。其中与酸成盐 是指，通过母体化合物的游离碱与无机酸或有机酸的反应而得。无机酸包括盐酸、氢溴酸、 硝酸、 磷酸、 偏磷酸、硫酸、 亚硫酸和高氯酸等。 有机酸包括乙酸、 丙酸、 丙烯酸、 草酸、 (D) 或 （L) 苹果酸、 富马酸、 马来酸、 羟基苯甲酸、 γ-羟基丁酸、 甲氧基苯甲酸、 邻苯 二甲酸、 甲磺酸、 乙磺酸、 萘 -1-磺酸、 萘 -2-磺酸、 对甲苯磺酸、 水杨酸、 酒石酸、 柠檬 酸、 乳酸、 扁桃酸、 琥珀酸或丙二酸等。  Pharmaceutically acceptable 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, γ-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.
药用组合物指的是一种或多种本发明化合物或者它们的药学上可接受的盐和前药与 其它的化学成分， 包括药学上可接受的载体和赋形剂的混合物。 药用组合物的目的是促进 化合物对生物体的给药。  Pharmaceutical 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.
药学上可接受的载体指的是对有机体不引起明显的刺激性和不干扰所给予化合物的 生物活性和性质的载体或稀释剂。  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.
赋形剂指的是加入到药用组合物中以进一步便利于给予化合物的惰性物质。赋形剂的 实例包括（不局限于）碳酸钙、 磷酸钙、 多种糖类和多种类型的淀粉、 纤维素衍生物、 明 胶、 植物油和聚乙二醇。 本发明还涉及具有通式 （I) 的制备方法， 其特征在于， 包括， Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound. Examples of 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
1. (a) 胺片段 （III) 与取代羧酸 （Π) 在溶剂 Si中碱 催化剂 d、 縮合剂 存在下 在温度 1 条件下反应生成化合物 （1)。 1. (a) Amine fragment (III) and substituted carboxylic acid (Π) are reacted in the presence of a condensing agent in the solvent Si in the presence of a condensing agent to form a compound (1) at a temperature of 1.
Figure imgf000010_0001
Figure imgf000010_0001
(b) 胺片段 （III) 与取代酰氯 （Π) 在溶剂 S2中碱 B2存在下在温度 T2条件下反应 生成化合物 （1)。 (b) The amine fragment (III) is reacted with a substituted acid chloride (Π) in the presence of a base B 2 in a solvent S 2 at a temperature T 2 to give a compound (1).
Figure imgf000010_0002
Figure imgf000010_0002
为了制备本发明通式 （I) 中所述的化合物， 所述的制备方法， 其特征在于， 在制备 过程中， 所述的溶剂 Si选自有机溶剂， 如二氯甲烷、 乙酸乙酯， 优选为二氯甲烷； 所述 的碱 ^选自有机碱， 如三乙胺、 N-乙基二异丙胺， 优选为三乙胺； 所述的催化剂 可以 对二甲氨基吡啶、 4-吡咯烷基吡啶、 1-羟基苯并三唑、三丁基膦， 优选为 1-羟基苯并三唑； 縮合剂 1^为碳酰二咪唑、 二环己基碳二亚胺、 1-乙基- (3-二甲基氨基丙基） 碳二亚胺， 优选为 1-乙基- (3-二甲基氨基丙基） 碳二亚胺； 温度 为-15-15 ° 优选为 0 °C。  In order to prepare the compound of the formula (I) of the present invention, 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 °, preferably 0 °C.
本发明还提供了新的嘧啶类衍生物的用途，具体地说是作为 Janus激酶抑制剂的用途。 其中包括但不局限于， 真性红细胞增多， 自发性血小板增多， 慢性特发性骨髓纤维化， 伴 有骨髓纤维化的骨髓性组织转化， 慢性特骨髓性白血病， 慢性骨髓单核细胞性白血病， 变 态反应， 哮喘， 自身免疫疾病如抑制移植排斥， 类风湿性关节炎， 肌肉縮性侧索硬化和多 发性硬化以及实体和血液恶性肿瘤如白血病， 淋巴瘤等。  The invention also provides for the use of novel pyrimidine derivatives, in particular as Janus kinase inhibitors. These 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.
发明还提供了上述各化合物在制备治疗 JAK2、 JAK3介导的病症药物方面的应用，包 括向需要此类治疗的系统或个体施用有效量的本发明中任一所定义的化合物或其药物组 合物， 从而治疗所述病症。  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.
为了检验本发明提供的化合物对于 JAK激酶的作用水平， 采用生化水平酶活性测试 来确定本发明的各种化合物对一种或多种 PK的活性和作用水平。使用工艺中熟知的方法， 对于任何激酶均可按照同样的方式设计类似的实验。 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.
在生化水平酶活性测试中， 利用 HTRF技术检测酪氨酸激酶的活性， HTRF是一种时 间分辨荧光共振能力转移技术。 HTRF (均相时间分辨荧光)是用来检测均相体系中待测物的 一种最常用的方法， 这种技术结合了荧光共振能量转移 (FRET) 和时间分辨技术 (TR)， 已 经被广泛应用于基于细胞实验和生化实验的药物研发的不同阶段。根据 HTRF法的测定原 理，将纯酶 JAK2与生物素化的底物以及 ATP—起孵育反应后，加入亲和素标记的 XL-665 和识别底物磷酸化的 Eu标记的抗体， 当底物被 JAK2磷酸化后， Eu标记的抗体即可以识 别该磷酸化产物， 与亲和素标记的 XL665 形成时间分辨的荧光共振能量转移 （FRET), 而未被磷酸化的底物由于不能被抗体识别而无法形成 FRET信号，通过测定 665 nm和 620 nm的荧光信号差值测定待测物在不同浓度下对 JAK2、 JAK3激酶的抑制活性。 因而， 采 用此法可测定本发明化合物对上述酪氨酸激酶的生化水平的活性作用， 同时利用本领域熟 知的方法， 可以对其它蛋白激酶使用相似的测定方法。  In the biochemical level enzyme activity test, HTRF technology is used to detect the activity of tyrosine kinase, and HTRF is a time-resolved fluorescence resonance ability transfer technique. HTRF (Homogeneous Time-Resolved Fluorescence) is one of the most commonly used methods for detecting analytes in homogeneous systems. This technique combines fluorescence resonance energy transfer (FRET) and time-resolved (TR) techniques and has been widely used. It is applied to different stages of drug development based on cell experiments and biochemical experiments. According to the measurement principle of HTRF method, after the pure enzyme JAK2 is incubated with the biotinylated substrate and ATP, the avidin-labeled XL-665 and the substrate-phosphorylated Eu-labeled antibody are added as the substrate. Upon phosphorylation by JAK2, 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. 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. Thus, 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.
本发明制备的结构如式 I 所示的化合物对多种激酶活性具有很好的抑制作用， 其对 JAK2、 JAK3激酶的半数抑制浓度 （IC5Q) 普遍在 10—7 mol.L- 1以下。 由此推知， 本发明具 有式 I结构的化合物可应用于制备治疗有机体中 JAK激酶相关疾病的药物。 Preparation of the compounds of the present invention as shown in Formula I having a more excellent inhibitory effect on kinase activity, which inhibitory concentration (IC 5Q) common in 10- 7 mol.L- 1 Hereinafter, JAK2, JAK3 kinase half. It is thus inferred that the compounds of the present invention having the structure of formula I are useful for the preparation of a medicament for treating JAK kinase-associated diseases in an organism.
具体实施方法： Specific implementation method:
本发明公开了一种化合物及其制备方法、该化合物的中间体及其制备方法， 及其该化 合物作为 JAK激酶抑制剂的应用， 本领域技术人员可以借鉴本文内容， 适当改进工艺参 数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的， 它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述， 相关 人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当 变更与组合， 来实现和应用本发明技术。  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.
下面结合实施例， 进一步阐述本发明：  The present invention will be further explained below in conjunction with the embodiments:
实施例 1: 化合物 1的制备
Figure imgf000012_0001
Example 1: Preparation of Compound 1
Figure imgf000012_0001
1-苄基 -4-三丁基锡-呋喃并 [3,2-c] 哌啶  1-benzyl-4-tributyltin-furo[3,2-c] piperidine
氮气保护下， 向反应瓶中加入 1-苄基-呋喃并 [3，2-c] 哌啶 （11.2mg， leq)和干燥四氢呋 喃（150 μ L)，冰浴条件下滴加正丁基锂（16.05 μ L， leq),继续滴加三丁基氯化锡（20.8mg， 1.6eq)， 滴加完毕， 继续反应 2.5小时。 停止反应， 加水淬灭， 乙酸乙酯 （10 mL*5 ) 萃 取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮， 粗品硅胶柱层析得到 1-苄基 -4-三丁基 锡-呋喃并 [3，2-c] 哌啶 （19.25mg) . Under a nitrogen atmosphere, 1-benzyl-furo[3,2-c]piperidine (11.2 mg, leq) and dry tetrahydrofuran (150 μL) were added to the reaction flask, and n-butyllithium was added dropwise under ice bath. (16.05 μL, leq), tributyltin chloride (20.8 mg, 1.6 eq) was added dropwise, and the reaction was continued for 2.5 hours. The reaction was quenched, quenched with EtOAc EtOAc (EtOAc) Furo[3,2-c] piperidine (19.25 mg).
1-苄基 -4- (3-氯 -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 1-benzyl-4-(3-chloro-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
向反应瓶中加入 1-苄基 -4-三丁基锡-呋喃并 [3，2-c] 哌啶 （3.2mg， leq), 2，4-二氯 -5-甲基 -嘧啶 （0.97mg， leq), Pd(PPh3)2Cl2 (0.42mg， O.leq) 和 DMF (5mL)， 80度加热反应 5 小时。 停止反应， 加水 （5 mL)， 二氯甲烷 （5 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干 燥， 抽滤， 浓縮， 粗品硅胶柱层析得到 1-苄基 -4- (3-氯 -6-甲基) 嘧啶基-呋喃并 [3,2-c] 哌啶 （0.47mg) . To the reaction flask was added 1-benzyl-4-tributyltin-furo[3,2-c]piperidine (3.2 mg, leq), 2,4-dichloro-5-methyl-pyrimidine (0.97 mg, Leq), Pd(PPh 3 ) 2 Cl 2 (0.42 mg, O.leq) and DMF (5 mL) were heated at 80 °C for 5 hours. The reaction was stopped, water (5 mL), dichloromethane (5 mL*5) was evaporated, evaporated, evaporated, evaporated. 3-Chloro-6-methyl)pyrimidinyl-furo[3,2-c]piperidine (0.47 mg).
1—苄基—4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 向微波瓶中加入 3，5-二氟 -4-吗啉基苯胺 （347.0mg， l.leq), 1-苄基 -4- (3-氯 -6-甲基） 嘧 啶基-呋喃并 [3,2-c] 哌啶 ( 500.0mg， leq), 二氧六环的盐酸溶液 (6.6M) (668 L), 碘化钾（97mg， 0.4eq)和三氟乙醇（5mL)， 于微波下 145 °C反应 1小时。加水（20 mL)， 饱和 NaHC03水溶液洗， 二氯甲烷 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽 滤， 浓縮， 粗品硅胶柱层析得到 1-苄基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基）嘧啶 基-呋喃并 [3，2-c] 哌啶 （723.6mg)。 1-benzyl-4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine into a microwave vial Add 3,5-difluoro-4-morpholinylaniline (347.0 mg, l.leq), 1-benzyl-4-(3-chloro-6-methyl)pyrimidinyl-furo[3,2- c] Piperidine (500.0mg, leq), dioxane in hydrochloric acid (6.6M) (668 L), potassium iodide (97mg, 0.4eq) and trifluoroethanol (5mL), reacted at 145 °C in the microwave 1 hour. Water was added (20 mL), washed with saturated aqueous NaHC0 3, (10 mL * 5) was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and the crude product by silica gel column chromatography to give 1-benzyl - 4-(3-(3,5-Difluoro-4-morpholinanilide)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine (723.6 mg).
4- (3- (3,5二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  4-(3-(3,5-Difluoro-4-morpholinanilinyl)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
向反应瓶中加入 1-苄基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶 （300.0mg， leq)， 氯甲酸 -1-氯乙酯 （125 L， 2eq)， 三乙胺 （80.75 L) 和二氯甲 烷 （9mL)， 室温搅拌 7小时， 浓縮反应液， 加入甲醇 （10mL)， 60度加热反应 2小时， 冷至室温， 有固体析出， 抽滤， 用少量甲醇洗涤得 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6- 甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 (157.9mg)。 Add 1-benzyl-4-(3-(3,5-difluoro-4-morpholinanilinyl)-6-methyl)pyrimidinyl-furo[3,2-c] to the reaction flask. Piperidine (300.0 mg, leq), 1-chloroethyl chloroformate (125 L, 2 eq), triethylamine (80.75 L) and dichloromethane (9 mL), stirred at room temperature for 7 hr. Methanol (10 mL), heated at 60 °C for 2 hours, cooled to room temperature, solid precipitated, suction filtered, washed with a small amount of methanol to give 4-(3-(3,5-difluoro-4-morpholinylanilide)- 6-Methyl)pyrimidinyl-furo[3,2-c]piperidine (157.9 mg).
1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 向反应瓶中加入 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌 啶 （108mg， leq)， 氰基乙酸 （42.84mg， 2eq)， 1-羟基-苯并-三氮唑 （85.11mg， 2.5eq)， 1-乙基 -3-(3-二甲胺丙基)碳二亚胺盐酸盐（120.77mg， 2.5eq)， 催化量的 DIPEA和二氯甲 烷 （20mL)， 室温反应 4小时， 电磁搅拌。 停止反应， 加水 （20 mL)， 饱和 NaHC03水 溶液洗， 二氯甲烷 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮， 粗品 硅胶柱层析得到 1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并1-cyanoyl-4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine to reaction flask 4-(3-(3,5-Difluoro-4-morpholinanilinyl)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine (108 mg, leq), cyanide Acetic acid (42.84 mg, 2 eq), 1-hydroxy-benzo-triazole (85.11 mg, 2.5 eq), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (120.77 mg, 2.5 eq), a catalytic amount of DIPEA and dichloromethane (20 mL) were reacted at room temperature for 4 hours with electromagnetic stirring. The reaction was stopped, water (20 mL), washed with saturated aqueous NaHC0 3, (10 mL * 5). The combined methylene chloride organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and the crude product on silica gel column chromatography to give 1- Nitrile acyl-4-(3-(3,5-difluoro-4-morpholinanilinyl)-6-methyl)pyrimidinyl-furan
[3,2-c] 哌啶 （66.0mg)。 [3,2-c] Piperidine (66.0 mg).
MS: [M+H]+ = 495.0. MS: [M+H] + = 495.0.
1H-NMR (500 M， DMSO- e) δ 9.85 (s， 1H)， 8.42 (s， 1H)， 7.59-7.62 (d， 2H), 7.18-7.27 (d， 1H), 4.54 (s， 2H), 4.18-4.23 (d， 2H), 3.70 (s， 6H)， 3.05 (s， 6H),2.38 (s， 3H) ppm。  1H-NMR (500 M, DMSO-e) δ 9.85 (s, 1H), 8.42 (s, 1H), 7.59-7.62 (d, 2H), 7.18-7.27 (d, 1H), 4.54 (s, 2H) , 4.18-4.23 (d, 2H), 3.70 (s, 6H), 3.05 (s, 6H), 2.38 (s, 3H) ppm.
实施例 2: 化合物 2的制备
Figure imgf000013_0001
Example 2: Preparation of Compound 2
Figure imgf000013_0001
4-氯 -N-苯基 -7-对甲苯磺酰基 -7H-吡咯 [2,3-d] 嘧啶 -2-胺  4-chloro-N-phenyl-7-p-toluenesulfonyl-7H-pyrrole [2,3-d]pyrimidine-2-amine
向反应瓶中加入 4-氯 -7-对甲本磺酰基 7H-B比咯 [2，3-d]嘧啶 -2-胺 （322.0mg， leq)， 碘代 苯（204.1mg， leq), Pd(OAC)2 ( 16.2mg， O.leq), Cs2C03 ( 32.5mg, O.leq)和二恶烷（5mL)， 110度反应， 电磁搅拌。 停止反应， 加水 （5 mL)， 二氯甲烷 （5 mL*5 ) 萃取， 合并有机 相，无水硫酸钠干燥，抽滤，浓縮，粗品硅胶柱层析得到 4-氯 -N-苯基 -7-对甲苯磺酰基 -7H- 吡咯 [2,3-d] 嘧啶 -2-胺 ( 367.0mg) o To the reaction flask was added 4-chloro-7-p-methylsulfonyl 7H-B than [2,3-d]pyrimidin-2-amine (322.0 mg, leq), iodobenzene (204.1 mg, leq), Pd(OAC) 2 ( 16.2 mg, O.leq), Cs 2 C0 3 (32.5 mg, O.leq) and dioxane (5 mL), 110 degree reaction, electromagnetic stirring. The reaction was quenched, water (5 mL), EtOAc (EtOAc m. -7-p-toluenesulfonyl-7H-pyrrole [2,3-d]pyrimidin-2-amine ( 367.0 mg) o
1-苄基 -4- (3-苯胺基 -5-对甲苯磺酰基吡咯并 [4,3-b] 嘧啶基） -呋喃并 [3,2-c] 哌啶 向反应瓶中加入 1-苄基 -4-三丁基锡-呋喃并 [3，2-c] 哌啶 （502.0mg， leq)， 4-氯 -N-苯基 -7-对甲苯磺酸 -7H-吡咯 [2，3-d]嘧啶 -2-胺（398.8mg， leq), Pd(PPh3)2Cl2 (70.1mg, O.leq) 禾口 DMF ( lOmL), 95度加热反应 2小时。 停止反应， 加水 （5 mL)， 二氯甲烷 （5 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮， 粗品硅胶柱层析得到 1-苄基 -4- (3- 苯胺基 -5-对甲苯磺酰基吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶 (532.7mg)。 1-benzyl-4-(3-anilino-5-p-toluenesulfonylpyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine To the reaction flask was added 1-benzyl-4-tributyltin-furo[3,2-c]piperidine (502.0 mg, leq), 4-chloro-N-phenyl-7-p-toluenesulfonic acid-7H -pyrrole [2,3-d]pyrimidin-2-amine (398.8 mg, leq), Pd(PPh 3 ) 2 Cl 2 (70.1 mg, O.leq) and DMF (10 mL), heated at 95 °C for 2 hours . The reaction was stopped, water (5 mL), dichloromethane (5 mL*5) was evaporated, evaporated, evaporated, evaporated. 3-anilino-5-p-toluenesulfonylpyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine (532.7 mg).
4- (3-苯胺基 -5-对甲苯磺酰基吡咯并 [4,3-b ]嘧啶基） -呋喃并 [3,2-c] 哌啶 4-(3-anilino-5-p-toluenesulfonylpyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine
向反应瓶中加入 1-苄基 -4- (3-苯胺基 -5-对甲苯磺酰基吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3,2-c] 哌啶 （120mg， leq), 氯乙酸 -1-氯乙酯 (34 L, 1.5eq)， 二氯甲烷 5mL， 室温 反应 1小时， 浓縮反应液， 加入甲醇 5mL， 升温至回流反应 2小时， 电磁搅拌。 停止反 应， 加水 （10 mL)， 二氯甲烷 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮， 粗品硅胶柱层析得到 4- (3-苯胺基 -5-对甲苯磺酰基吡咯并 [4，3-b] 嘧啶基） -呋喃 并 [3,2-c] 哌啶 (43.0mg) o To the reaction flask was added 1-benzyl-4-(3-anilino-5-p-toluenesulfonylpyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine (120 mg) , leq), chloroacetic acid-1-chloroethyl ester (34 L, 1.5 eq), dichloromethane (5 mL), and reacted at room temperature for 1 hour. The reaction mixture was concentrated, and 5 mL of methanol was added thereto, and the mixture was warmed to reflux for 2 hours, and was stirred magnetically. The reaction was quenched, water (10 mL), dichloromethane (10 mL*5) eluted eluted eluted eluted eluted eluted eluted 5-p-toluenesulfonylpyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine (43.0 mg) o
4- (3-苯胺基吡咯并 [4,3-b] 嘧啶基） -呋喃并 [3,2-c] 哌啶  4-(3-anilinopyrrol[4,3-b]pyrimidinyl)-furo[3,2-c] piperidine
向反应瓶中加入 4- (3-苯胺基 -5-对甲苯磺酰基吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶 （20mg， leq), 甲醇 5mL， 二氯甲烷 2mL， 2MNaOHlmL, 升温至回流， 反应 1小 时， 电磁搅拌。 停止搅拌， 浓縮反应液， 加水 （10 mL)， 二氯甲烷 （10 mL*5 ) 萃取， 合 并有机相，无水硫酸钠干燥，抽滤，浓縮，粗品硅胶柱层析得到 4- (3-苯胺基吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3,2-c] 哌啶 (6.1mg)。 To the reaction flask was added 4-(3-anilino-5-p-toluenesulfonylpyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine (20 mg, leq), methanol 5 mL, 2 mL of dichloromethane, 1 M NaOH 1 mL, warmed to reflux, reacted for 1 hour, and stirred magnetically. Stirring was continued, the reaction mixture was concentrated, EtOAc (EtOAc) (EtOAc) 3-anilinopyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine (6.1 mg).
MS: [M+H]+ = 332.1. MS: [M+H] + = 332.1.
1H-NMR (500 M， DMSO- e) δ 11.52 (s, 1H), 9.20 (s, 1H), 7.89 (d， 2H), 7.29-7.19 (m， 4H): 6.88 (t， 1H), 6.75 (d， 1H), 3.71 (s， 2H), 3.05 (t， 2H), 2.72(s, 2H) ppm。 1H-NMR (500 M, DMSO-e) δ 11.52 (s, 1H), 9.20 (s, 1H), 7.89 (d, 2H), 7.29-7.19 (m, 4H) : 6.88 (t, 1H), 6.75 (d, 1H), 3.71 (s, 2H), 3.05 (t, 2H), 2.72 (s, 2H) ppm.
Figure imgf000014_0001
Figure imgf000014_0001
1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 1-benzyl-4-(3-(4-morpholinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
向微波瓶中加入 1-苄基 -4- (3-氯 -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 （2.85g， leq), 4- 吗啉苯胺 （1.5g， leq)， 二氧六环的盐酸溶液 （6.6M) (2.8mL， 2.2eq)， 碘化钾 （0.5g， 0.04eq)和三氟乙醇（ 10mL)，于微波下 165 °C反应 2小时。加水（20 mL)，饱和 NaHC03 水溶液洗， 二氯甲烷 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮， 粗 品硅胶柱层析得到 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌 啶 （3.4g)。 Add 1-benzyl-4-(3-chloro-6-methyl)pyrimidinyl-furo[3,2-c]piperidine (2.85 g, leq), 4- Morpholine aniline (1.5g, leq), dioxane in hydrochloric acid (6.6M) (2.8mL, 2.2eq), potassium iodide (0.5g, 0.04eq) and trifluoroethanol (10mL), 165 ° under microwave C reacted for 2 hours. Water was added (20 mL), washed with saturated aqueous NaHC0 3, (10 mL * 5) was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and the crude product by silica gel column chromatography to give 1-benzyl - 4-(3-(4-morpholinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine (3.4 g).
4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  4-(3- (4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
向反应瓶中加入 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 (3.35g, leq)， 氯甲酸 -1-氯乙酯（1.8mL， 2.5eq)， 三乙胺 (2.4mL)和二氯甲烷（80mL)， 室温搅拌 7小时， 浓縮反应液， 加入甲醇 （20mL)， 60度加热反应 2小时， 冷至室温， 有固体析出， 抽滤， 用少量甲醇洗涤得 4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基 -呋喃 并 [3,2-c] 哌啶 (2.34g)。 To the reaction flask was added 1-benzyl-4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine (3.35 g, leq) , 1-chloroethyl chloroformate (1.8 mL, 2.5 eq), triethylamine (2.4 mL) and dichloromethane (80 mL), stirred at room temperature for 7 hr, concentrated, and then added to methanol (20 mL) The reaction was heated for 2 hours, cooled to room temperature, and solid was precipitated, suction filtered, and washed with a small amount of methanol to give 4-(3-(4-morpholinylanilinyl)-6-methyl)pyrimidinyl-furo[3,2 -c] piperidine (2.34 g).
1-腈基乙酰基 -4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-cyanoacetyl-4-(3-(4-morpholinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 1中 1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基- 呋喃并 [3，2-c]哌啶的合成， 不同之处在于将 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基) 嘧啶基-呋喃并 [3，2-c]哌啶改为 4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
MS: [M+H]+ = 459.2. MS: [M+H] + = 459.2.
1H-NMR (500 M， DMSO- e) δ 9.21-9.22 (d, 1H), 8.28 (s, 1H), 7.64-7.66 (d, 2H), 7.17 (s， 1H)， 6.88-6.90 (d, 2H), 4.51 (s， 1H), 4.43 (s， 1H), 4.19 (s， 1H), 4.14 (s， 1H), 3.85-3.88 (t， 1H)， 3.70-3.74 (m， 5H)， 3.01-3.03 (t, 3H), 2.91-2.92 (m， 2H), 2.79-2.81 (m， lH),2.33(s, 3H)ppm。  1H-NMR (500 M, DMSO-e) δ 9.21-9.22 (d, 1H), 8.28 (s, 1H), 7.64-7.66 (d, 2H), 7.17 (s, 1H), 6.88-6.90 (d, 2H), 4.51 (s, 1H), 4.43 (s, 1H), 4.19 (s, 1H), 4.14 (s, 1H), 3.85-3.88 (t, 1H), 3.70-3.74 (m, 5H), 3.01 -3.03 (t, 3H), 2.91-2.92 (m, 2H), 2.79-2.81 (m, lH), 2.33 (s, 3H) ppm.
Figure imgf000015_0001
Figure imgf000015_0001
1-苄基 -4- (3- (4- N-甲基哌嗪基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 3中 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4-吗啉基苯胺改为 N-甲基哌嗪基苯胺。  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.
4- (3- (4- N-甲基哌嗪基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 3中 4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 的合成，不同之处在于将 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶改为 1-苄基 -4- (3- (4- N-甲基哌嗪基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c]哌啶。 1-腈基乙酰基 -4- (3- (4-N-甲基哌嗪基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 3中 1-腈基乙酰基 -4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶的合成， 不同之处在于将 4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基 -呋喃 并 [3，2-c] 哌啶改为 4- (3- (4- N-甲基哌嗪基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。 4-(3- (4- N-methylpiperazinylanilide)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine 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-Methylpiperazinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine. 1-Nitrile acetyl-4-(3-(4-N-methylpiperazinylanilide)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine preparation method same as the example Synthesis of 3-cyanoacetyl-4-(3-(4-morpholinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in 3 Change 4-(3-(4-morpholinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine to 4-(3-(4-N-methylpiperidine) Pyridazinoanilino-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
MS: [M+H]+ = 472.3. MS: [M+H] + = 472.3.
1H-NMR (400 M， DMSO- e) δ 9.26-9.27 (d, 1H), 8.30 (s, 1H), 7.64-7.67 (d, 2H), 7.16-7.20(d,lH),6.90-6.92(d,2H), 4.44-4.53 (d,2H), 4.17-4.22 (d, 2H),3.86-3.89(t,lH), 3.71-3.74 (t， 1H), 3.11 (s， 4H)， 2.92 (s， 1H), 2.82 (s， 1H)， 2.64 (s， 4H)， 2.34 (s， 6H)ppm。 实施例 5: 化合物 5的制备  1H-NMR (400 M, DMSO-e) δ 9.26-9.27 (d, 1H), 8.30 (s, 1H), 7.64-7.67 (d, 2H), 7.16-7.20 (d, lH), 6.90-6.92 ( d, 2H), 4.44-4.53 (d, 2H), 4.17-4.22 (d, 2H), 3.86-3.89 (t, lH), 3.71-3.74 (t, 1H), 3.11 (s, 4H), 2.92 ( s, 1H), 2.82 (s, 1H), 2.64 (s, 4H), 2.34 (s, 6H) ppm. Example 5: Preparation of Compound 5
Figure imgf000016_0001
Figure imgf000016_0001
1-苄基 -4- (3- (4- (2-吡咯垸 -1-乙氧基）苯胺基） -6-甲基）嘧啶基-呋喃并 [3,2-c]哌啶 制备方法同实施例 3中 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4-吗啉基苯胺改为 2-吡咯烷 -1-乙氧基苯胺。  Preparation method of 1-benzyl-4-(3-(4-(2-pyrrole-1-ethoxy)anilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine Synthesis of 1-benzyl-4-(3-(4-morpholinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine in the same manner as in Example 3, the difference It is to change 4-morpholinylaniline to 2-pyrrolidine-1-ethoxyaniline.
4- (3- (4- (2-吡咯烷 -1-乙氧基）苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 3中 4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 的合成，不同之处在于将 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶改为 1-苄基 -4- (3- (4- (2-吡咯烷 -1-乙氧基）苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶。  4-(3-(4-(2-Pyrrolidin-1-ethoxy)anilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine was prepared in the same manner as in Example 3. Synthesis of 4-(3-(4-morpholinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine, except that 1-benzyl-4-( 3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine was changed to 1-benzyl-4-(3-(4-(2-pyrrole) Alkyl-1-ethoxy)anilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
1-腈基乙酰基 -4- (3- (4- (2-吡咯垸 -1-乙氧基）苯胺基） -6-甲基）嘧啶基-呋喃并 [3,2-c] 哌啶  1-cyanoacetyl-4-(3-(4-(2-pyrrole-1-ethoxy)anilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 1中 1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基- 呋喃并 [3，2-c]哌啶的合成， 不同之处在于将 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基) 嘧啶基-呋喃并 [3,2-c] 哌啶改为 4- (3- (4- (2-吡咯烷 -1-乙氧基） 苯胺基） -6-甲基) 嘧 啶基-呋喃并 [3,2-c] 哌啶。 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.
MS: [M+H]+ = 487.3. MS: [M+H] + = 487.3.
1H-NMR (400 M， CDCls) ^8.23(s, 1H), 7.52-7.54(d, 2H), 7.01-7.06(t, 2H), 6.93-6.95(d, 2H), 4.51-4.64(d, 2H), 4.21-4.22(d, 2H), 3.81-3.84, 4.01-4.04(dt, 2H), 3.04(s, 2H), 2.82-2.91(d, 2H), 2.82(s, 4H)， 2.40(s, 3H), 2.24-2.26(m, 2H), 1.90(s, 4H)ppm。 6: 化合物 6的制备  1H-NMR (400 M, CDCls) ^ 8.23 (s, 1H), 7.52-7.54 (d, 2H), 7.01-7.06 (t, 2H), 6.93-6.95 (d, 2H), 4.51-4.64 (d, 2H), 4.21-4.22(d, 2H), 3.81-3.84, 4.01-4.04(dt, 2H), 3.04(s, 2H), 2.82-2.91(d, 2H), 2.82(s, 4H), 2.40( s, 3H), 2.24-2.26 (m, 2H), 1.90 (s, 4H) ppm. 6: Preparation of compound 6
Figure imgf000017_0001
Figure imgf000017_0001
1-苄基 -4- (3-氯） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-benzyl-4-(3-chloro)pyrimidinyl-furo[3,2-c] piperidine
向反应瓶中加入 1-苄基 -4-三丁基锡-呋喃并 [3，2-c] 哌啶 （1.69g， leq)， 2，4-二氯 -嘧啶 (500.0mg， leq), Pd(PPh3)2Cl2 (0.24g， O.leq)和 DMF ( 15mL)， 80度加热反应 2小时。 停止反应， 加水 （5 mL)， 二氯甲烷 （5 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽 滤，浓縮，粗品硅胶柱层析得到 1-苄基 -4- (3-氯）嘧啶基-呋喃并 [3，2-c]哌啶（365.0mg) . 1-苄基 -4- (3- (4-吗啉基苯胺基）） 嘧啶基-呋喃并 [3,2-c] 哌啶 To the reaction flask was added 1-benzyl-4-tributyltin-furo[3,2-c]piperidine (1.69 g, leq), 2,4-dichloro-pyrimidine (500.0 mg, leq), Pd ( PPh 3 ) 2 Cl 2 (0.24 g, O.leq) and DMF (15 mL) were reacted at 80 °C for 2 hours. The reaction was quenched, EtOAc (5 mL) (EtOAc) 3-chloro)pyrimidinyl-furo[3,2-c]piperidine (365.0 mg) . 1-Benzyl-4-(3-(4-morpholinylanilino)pyrimidinyl-furo[3 ,2-c] piperidine
向微波瓶中加入 4-吗啉基苯胺（65.0mg， l.leq), 1-苄基 -4- (3-氯-)嘧啶基-呋喃并 [3，2-c] 哌啶 ( 120.0mg, leq), 二氧六环的盐酸溶液 (6.6M) ( 184 L), 碘化钾 (20.6mg， 0.4eq) 和三氟乙醇 （5mL)， 于微波下 160 °C反应 2小时。 加水 （20 mL)， 饱和 NaHC03水溶液 洗， 二氯甲烷 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮， 粗品硅胶 柱层析得到 1-苄基 -4- (3- (4-吗啉基苯胺基）） 嘧啶基-呋喃并 [3，2-c] 哌啶 (127.5mg)。 4- (3- (4-吗啉基苯胺基）） 嘧啶基-呋喃并 [3,2-c] 哌啶 To the microwave vial was added 4-morpholinylaniline (65.0 mg, l.leq), 1-benzyl-4-(3-chloro-)pyrimidinyl-furo[3,2-c]piperidine (120.0 mg) , leq), dioxane in hydrochloric acid (6.6 M) (184 L), potassium iodide (20.6 mg, 0.4 eq) and trifluoroethanol (5 mL), and reacted at 160 ° C for 2 hours under microwave. Water was added (20 mL), washed with saturated aqueous NaHC0 3, (10 mL * 5) was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and the crude product by silica gel column chromatography to give 1-benzyl - 4-(3-(4-Morolinylanilino)pyrimidinyl-furo[3,2-c]piperidine (127.5 mg). 4-(3-(4-morpholinoanilino))pyrimidinyl-furo[3,2-c] piperidine
向反应瓶中加入 1-苄基 -4- (3- (4-吗啉基苯胺基））嘧啶基-呋喃并 [3，2-c]哌啶（124.0mg， leq), 氯甲酸 -1-氯乙酯 （105 L， 2eq)， 三乙胺 （80.75mg) 和二氯甲烷 （10mL)， 室温 搅拌 7小时， 浓縮反应液， 加入甲醇 （10mL)， 60度加热反应 2小时， 冷至室温， 有固 体析出， 抽滤， 用少量甲醇洗涤得 4- (3- (4-吗啉基苯胺基）） 嘧啶基-呋喃并 [3，2-c] 哌 啶 （85.6mg)。 To the reaction flask was added 1-benzyl-4-(3-(4-morpholinylanilino)pyrimidinyl-furo[3,2-c]piperidine (124.0 mg, leq), chloroformic acid-1 -Chloroethyl ester (105 L, 2 eq), triethylamine (80.75 mg) and dichloromethane (10 mL), stirred at room temperature for 7 hr, concentrated, and then evaporated. To room temperature, solid The organic layer was separated, filtered, and washed with a small amount of methanol to give 4-(3-(4-morpholinylanilinyl) pyrimidinyl-furo[3,2-c]piperidine (85.6 mg).
1-氰基乙酰基 -4- (3- (4-吗啉基苯胺基）） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-cyanoacetyl-4-(3-(4-morpholinylanilino))pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 1中 1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基- 呋喃并 [3，2-c]哌啶的合成， 不同之处在于将 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基) 嘧啶基-呋喃并 [3，2-c]哌啶改为 4- (3- (4-吗啉基苯胺基））嘧啶基-呋喃并 [3，2-c]哌啶。 MS: [M+H]+ = 445.1. 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)pyrimidinyl-furo[3,2-c]piperidine. MS: [M+H] + = 445.1.
1H-NMR (400 M， CDCls) δ 8.38-8.40 (d， 1Η), 7.54-7.56(d, 2H), 7.23(s, 1H), 7.08(s, 1H)， 6.99(s， 1H), 6.96-6.97(d, 2H), 4.37(s, 2H), 3.90-3.92(t, 4H)， 3.72-3.75(t, 2H)， 3.15-3.17(t, 4H)， 2.95-2.98(t, 2H), 2.90 (s， 2H) ppm。  1H-NMR (400 M, CDCls) δ 8.38-8.40 (d, 1 Η), 7.54-7.56 (d, 2H), 7.23 (s, 1H), 7.08 (s, 1H), 6.99 (s, 1H), 6.96 -6.97(d, 2H), 4.37(s, 2H), 3.90-3.92(t, 4H), 3.72-3.75(t, 2H), 3.15-3.17(t, 4H), 2.95-2.98(t, 2H) , 2.90 (s, 2H) ppm.
Figure imgf000018_0001
Figure imgf000018_0001
1-苄基 -4- (3- (4-N-甲基哌嗪基苯胺基）） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-benzyl-4-(3-(4-N-methylpiperazinylphenyl))pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 6中 1-苄基 -4- (3- (4-吗啉基苯胺基）） 嘧啶基-呋喃并 [3，2-c] 哌啶 的合成， 不同之处在于将 4-吗啉基苯胺改为 N-甲基哌嗪基苯胺。 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.
4- (3- (4-N-甲基哌嗪基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  4-(3- (4-N-Methylpiperazinylanilide)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 6中 4- (3- (4-吗啉基苯胺基）） 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 1-苄基 -4- (3- (4-吗啉基苯胺基）） 嘧啶基-呋喃并 [3，2-c] 哌啶改为 1- 苄基 -4- (3- (4-N-甲基哌嗪基苯胺基）） 嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
1-腈基乙酰基 -4- (3- (4-N-甲基哌嗪基苯胺基）） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-cyanoacetyl-4-(3-(4-N-methylpiperazinylphenyl))pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 1中 1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基- 呋喃并 [3，2-c]哌啶的合成， 不同之处在于将 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c]哌啶改为 4- (3- (4-N-甲基哌嗪基苯胺基））嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
MS: [M+H]+ = 458.4.  MS: [M+H]+ = 458.4.
1H-NMR (400 M， CDCI3) δ 8.38-8.48(dd, 1Η), 7.52-7.54 (d， 2H), 7.06 (s, 2H), 6.95-6.98(q: 3H), 4.48-4.62 (d, 2H), 3.80-3.83,4.00-4.03 (dt, 2H), 3.61-3.62 (d, 2H),3.22-3.24 (t 4H) ,2.88-2.91,3.00-3.03 (dt, 2H), 2.65-2.67(t, 4H)， 2.41(s, 3H)ppm。 1H-NMR (400 M, CDCI3) δ 8.38-8.48 (dd, 1 Η), 7.52-7.54 (d, 2H), 7.06 (s, 2H), 6.95-6.98 (q : 3H), 4.48-4.62 (d, 2H), 3.80-3.83, 4.00-4.03 (dt, 2H), 3.61-3.62 (d, 2H), 3.22-3.24 (t 4H), 2.88-2.91, 3.00-3.03 ( Dt, 2H), 2.65-2.67 (t, 4H), 2.41 (s, 3H) ppm.
Figure imgf000019_0001
Figure imgf000019_0001
2- ((呋喃 -3-甲基） -(4-甲氧苯基)氨基） 乙醇  2-((furan-3-methyl)-(4-methoxyphenyl)amino)ethanol
向反应瓶中加入 1- (呋喃基 -3-) -N-(4-甲氧苯基)甲胺（65.0mg， leq), 溴乙醇（74.27mg， 20eq)， 碳酸钾 （122.21mg， 30eq) 和乙腈 （500 L)， 加热回流 12小时， 电磁搅拌。 停 止反应， 滤除固体， 饱和 NaHC03水溶液洗， 二氯甲烷 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮得 2- ( (呋喃 -3-甲基） -(4-甲氧苯基)氨基） 乙醇 （87.3mg)。 2-氯 -N- (呋喃 -3-甲基） -N-(4-甲氧苯基)乙胺 Add 1-(furyl-3-)-N-(4-methoxyphenyl)methylamine (65.0 mg, leq), bromoethanol (74.27 mg, 20 eq), potassium carbonate (122.21 mg, 30 eq) ) and acetonitrile (500 L), heated to reflux for 12 hours, and electromagnetically stirred. The reaction was stopped, the solid was filtered off, washed with saturated aqueous NaHC0 3, (10 mL * 5). The combined methylene chloride organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 2- ((3-methyl-furan -(4-Methoxyphenyl)amino)ethanol (87.3 mg). 2-chloro-N-(furan-3-methyl)-N-(4-methoxyphenyl)ethylamine
向反应瓶中加入 2- ( (呋喃 -3-甲基） -(4-甲氧苯基)氨基） 乙醇 （87.3mg， leq), 二氯亚砜 (68.38mg， 2eq) 和二氯甲烷 （500 L)， 冰浴下反应 5小时。 停止反应， 饱和 NaHC03 水溶液洗， 二氯甲烷 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮得 2- 氯 -N- (呋喃 -3-甲基） -N-(4-甲氧苯基)乙胺 （63.53mg)。 To the reaction flask was added 2-((furan-3-methyl)-(4-methoxyphenyl)amino)ethanol (87.3 mg, leq), chlorosulfoxide (68.38 mg, 2 eq) and dichloromethane ( 500 L), reacted for 5 hours in an ice bath. The reaction was stopped, washed with saturated aqueous NaHC0 3, (10 mL * 5) was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-chloro -N- (furan-3-methyl) -N-(4-methoxyphenyl)ethylamine (63.53 mg).
5- (4-甲氧基苯基） -2-三正丁基锡 -4,5,6,7-呋喃并 [3,2-c] 哌啶 5-(4-methoxyphenyl)-2-tri-n-butyltin-4,5,6,7-furo[3,2-c] piperidine
氮气保护下， 向反应瓶中加入 2-氯 -N- (呋喃 -3-甲基） -N-(4-甲氧苯基)乙胺（63.0mg， leq) 和干燥四氢呋喃 （600 L)， 冰浴条件下滴加正丁基锂 （ 108.2 L， 1.2eq)， 继续滴加三 丁基氯化锡 （146.77mg， 2eq), 滴加完毕， 继续反应 2.5小时。 停止反应， 加水淬灭， 乙 酸乙酯 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮， 粗品硅胶柱层析 得到 1-对甲氧苄基 -4-三丁基锡-呋喃并 [3，2-c] 哌啶 （94.37mg)。 2-Chloro-N-(furan-3-methyl)-N-(4-methoxyphenyl)ethylamine (63.0 mg, leq) and dry tetrahydrofuran (600 L) were added to the reaction flask under nitrogen. Under ice bath, n-butyllithium (108.2 L, 1.2 eq) was added dropwise, and tributyltin chloride (146.77 mg, 2 eq) was further added dropwise, and the addition was completed, and the reaction was continued for 2.5 hours. The reaction was quenched, quenched with water, EtOAc (EtOAc (EtOAc)EtOAc. Tributyltin-furo[3,2-c]piperidine (94.37 mg).
2- (4-吗啉基苯胺基） 4-氯 -5-三氟甲基嘧啶 2-(4-morpholinylanilino) 4-chloro-5-trifluoromethylpyrimidine
向反应瓶中加入乙醚（50 L)， 叔丁醇（50 L)， 二氯甲烷（50 L)和氯化锌（9.99mg， 2.2eq), 冰浴条件下加入 2,4-二氯 -5-三氟甲基嘧啶（7.24mg， leq), 4-吗啉苯胺（9.66mg， l.leq) 和三乙胺 （6.54mg)， 反应 2小时， 电磁搅拌。 停止反应， 乙酸乙酯 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮， 粗品硅胶柱层析得到 2- (4-吗啉基苯 胺基） -4-氯 -5-三氟甲基嘧啶 （12.4mg)。 To the reaction flask were added diethyl ether (50 L), tert-butanol (50 L), dichloromethane (50 L) and zinc chloride (9.99 mg, 2.2 eq), 2,4-dichloro-5-trifluoromethylpyrimidine (7.24 mg, leq), 4-morpholinaniline (9.66 mg, l.leq) and triethylamine (6.54 mg) under ice bath ), react for 2 hours, electromagnetic stirring. The reaction was stopped, and ethyl acetate (10 mL*5) was evaporated. EtOAcjjjjjjjjjjj Chloro-5-trifluoromethylpyrimidine (12.4 mg).
1-对甲氧基苄基 -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 向反应瓶中加入 2- (4-吗啉基苯胺基） -4-氯 -5-三氟甲基嘧啶 （22.2mg， 1.5eq)， 1-对甲氧 苄基 -4-三丁基锡-呋喃并 [3,2-c] 哌啶 ( lO.Omg, leq), Pd(PPh3)2Cl2 ( 1.95mg， 0.06eq) 禾口 DMF (2mL)， 90度加热反应 6小时， 电磁搅拌。 停止反应， 乙酸乙酯 （10 mL*5 ) 萃 取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮， 粗品硅胶柱层析得到 1-对甲氧基苄基 -4-1-p-methoxybenzyl-4-(3-(4-morpholinoanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] piperidine was added to the reaction flask. 2-(4-morpholinylanilino)-4-chloro-5-trifluoromethylpyrimidine (22.2 mg, 1.5 eq), 1-p-methoxybenzyl-4-tributyltin-furo[3,2 -C] piperidine (lO.Omg, leq), Pd ( PPh 3) 2 Cl 2 (1.95mg, 0.06eq) Wo port DMF (2mL), 90 degrees reaction was heated for 6 hours electromagnetic stirring. The reaction was quenched, ethyl acetate (10 mL*5) was evaporated, evaporated, evaporated, evaporated.
(3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 （12.6mg)。 (3-(4-Morpholinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine (12.6 mg).
4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 4-(3-(4-morpholinoanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] piperidine
向微波瓶中加入 1-对甲氧基苄基 -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并Add 1-p-methoxybenzyl-4-(3-(4-morpholinoanilino)-6-trifluoromethyl)pyrimidinyl-furan to the microwave vial
[3,2-c] 哌啶 （5.5mg)， 溴化氢 （6 L) 和三氟乙醇 （2mL)， 150 °C反应 1小时。 停止 反应， 饱和 NaHC03水溶液洗， 二氯甲烷 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干 燥，抽滤，浓縮，粗品过柱得 4- (3- (4-吗啉基苯胺基）-6-三氟甲基）嘧啶基-呋喃并 [3，2-c] 哌啶 （0.8mg)。 [3,2-c] Piperidine (5.5 mg), hydrogen bromide (6 L) and trifluoroethanol (2 mL) were reacted at 150 ° C for 1 hour. The reaction was stopped, washed with saturated aqueous NaHC0 3, (10 mL * 5) was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and the crude product by column to give 4- (3- (4-morpholinyl Benzimino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine (0.8 mg).
1-氰基乙酰基 -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 1中 1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基- 呋喃并 [3，2-c]哌啶的合成， 不同之处在于将 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基) 嘧啶基-呋喃并 [3，2-c] 哌啶改为 4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶。  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.
MS: [M+H]+ = 513.9. MS: [M+H] + = 513.9.
1H-NMR (400 M， CDCls) δ 8.66 (s， 1Η), 7.53-7.55 (t， 2H), 7.28 (s， 1H), 7.23-7.24(d, 1H)， 7.01-7.02(t, 2H), 4.52-4.65 (d, 2H), 4.02-4.05, 3.82-3.85(dt, 2H), 3.92 (s, 4H)， 3.61-3.63(d, 2H): 3.02 (s, 4H)， 3.04-3.07, 2.92-2.95(dt, 2H) ppm。 1H-NMR (400 M, CDCls) δ 8.66 (s, 1 Η), 7.53-7.55 (t, 2H), 7.28 (s, 1H), 7.23-7.24 (d, 1H), 7.01-7.02 (t, 2H) , 4.52-4.65 (d, 2H), 4.02-4.05, 3.82-3.85(dt, 2H), 3.92 (s, 4H), 3.61-3.63(d, 2H) : 3.02 (s, 4H), 3.04-3.07, 2.92-2.95 (dt, 2H) ppm.
实施例 9: 化合物 9的制备
Figure imgf000021_0001
Example 9: Preparation of Compound 9
Figure imgf000021_0001
1-苄基 -4- (3- (4- N-乙基哌嗪基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-benzyl-4-(3-(4-N-ethylpiperazinylphenyl)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 3中 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4-吗啉基苯胺改为 N-乙基哌嗪基苯胺。 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.
4- (3- (4- N-乙基哌嗪基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  4-(3- (4- N-Ethylpiperazinylphenyl)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 3中 4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 的合成，不同之处在于将 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶改为 1-苄基 -4- (3- (4- N-乙基哌嗪基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c]哌啶。 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.
1-腈基乙酰基 -4- (3- (4-N-乙基哌嗪基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 1中 1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基- 呋喃并 [3，2-c]哌啶的合成， 不同之处在于将 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基) 嘧啶基-呋喃并 [3，2-c] 哌啶改为 4- (3- (4-N-乙基哌嗪基苯胺基） -6-甲基） 嘧啶基 -呋喃 并 [3,2-c] 哌啶。  1-Nitrile acetyl-4-(3-(4-N-ethylpiperazinylanilide)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine preparation method same as the examples 1-1-cyanoyl-4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine Synthesis, except that 4-(3-(3,5-difluoro-4-morpholinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine was changed to 4-(3-(4-N-Ethylpiperazinylanilide)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
MS: [M+H]+ = 486.0. MS: [M+H] + = 486.0.
1H-NMR (500 M， DMSO- e) δ 9.21-9.22(d, 1H)， 8.28(s, 1H)， 7.61-7.64(d, 2H), 7.18 (s， 1H), 6.87-6.89(d, 2H), 5.75(s, 1H), 4.51(s， 2H), 4.20(d, 2H), 3.87(s, 2H), 3.69-3.72(m, 2H), 3.45(s, 2H), 3.04-3.06 (m， 4H)， 2.89-2.92 (m， 2H), 2.81-2.82(m, 1H), 2.33-2.37(m, 3H), 1.03(s, 3H)ppm。  1H-NMR (500 M, DMSO-e) δ 9.21-9.22 (d, 1H), 8.28 (s, 1H), 7.61-7.64 (d, 2H), 7.18 (s, 1H), 6.87-6.89 (d, 2H), 5.75(s, 1H), 4.51(s, 2H), 4.20(d, 2H), 3.87(s, 2H), 3.69-3.72(m, 2H), 3.45(s, 2H), 3.04-3.06 (m, 4H), 2.89-2.92 (m, 2H), 2.81-2.82 (m, 1H), 2.33-2.37 (m, 3H), 1.03 (s, 3H) ppm.
实施例 10: 化合物 10的制备
Figure imgf000021_0002
Example 10: Preparation of Compound 10
Figure imgf000021_0002
1-苄基 -4- (3- (3,4,5-三甲氧基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-benzyl-4-(3-(3,4,5-trimethoxyanilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 3中 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4-吗啉基苯胺改为 3，4，5-三甲氧基苯胺。 4- (3- (3,4,5-三甲氧基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 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. 4-(3-(3,4,5-Trimethoxyanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 3中 4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 的合成，不同之处在于将 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶改为 1-苄基 -4- (3- (3，4，5-三甲氧基苯胺基) -6-甲基) 嘧啶基-呋喃并 [3,2-c] 哌啶。 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.
1-腈基乙酰基 -4- (3- (3， 4， 5-三甲氧基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 1中 1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基- 呋喃并 [3，2-c]哌啶的合成， 不同之处在于将 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基) 嘧啶基-呋喃并 [3，2-c] 哌啶改为 4- (3- (3， 4， 5-三甲氧基苯胺基） -6-甲基） 嘧啶基-呋 喃并 [3,2-c] 哌啶。 Preparation method of 1-cyanoacetyl-4-(3-(3,4,5-trimethoxyanilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine 1-1-cyanoyl-4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine Synthesis, except that 4-(3-(3,5-difluoro-4-morpholinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine was changed to 4-(3-(3,4,5-Trimethoxyanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
MS: [M+H]+ = 464.0. MS: [M+H] + = 464.0.
1H-NMR (500 M， DMSO- e) δ 9.37(s, 1H), 8.35(s, 1H), 7.37-7.38(d, 2H), 7.19 (s， 1H)， 5.75(s, 1H), 4.51(s， 2H), 4.15-4.20(d, 2H), 3.80(s, 6H)， 3.61(s, 3H), 2.89-2.92 (m， 2H), 2.81-2.82(m, 1H), 2.35(s, 3H)ppm。  1H-NMR (500 M, DMSO-e) δ 9.37 (s, 1H), 8.35 (s, 1H), 7.37-7.38 (d, 2H), 7.19 (s, 1H), 5.75 (s, 1H), 4.51 (s, 2H), 4.15-4.20(d, 2H), 3.80(s, 6H), 3.61(s, 3H), 2.89-2.92 (m, 2H), 2.81-2.82(m, 1H), 2.35(s , 3H)ppm.
实施例 11: 化合物 11的制备
Figure imgf000022_0001
Example 11: Preparation of Compound 11
Figure imgf000022_0001
1-苄基 -4- (3-苯胺基 -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-benzyl-4-(3-anilino-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 3中 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4-吗啉基苯胺改为苯胺。 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.
4- (3-苯胺基 -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 4-(3-anilino-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 3中 4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 的合成，不同之处在于将 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶改为 1-苄基 -4- (3-苯胺基 -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
1-氰基乙酰基 -4- (3- (苯胺基 -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 1-cyanoacetyl-4-(3-(anilino-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 1中 1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基- 呋喃并 [3，2-c]哌啶的合成， 不同之处在于将 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基) 嘧啶基-呋喃并 [3，2-c] 哌啶改为 4- (3- (苯胺基 -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
MS: [M+H]+ = 374.1. Ή-NMR (500 M， DMSO- 6) δ 9.46-9.47 (d， 1H)， 8.34-8.35 (d, 1H)， 7.80-7.82 (d， 2H): 7.25-7.29 (t， 2H), 7.17-7.21 (d， 1H), 6.90-6.93 (t， 1H), 4.52 (s, 1H), 4.44 (s, 1H), 3.86-3.88 (t 1H), 3.70-3.73 (t， 2H), 2.89-2.92 (m， 2H), 2.81-2.82 (m， 1H), 2.35(s, 3H)ppm。 MS: [M+H] + = 374.1. Ή-NMR (500 M, DMSO- 6 ) δ 9.46-9.47 (d, 1H), 8.34-8.35 (d, 1H), 7.80-7.82 (d, 2H) : 7.25-7.29 (t, 2H), 7.17- 7.21 (d, 1H), 6.90-6.93 (t, 1H), 4.52 (s, 1H), 4.44 (s, 1H), 3.86-3.88 (t 1H), 3.70-3.73 (t, 2H), 2.89-2.92 (m, 2H), 2.81-2.82 (m, 1H), 2.35 (s, 3H) ppm.
实施例 12: 化合物 12的制备
Figure imgf000023_0001
Example 12: Preparation of Compound 12
Figure imgf000023_0001
1-苄基 -4- (3- (4-硝基-苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-benzyl-4-(3-(4-nitro-anilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 3中 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4-吗啉基苯胺改为 4-硝基苯胺。 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.
4- (3- (4-硝基-苯胺基） 6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  4-(3-(4-Nitro-anilino) 6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 3中 4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 的合成，不同之处在于将 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶改为 1-苄基 -4- (3- (4-硝基-苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
1-腈基酰基 -4- (3- (4-硝基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 1-cyanoyl-4-(3-(4-nitroanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 1中 1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基- 呋喃并 [3，2-c]哌啶的合成， 不同之处在于将 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基) 嘧啶基-呋喃并 [3，2-c]哌啶改为 4- (3- (4-硝基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
MS: [M+H]+ = 418.9.  MS: [M+H]+ = 418.9.
1H-NMR (500 M， DMSO- e) δ 10.39-10.40 (d， 1H), 8.47-8.48 (d, 1H), 8.20-8.23 (d, 2H), 8.06-8.09 (d, 2H), 7.26-7.33(m, 1H), 4.53 (s, 2H), 4.17-4.21(d, 2H), 3.87-3.89 (m， 2H), 2.83-2.94 (m， 2H), 2.40(s, 3H)ppm。  1H-NMR (500 M, DMSO-e) δ 10.39-10.40 (d, 1H), 8.47-8.48 (d, 1H), 8.20-8.23 (d, 2H), 8.06-8.09 (d, 2H), 7.26- 7.33 (m, 1H), 4.53 (s, 2H), 4.17-4.21 (d, 2H), 3.87-3.89 (m, 2H), 2.83-2.94 (m, 2H), 2.40 (s, 3H) ppm.
实施例 13: 化合物 13的制备
Figure imgf000024_0001
Example 13: Preparation of Compound 13
Figure imgf000024_0001
1-苄基 -4- (3- (4-氟-苯胺基) -6-甲基) 嘧啶基-呋喃并 [3,2-c] 哌啶  1-benzyl-4-(3-(4-fluoro-anilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 3中 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4-吗啉基苯胺改为 4-氟苯胺。 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.
4- (3- (4-氟-苯胺基） 6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  4-(3-(4-Fluoro-anilino) 6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 3中 4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 的合成，不同之处在于将 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶改为 1-苄基 -4- (3- (4-氟-苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
1-腈基酰基 -4- (3- (4-氟苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 1-cyanoyl-4-(3-(4-fluoroanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 1中 1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基- 呋喃并 [3，2-c]哌啶的合成， 不同之处在于将 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶改为 4- (3- (4-氟苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
MS: [M+H]+ = 392.2. MS: [M+H] + = 392.2.
1H-NMR (500M, CDCls) δ 8.26(s, 1H), 7.58-7.62(m, 2H), 7.04-7.08(m, 4H), 4.52-4.66 (m: 2H), 4.02-4.05 (m， 1H), 3.82-3.85(m, 1H), 3.62-3.63(m, 2H), 3.04-3.07 (m， 1H), 2.91-2.94 (m， 1H), 2.42-2.43 (d， 3H)ppm。 实施例 14: 化合物 14的制备 1H-NMR (500M, CDCls) δ 8.26 (s, 1H), 7.58-7.62 (m, 2H), 7.04-7.08 (m, 4H), 4.52-4.66 (m : 2H), 4.02-4.05 (m, 1H) ), 3.82-3.85 (m, 1H), 3.62-3.63 (m, 2H), 3.04-3.07 (m, 1H), 2.91-2.94 (m, 1H), 2.42-2.43 (d, 3H) ppm. Example 14: Preparation of Compound 14
Figure imgf000025_0001
Figure imgf000025_0001
2- (4-N-Boc-哌嗪基苯胺基） -4-氯 -5-三氟甲基嘧啶  2-(4-N-Boc-piperazinylanilino)-4-chloro-5-trifluoromethylpyrimidine
制备方法同实施例 8中 2- (4-吗啉基苯胺基） -4-氯 -5-三氟甲基嘧啶， 不同之处在于将 4- 吗啉苯胺改为 N-Boc-哌嗪基苯胺。 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.
1-对甲氧基苄基 -4- ( 3- (4-N-Boc-哌嗪基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-p-methoxybenzyl-4-(3-(4-N-Boc-piperazinylphenyl)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 8中 1-对甲氧基苄基 -4- ( 3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基- 呋喃并 [3，2-c] 哌啶， 不同之处在于将 2- (4-吗啉基苯胺基） -4-氯 -5-三氟甲基嘧啶改为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
2- (4-N-Boc-哌嗪基苯胺基） -4-氯 -5-三氟甲基嘧啶。 2-(4-N-Boc-piperazinylanilino)-4-chloro-5-trifluoromethylpyrimidine.
1-对甲氧基苄基 -4- (3- (4 -哌嗪基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 向反应瓶中加入 1-对甲氧基苄基 -4- ( 3- (4-N-Boc-哌嗪基苯胺基） -6-三氟甲基） 嘧啶基- 呋喃并 [3，2-c] 哌啶 （190mg)， 三氟乙酸 （2mL) 和二氯甲烷 （10mL)， 室温反应 2 小 时。 停止反应， 饱和 NaHC03水溶液洗， 二氯甲烷 （10 mL*5 ) 萃取， 合并有机相， 无水 硫酸钠干燥， 抽滤， 浓縮得粗品 1-对甲氧基苄基 -4- ( 3- (4 -哌嗪基苯胺基） -6-三氟甲基) 嘧啶基-呋喃并 [3，2-c] 哌啶 （410mg)。 1-p-methoxybenzyl-4-(3-(4-piperazinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] piperidine was added to the reaction flask. 1-p-methoxybenzyl-4-(3-(4-N-Boc-piperazinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine ( 190 mg), trifluoroacetic acid (2 mL) and dichloromethane (10 mL) were reacted at room temperature for 2 hr. The reaction was stopped, washed with saturated aqueous NaHCO 3, (10 mL * 5) was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 1-p-methoxybenzyl-4- (3 -(4-piperazinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine (410 mg).
1-对甲氧基苄基 -4- ( 3- (4 -N—乙基哌嗪基苯胺基） -6-三氟甲基）嘧啶基-呋喃并 [3,2-c] 哌啶  1-p-methoxybenzyl-4-(3-(4-N-ethylpiperazinylphenyl)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine
向反应瓶中加入 1-对甲氧基苄基 -4- ( 3- (4 -哌嗪基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 （2.0mg)， 溴乙烷 （0.5mL)， 碳酸钾 ( lOmg)和丙酮 （3mL)， 加热至回流 0.5小时。 停止反应， 饱和 NaHC03水溶液洗， 二氯甲烷 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮得粗品 1-对甲氧基苄基 -4- ( 3- (4 -N—乙基哌嗪基苯胺基) -6-三氟甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 （2.1mg)。 To the reaction flask was added 1-p-methoxybenzyl-4-(3-(4-piperazinylanilide)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine. (2.0 mg), bromoethane (0.5 mL), potassium carbonate (10 mg) and acetone (3 mL). The reaction was stopped, washed with saturated aqueous NaHCO 3, (10 mL * 5) was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 1-p-methoxybenzyl-4- (3 - (4-N-ethylpiperazinylanilide) -6-Trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine (2.1 mg).
4- (3- (4 -N—乙基哌嗪基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 8中 4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶， 不同之处在于将 1-对甲氧基苄基 -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基- 呋喃并 [3，2-c] 哌啶改为 1-对甲氧基苄基 -4- (3- (4 -N—乙基哌嗪基苯胺基） -6-三氟甲 基） 嘧啶基-呋喃并 [3,2-c] 哌啶。  4-(3-(4-N-ethylpiperazinylanilide)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] piperidine was prepared in the same manner as in Example 8 4-( 3-(4-morpholinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine, except that 1-p-methoxybenzyl-4- (3-(4-morpholinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] piperidine was changed to 1-p-methoxybenzyl-4-(3- (4-N-Ethylpiperazinylanilide)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine.
1-腈基乙酰基 -4- (4-N-乙基哌嗪基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 1中 1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基- 呋喃并 [3，2-c]哌啶的合成， 不同之处在于将 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基) 嘧啶基-呋喃并 [3，2-c] 哌啶改为 4- (4-N-乙基哌嗪基苯胺基） -6-三氟甲基）嘧啶基 -呋喃 并 [3,2-c] 哌啶  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
MS: [M+H]+ = 540.3. MS: [M+H] + = 540.3.
1H-NMR (500 M， CDCls) δ 10.03 (s, 1Η)， 8.72(s, 1Η)， 7.61(s, 2Η), 7.35(s, 1H)， 6.94-6.96 (s， 2H), 4.54 (s， 2H), 4.21 (s， 2H), 3.13(s, 6H)， 2.92 (s， 2H), 2.80(s, 2H), 2.57 (s， 2H), 2.44 (s， 2H), 1.05-1.08 (t, 3H)ppm。  1H-NMR (500 M, CDCls) δ 10.03 (s, 1 Η), 8.72 (s, 1 Η), 7.61 (s, 2 Η), 7.35 (s, 1H), 6.94-6.96 (s, 2H), 4.54 (s , 2H), 4.21 (s, 2H), 3.13(s, 6H), 2.92 (s, 2H), 2.80(s, 2H), 2.57 (s, 2H), 2.44 (s, 2H), 1.05-1.08 ( t, 3H) ppm.
Figure imgf000026_0001
Figure imgf000026_0001
2- (4- (2-氯 -1-乙氧基）苯胺基） -4-氯 -5-三氟甲基嘧啶  2-(4-(2-Chloro-1-ethoxy)anilino)-4-chloro-5-trifluoromethylpyrimidine
制备方法同实施例 8中 2- (4-吗啉基苯胺基） -4-氯 -5-三氟甲基嘧啶的合成， 不同之处在 于将 4-吗啉苯胺改为 2-氯 -1-乙氧基苯胺。 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.
1-对甲氧基苄基 -4- (3- (4- (2-氯 -1-乙氧基）苯胺基） -6-三氟甲基）嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 8中 1-对甲氧基苄基 -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基- 呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 2- (4-吗啉基苯胺基） -4-氯 -5-三氟甲基嘧 啶改为 2- (4- (2-氯 -1-乙氧基） 苯胺基） —4-氯 -5-三氟甲基嘧啶。 1-p-methoxybenzyl-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 8, 1-p-methoxybenzyl-4-(3-(4-morpholinoanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] Synthesis of piperidine, except that 2-(4-morpholinylanilino)-4-chloro-5-trifluoromethylpyrimidine was changed to 2-(4-(2-chloro-1-ethoxy) Anilino) 4-chloro-5-trifluoromethylpyrimidine.
4- (3- (4- (2-氯 -1-乙氧基） 苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 8中的 4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 1-对甲氧基苄基 -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶改为 1-对甲氧基苄基 -4- (3- (4- (2-氯 -1-乙氧基） 苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。 4-(3-(4-(2-Chloro-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] piperidine was prepared in the same manner as in Example 8. Synthesis of 4-(3-(4-morpholinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine, except that 1-pair Oxybenzyl-4-(3-(4-morpholinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] piperidine is changed to 1-p-methoxybenzyl 4-(3-(4-(2-Chloro-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine.
1-腈基乙酰基 -4- (3- (4- (2-氯 -1-乙氧基）苯胺基） -6-三氟甲基）嘧啶基-呋喃并 [3,2-c] 哌啶  1-cyanoacetyl-4-(3-(4-(2-chloro-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] Pyridine
制备方法同实施例 1中 1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基- 呋喃并 [3，2-c]哌啶的合成， 不同之处在于将 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基) 嘧啶基-呋喃并 [3，2-c] 哌啶改为 4- (3- (4- (2-氯 -1-乙氧基） 苯胺基） -6-三氟甲基） 嘧 啶基-呋喃并 [3,2-c] 哌啶。 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.
1-腈基乙酰基 -4- (3- (4- (2-吡咯垸 -1-乙氧基）苯胺基） -6-三氟甲基）嘧啶基-呋喃并 [3,2-c] 哌啶  1-cyanoacetyl-4-(3-(4-(2-pyrrole-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] Piperidine
向反应瓶中加入 1-腈基乙酰基 -4- (3- (4- (2-溴小乙氧基） 苯胺基） -6-三氟甲基） 嘧啶 基-呋喃并 [3，2-c]哌啶（160mg， leq)， 吡咯烷（51.4mg， 3eq)， 碘化钾（9.6mg， 0.054eq) 和 N，N-二甲基甲酰胺（10mL)， 80度加热反应 3小时，电磁搅拌。停止反应，加水（10 mL) 和二氯甲烷 （10 mL) 分液， 二氯甲烷 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮， 粗品硅胶柱层析得到 1-腈基乙酰基 -4- (3- (4- (2-吡咯烷 -1-乙氧基）苯胺基) -6-三氟甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 （62.3mg)。 To the reaction flask was added 1-cyanoacetyl-4-(3-(4-(2-bromosuccinyl)anilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2- c] piperidine (160 mg, leq), pyrrolidine (51.4 mg, 3 eq), potassium iodide (9.6 mg, 0.054 eq) and N,N-dimethylformamide (10 mL), heated at 80 °C for 3 hours, electromagnetic stirring . The reaction was stopped, and water (10 mL) and dichloromethane (10 mL) were separated, dichloromethane (10 mL*5), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, 1-Acidylacetyl-4-(3-(4-(2-pyrrolidin-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2- c] Piperidine (62.3 mg).
MS: [M+H]+ = 541.3. MS: [M+H] + = 541.3.
1H-NMR (400 M， CDCls) ^8.60(s, 1H), 7.86-7.89(d, 1H), 7.46-7.48(d, 2H), 7.16(s, 1H), 6.91-6.93(t, 2H), 4.43-4.58(d, 2H), 4.13-4.16(t, 2H), 3.95-3.97, 3.74-3.76 (dt， 2H), 3.64-3.65(d, 2H), 2.95-2.97(t, 3H), 2.84(s, 1H), 2.70(s, 4H)， 1.84(s, 4H)ppm。 实施例 16: 化合物 16的制备
Figure imgf000028_0001
1H-NMR (400 M, CDCls) ^8.60 (s, 1H), 7.86-7.89 (d, 1H), 7.46-7.48 (d, 2H), 7.16 (s, 1H), 6.91-6.93 (t, 2H) , 4.43-4.58(d, 2H), 4.13-4.16(t, 2H), 3.95-3.97, 3.74-3.76 (dt, 2H), 3.64-3.65(d, 2H), 2.95-2.97(t, 3H), 2.84 (s, 1H), 2.70 (s, 4H), 1.84 (s, 4H) ppm. Example 16: Preparation of Compound 16
Figure imgf000028_0001
1-甲磺酰基 -4- (3-苯胺基 -5-对甲苯磺酰基吡咯并 [4,3-b ]嘧啶基） -呋喃并 [3,2-c]哌啶 向反应瓶中加入 4- (3-苯胺基 -5-对甲苯磺酰基吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶（485.0mg， leq)， 甲磺酰氯（228.7mg， 2eq)， 催化量的 DIPEA和二氯甲烷（30mL)， 室温反应 2小时， 电磁搅拌。 停止反应， 加水 （20 mL)， 饱和 NaHC03水溶液洗， 二氯 甲烷 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮， 粗品硅胶柱层析得 到 1-甲磺酰基 -4- (3-苯胺基 -5-对甲苯磺酰基吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌 啶 （485.6mg)。 1-Methanesulfonyl-4-(3-anilino-5-p-toluenesulfonylpyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine was added to the reaction flask. -(3-anilino-5-p-toluenesulfonylpyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine (485.0 mg, leq), methanesulfonyl chloride (228.7 mg , 2 eq), a catalytic amount of DIPEA and dichloromethane (30 mL), reacted at room temperature for 2 hours, and stirred magnetically. The reaction was stopped, water (20 mL), washed with saturated aqueous NaHC0 3, (10 mL * 5). The combined methylene chloride organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and the crude product on silica gel column chromatography to give 1- Methanesulfonyl-4-(3-anilino-5-p-toluenesulfonylpyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine (485.6 mg).
1-甲磺酰基 -4- ((3-苯胺基） 吡咯并 [4,3-b] 嘧啶基） -呋喃并 [3,2-c] 哌啶  1-methanesulfonyl-4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c] piperidine
向反应瓶中加入 1-甲磺酰基 -4- (3-苯胺基 -5-对甲苯磺酰基吡咯并 [4，3-b] 嘧啶基） -呋喃 并 [3,2-c] 哌啶 (243.0mg, leq)， 饱和碳酸钠 (2M) ( lOmL), 甲醇 ( lOmL) 和四氢呋 喃 ( lOmL),升温至回流，反应 15分钟，电磁搅拌。停止反应，加水（ 10 mL)，饱和 NaHC03 水溶液洗， 二氯甲烷 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮， 粗 品硅胶柱层析得到 1-甲磺酰基 -4- ( (3-苯胺基） 吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶 (150mg)。 To the reaction flask was added 1-methanesulfonyl-4-(3-anilino-5-p-toluenesulfonylpyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine ( 243.0 mg, leq), saturated sodium carbonate (2M) (10 mL), methanol (10 mL) and THF (10 mL), warmed to reflux, 15 min. The reaction was stopped, water (10 mL), washed with saturated aqueous NaHC0 3, (10 mL * 5). The combined methylene chloride organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and the crude product on silica gel column chromatography to give 1- Methanesulfonyl-4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine (150 mg).
MS: [M+H]+ = 410.1. MS: [M+H] + = 410.1.
1H-NMR (500 M， DMSO- e) δ 11.58 (s, 1H), 9.25 (s, 1H), 7.89-7.91(dd, 2H), 7.32 (s, 1H): 7.29-7.22(m, 3H), 6.92-6.84 (m, 1H), 6.75-6.77(dd, 1H), 4.31(s, 2H), 3.62-3.65 (t, 2H), 2.97 (s, 3H), 2.96-2.98 (t， 2H) ppm。 17: 化合物 17的制备
Figure imgf000028_0002
1H-NMR (500 M, DMSO-e) δ 11.58 (s, 1H), 9.25 (s, 1H), 7.89-7.91 (dd, 2H), 7.32 (s, 1H) : 7.29-7.22 (m, 3H) , 6.92-6.84 (m, 1H), 6.75-6.77 (dd, 1H), 4.31(s, 2H), 3.62-3.65 (t, 2H), 2.97 (s, 3H), 2.96-2.98 (t, 2H) Ppm. 17: Preparation of Compound 17
Figure imgf000028_0002
1-甲磺酰基 -4- (3- (苯胺基 -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-methanesulfonyl-4-(3-(anilino-6-methyl)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 16中 1-甲磺酰基 -4-( (3-苯胺基）吡咯并 [4，3-b]嘧啶基） -呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4- ( (3-苯胺基） 吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶改为- (3- (苯胺基 -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。 MS: [M+H]十 = 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 -(3-(anilino-6-) Pyrimidinyl-furo[3,2-c] piperidine. MS: [M+H] ten = 385.1.
1H-NMR (500 M， DMSO- e) δ 9.47 (s, 1H), 8.35 (s, 1H), 7.82-7.85(d, 2H), 7.28-7.3 l(t, 2H), 7.21(s, 1H), 6.92-6.95(t, 1H), 4.29 (s， 2H), 3.59-3.62(t, 2H), 2.97 (s， 3H), 2.92-2.95(d, 2H) 2.36 (s, 3H) ppm。  1H-NMR (500 M, DMSO-e) δ 9.47 (s, 1H), 8.35 (s, 1H), 7.82-7.85 (d, 2H), 7.28-7.3 l(t, 2H), 7.21(s, 1H ), 6.92-6.95(t, 1H), 4.29 (s, 2H), 3.59-3.62 (t, 2H), 2.97 (s, 3H), 2.92-2.95 (d, 2H) 2.36 (s, 3H) ppm.
实施例 18: 化合物 18的制备
Figure imgf000029_0001
Example 18: Preparation of Compound 18
Figure imgf000029_0001
1-甲磺酰基 -4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-methanesulfonyl-4-(3-(4-morpholinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 16中 1-甲磺酰基 -4-( (3-苯胺基）吡咯并 [4，3-b]嘧啶基） -呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4- ( (3-苯胺基） 吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶改为 4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
MS: [M+H]+ = 470.1. MS: [M+H] + = 470.1.
1H-NMR (500 M， DMSO- e) δ 9.22 (s, 1H), 8.29 (s, 1H), 7.65-7.66 (d, 2H), 7.18 (S， 1H)， 6.90(S， 2H), 4.28 (s, 2H), 3.74 (S， 4H)， 3.58-3.60 (t， 2H), 3.02 (s, 4H)， 2.97 (s, 3H)， 2.92 (s， 2H)， 2.34 (s， 3H)ppm 实施例 19: 化合物 19的制备
Figure imgf000029_0002
1H-NMR (500 M, DMSO-e) δ 9.22 (s, 1H), 8.29 (s, 1H), 7.65-7.66 (d, 2H), 7.18 (S, 1H), 6.90 (S, 2H), 4.28 (s, 2H), 3.74 (S, 4H), 3.58-3.60 (t, 2H), 3.02 (s, 4H), 2.97 (s, 3H), 2.92 (s, 2H), 2.34 (s, 3H)ppm Example 19: Preparation of Compound 19
Figure imgf000029_0002
1-甲磺酰基 -4- (3- (4-N-甲基哌嗪基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 16中 1-甲磺酰基 -4-( (3-苯胺基）吡咯并 [4，3-b]嘧啶基） -呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4- ( (3-苯胺基） 吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶改为 4- (3- (4-N-甲基哌嗪基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。  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.
MS: [M+H]+ = 483.2. MS: [M+H] + = 483.2.
1H-NMR (400 M， DMSO- e) δ 9.26 (s， 1H), 8.30 (s， 1H), 7.64-7.66 (d, 2H), 7.20 (S， 1H)， 6.89-6.91(d, 2H), 4.30 (s, 2H), 3.60 (s, 3H), 3.07 (s, 5H)， 2.99 (s, 4H)， 2.94 (s, 3H)， 2.35 (s， 3H), 2.25 (s， 3H)ppm。 1H-NMR (400 M, DMSO-e) δ 9.26 (s, 1H), 8.30 (s, 1H), 7.64-7.66 (d, 2H), 7.20 (S, 1H), 6.89-6.91 (d, 2H) , 4.30 (s, 2H), 3.60 (s, 3H), 3.07 (s, 5H), 2.99 (s, 4H), 2.94 (s, 3H), 2.35 (s, 3H), 2.25 (s, 3H) ppm.
Figure imgf000030_0001
Figure imgf000030_0001
1-甲磺酰基 -4- (3- (4- (2-吡咯垸 -1-乙氧基)苯胺基） -6-甲基) 嘧啶基-呋喃并 [3,2-c] 哌啶  1-Methanesulfonyl-4-(3-(4-(2-pyrrole-1-enyloxy)anilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 16中 1-甲磺酰基 -4-( (3-苯胺基）吡咯并 [4，3-b]嘧啶基） -呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4- ( (3-苯胺基） 吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶改为 4- (3- (4- (2-吡咯烷 -1-乙氧基） 苯胺基） -6-甲基) 嘧啶基-呋喃并 [3,2-c] 哌 啶。 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.
MS: [M+H]+ = 498.2. MS: [M+H] + = 498.2.
1H-NMR(400M, CDC13)^ 8.24(s, 1H)， 7.52-7.54(d, 2H), 7.04(s, 1H)， 6.93-6.95(t, 3H), 4.39(s, 2H), 4.20(s, 2H), 3.72-3.75(t, 2H), 2.97-3.00(t, 3H), 2.90-2.9 l(dt, 2H), 2.65-2.67(s, 3H), 2.78(s, 3H), 2.41(s, 3H), 1.90(s, 4H) ppm。 1H-NMR (400M, CDC1 3 )^ 8.24 (s, 1H), 7.52-7.54 (d, 2H), 7.04 (s, 1H), 6.93-6.95 (t, 3H), 4.39 (s, 2H), 4.20 (s, 2H), 3.72-3.75(t, 2H), 2.97-3.00(t, 3H), 2.90-2.9 l(dt, 2H), 2.65-2.67(s, 3H), 2.78(s, 3H), 2.41 (s, 3H), 1.90 (s, 4H) ppm.
Figure imgf000030_0002
Figure imgf000030_0002
1-苄基 -4- (3- (4-咪唑苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-benzyl-4-(3-(4-imidazolidinyl)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 3中 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4-吗啉基苯胺改为 4-咪唑基苯胺。 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.
4- (3- (4-咪唑苯胺基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  4-(3-(4-imidazolidinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 3中 4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 的合成，不同之处在于将 1-苄基 -4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c] 哌啶改为 1-苄基 -4- (3- (4-咪唑苯胺基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。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.
1-甲磺酰基 -4- (3- (4-咪唑苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 1-methanesulfonyl-4-(3-(4-imidazolidinyl)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 19中 1-甲磺酰基 -4- (3- (4- (2-吡咯烷 -1-乙氧基） 苯胺基） -6-甲基) 嘧啶基-呋喃并 [3，2-c] 哌啶， 不同之处在于将 4- (3- (4- (2-吡咯烷 -1-乙氧基） 苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶改为 4- (3- (4-咪唑苯胺基苯胺基） -6-甲基） 嘧啶 基-呋喃并 [3,2-c] 哌啶。 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.
MS: [M-H]" = 489.3. MS: [M-H]" = 489.3.
1H-NMR (400 M， DMSO- e) δ 8.40 (s, 1H), 8.18 (s, 1H), 7.96-7.99(m, 2H), 7.54-7.67(m, 4H)， 7.25 (s， 1H), 7.11 (s， 1H), 4.28-4.30 (d, 2H), 3.58-3.62 (m， 2H), 3.00 (s， 3H)， 2.92-2.96 (m， 2H)， 2.38 (s， 3H) ppm。  1H-NMR (400 M, DMSO-e) δ 8.40 (s, 1H), 8.18 (s, 1H), 7.96-7.99 (m, 2H), 7.54-7.67 (m, 4H), 7.25 (s, 1H) , 7.11 (s, 1H), 4.28-4.30 (d, 2H), 3.58-3.62 (m, 2H), 3.00 (s, 3H), 2.92-2.96 (m, 2H), 2.38 (s, 3H) ppm.
备
Figure imgf000031_0001
Prepare
Figure imgf000031_0001
1-甲磺酰基 -4- (3- (3， 4, 5-三甲氧基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 10中 1-腈基乙酰基 -4- (3- (3， 4， 5-三甲氧基苯胺基） -6-甲基） 嘧啶 基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将氰基乙酸改为甲磺酸。  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.
MS: [M-H]" = 475.3. MS: [M-H]" = 475.3.
1H-NMR (400 M， DMSO- e) δ 9.40 (s, 1H), 8.37 (s, 1H), 7.40 (s, 2H), 7.20(s, 1H), 4.28 (s: 2H), 3.81 (s， 6H)， 3.63 (s， 3H), 3.61-3.62 (t， 2H), 2.99 (s， 3H)， 2.86-2.89 (m， 2H)， 2.35 (s， 3H) ppm。 1H-NMR (400 M, DMSO-e) δ 9.40 (s, 1H), 8.37 (s, 1H), 7.40 (s, 2H), 7.20 (s, 1H), 4.28 (s : 2H), 3.81 (s , 6H), 3.63 (s, 3H), 3.61-3.62 (t, 2H), 2.99 (s, 3H), 2.86-2.89 (m, 2H), 2.35 (s, 3H) ppm.
Figure imgf000031_0002
Figure imgf000031_0002
1-苄基 -4- (3- ( (4- (2-吡咯垸 -1-乙氧基）苯胺基）） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 6中 1-苄基 -4- (3- (4-吗啉基苯胺基））嘧啶基-呋喃并 [3，2-c] 哌啶的 合成， 不同之处在于将 4-吗啉基苯胺改为 4- (2-吡咯烷 -1-乙氧基） 苯胺。  1-Benzyl-4-(3-((4-(2-pyridin-1-yl)anilinyl))pyrimidinyl-furo[3,2-c] piperidine is prepared in the same manner as in Example 6 Synthesis of 1-benzyl-4-(3-(4-morpholinylanilino)pyrimidinyl-furo[3,2-c]piperidine, except that 4-morpholinylaniline was changed Is 4-(2-pyrrolidin-1-ethoxy)aniline.
4- (3- (4- (2-吡咯烷 -1-乙氧基）苯胺基）） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 6中 4- (3- (4-吗啉基苯胺基）） 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 1-苄基 -4- (3- (4-吗啉基苯胺基）） 嘧啶基-呋喃并 [3，2-c] 哌啶改为 1- 苄基—4- (3- ( (4- (2-吡咯烷 -1-乙氧基） 苯胺基）） 嘧啶基-呋喃并 [3,2-c] 哌啶。 4-(3-(4-(2-Pyrrolidin-1-ethoxy)anilino))pyrimidinyl-furo[3,2-c] piperidine 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-(2-pyrrolidine)- 1-ethoxy)anilino))pyrimidinyl-furo[3,2-c]piperidine.
1-甲磺酰基 -4- (3- (4- (2-吡咯烷 -1-乙氧基） 苯胺基）） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 19中 1-甲磺酰基 -4- (3- (4- (2-吡咯烷 -1-乙氧基） 苯胺基） -6-甲基) 嘧啶基-呋喃并 [3，2-c] 哌啶， 不同之处在于将 4- (3- (4- (2-吡咯烷 -1-乙氧基） 苯胺基） -6-甲基) 嘧啶基-呋喃并 [3,2-c] 哌啶改为 4- (3- (4- (2-吡咯烷 -1-乙氧基） 苯胺基）） 嘧 啶基-呋喃并 [3,2-c] 哌啶。 1-Methanesulfonyl-4-(3-(4-(2-pyrrolidin-1-ethoxy)anilino))pyrimidinyl-furo[3,2-c] piperidine was prepared in the same manner as in Example 19 1-Methanesulfonyl-4-(3-(4-(2-pyrrolidin-1-ethoxy)anilinyl)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine , except that 4-(3-(4-(2-pyrrolidin-1-ethoxy)anilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine was changed. Is 4-(3-(4-(2-pyrrolidin-1-ethoxy)anilino))pyrimidinyl-furo[3,2-c]piperidine.
MS: [M+H]+ = 484.1. MS: [M+H] + = 484.1.
1H-NMR (400 M， CDCI3) δ 8.40-8.41 (d, 1Η), 7.53-7.55 (dd， 2H), 7.05-7.06 (d, 2H), 6.94-6.98 (m, 3H), 4.37 (s, 2H), 4.167-4.18 (t, 2H), 3.12-3.13 (t, 2H), 2.95-3.00 (m, 4H), 2.90 (s 3H)， 2.74 (s， 4H)， 1.86-1.89 (m， 4H)ppm  1H-NMR (400 M, CDCI3) δ 8.40-8.41 (d, 1Η), 7.53-7.55 (dd, 2H), 7.05-7.06 (d, 2H), 6.94-6.98 (m, 3H), 4.37 (s, 2H), 4.167-4.18 (t, 2H), 3.12-3.13 (t, 2H), 2.95-3.00 (m, 4H), 2.90 (s 3H), 2.74 (s, 4H), 1.86-1.89 (m, 4H )ppm
Figure imgf000032_0001
Figure imgf000032_0001
1-甲磺酰基 -4- (3- (4-N-甲基哌嗪基苯胺基）） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-Methanesulfonyl-4-(3-(4-N-methylpiperazinylanilino)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 16中 1-甲磺酰基 -4-( (3-苯胺基）吡咯并 [4，3-b]嘧啶基） -呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4- ( (3-苯胺基） 吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶改为 4- (3- (4-N-甲基哌嗪基苯胺基）） 嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
MS: [M+H]+ = 469.2. MS: [M+H] + = 469.2.
1H-NMR (400 M， CDCI3) δ 8.39-8.40 (d, 1Η), 7.52-7.54 (d, 2H), 7.04-7.06(dd, 2H), 6.96-6.98 (q， 3H), 4.37 (s, 2H), 3.71-3.74 (t， 2H), 3.21-3.24 (t， 4H) ,2.95-2.98 (t， 2H), 2.89(s, 3H)2.64-2.66 (t， 4H)， 2.41(s, 3H)ppm。  1H-NMR (400 M, CDCI3) δ 8.39-8.40 (d, 1Η), 7.52-7.54 (d, 2H), 7.04-7.06 (dd, 2H), 6.96-6.98 (q, 3H), 4.37 (s, (H, 2H) )ppm.
Figure imgf000032_0002
Figure imgf000032_0002
1-甲磺酰基 -4- (3- (4-N-乙基哌嗪基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 16中 1-甲磺酰基 -4-( (3-苯胺基）吡咯并 [4，3-b]嘧啶基） -呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4- ( (3-苯胺基） 吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶改为 4- (3- (4-N-乙基哌嗪基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。 1-Methanesulfonyl-4-(3-(4-N-ethylpiperazinylphenyl)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine was prepared in the same manner as in Example 16 Medium 1-methanesulfonyl-4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c] Synthesis of piperidine, except that 4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine was changed to 4-(3- (4-N-Ethylpiperazinylanilide)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
MS: [M+H]+ = 497.0. MS: [M+H] + = 497.0.
1H-NMR (500 M， DMSO- e) δ 10.41 (s, 1H), 8.48 (s, 1H), 8.20-8.23 (d, 2H), 8.07-8.09 (d， 2H), 7.33 (s， 1H), 5.75 (s， 3H), 4.30 (s， 2H), 4.18 (s， 2H), 3.59-3.61(t, 2H), 3.37-3.41(m, 2H), 2.95-2.99(m, 6H)， 2.49-2.50(t, 2H), 2.41 (s， 3H), 1.07-l.ll(t, 3H) ppm。  1H-NMR (500 M, DMSO-e) δ 10.41 (s, 1H), 8.48 (s, 1H), 8.20-8.23 (d, 2H), 8.07-8.09 (d, 2H), 7.33 (s, 1H) , 5.75 (s, 3H), 4.30 (s, 2H), 4.18 (s, 2H), 3.59-3.61 (t, 2H), 3.37-3.41 (m, 2H), 2.95-2.99 (m, 6H), 2.49 - 2.50 (t, 2H), 2.41 (s, 3H), 1.07-l.ll (t, 3H) ppm.
Figure imgf000033_0001
Figure imgf000033_0001
1-甲磺酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 16中 1-甲磺酰基 -4-( (3-苯胺基）吡咯并 [4，3-b]嘧啶基） -呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4- ( (3-苯胺基） 吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶改为 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。  1-Methanesulfonyl-4-(3-(3,5-difluoro-4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine Synthesis of 1-methanesulfonyl-4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c]piperidine in Example 16, except that Change 4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c] piperidine to 4-(3-(3,5-difluoro-4) -morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine.
MS: [M+H]+ = 506.1. MS: [M+H] + = 506.1.
1H-NMR (500 M， DMSO- e) δ 9.86 (s, 1H), 8.43 (s, 1H), 7.59-7.64 (q, 2H), 7.22 (s, 1H), 5.78 (s， 3H), 4.32 (s， 2H), 3.70 (s， 4H)， 3.01-3.05(m, 6H)， 2.53(s, 2H), 2.39(s, 3H) ppm。  1H-NMR (500 M, DMSO-e) δ 9.86 (s, 1H), 8.43 (s, 1H), 7.59-7.64 (q, 2H), 7.22 (s, 1H), 5.78 (s, 3H), 4.32 (s, 2H), 3.70 (s, 4H), 3.01-3.05 (m, 6H), 2.53 (s, 2H), 2.39 (s, 3H) ppm.
Figure imgf000033_0002
Figure imgf000033_0002
1-苄基 -4- (3-氯 -6-氟） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-benzyl-4-(3-chloro-6-fluoro)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 1中 1-苄基 -4- (3-氯 -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不 同之处在于将 2，4-二氯 -5-甲基-嘧啶改为 2，4-二氯 -5-氟-嘧啶。 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.
1-苄基 -4- (3- (3,4,5-三甲氧基苯胺基） -6-氟） 嘧啶基-呋喃并 [3,2-c] 哌啶 1-benzyl-4-(3-(3,4,5-trimethoxyanilino)-6-fluoro)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 10中 1-苄基 -4- (3- (3，4，5-三甲氧基苯胺基） -6-甲基） 嘧啶基-呋喃并 The preparation method is the same as in Example 10, 1-benzyl-4-(3-(3,4,5-trimethoxyanilino)-6-methyl)pyrimidinyl-furan.
[3,2-c] 哌啶的合成， 不同之处在于将 1-苄基 -4- (3-氯 -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶改为 1-苄基 -4- (3-氯 -6-氟） 嘧啶基-呋喃并 [3，2-c] 哌啶。 [3,2-c] Synthesis of piperidine, except that 1-benzyl-4-(3-chloro-6-methyl)pyrimidinyl-furo[3,2-c] Piperidine was changed to 1-benzyl-4-(3-chloro-6-fluoro)pyrimidinyl-furo[3,2-c]piperidine.
4- (3- (3,4,5-三甲氧基苯胺基） -6-氟） 嘧啶基-呋喃并 [3,2-c] 哌啶  4-(3-(3,4,5-Trimethoxyanilino)-6-fluoro)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 10中 4- (3- (3，4，5-三甲氧基苯胺基) -6-甲基)嘧啶基-呋喃并 [3,2-c] 哌啶的合成， 不同之处在于将 1-苄基 -4- (3- (3，4，5-三甲氧基苯胺基） -6-甲基） 嘧啶基- 呋喃并 [3，2-c]哌啶改为 1-苄基 -4-(3-(3，4，5-三甲氧基苯胺基） -6-氟）嘧啶基-呋喃并 [3，2-c] 哌啶。 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. In the case of 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.
1-甲磺酰基 -4- (3- (3， 4， 5-三甲氧基苯胺基） -6-氟） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 19中 1-甲磺酰基 -4- (3- (4- (2-吡咯烷 -1-乙氧基） 苯胺基） -6-甲基) 嘧啶基-呋喃并 [3，2-c] 哌啶， 不同之处在于将 4- (3- (4- (2-吡咯烷 -1-乙氧基） 苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶改为 4- (3- (3， 4， 5-三甲氧基苯胺基） -6-氟） 嘧 啶基-呋喃并 [3,2-c] 哌啶。  1-Methanesulfonyl-4-(3-(3,4,5-trimethoxyanilino)-6-fluoro)pyrimidinyl-furo[3,2-c] piperidine is prepared in the same manner as in Example 19 1-methanesulfonyl-4-(3-(4-(2-pyrrolidin-1-ethoxy)anilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine, The difference is that 4-(3-(4-(2-pyrrolidin-1-ethoxy)anilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine is changed to 4-(3-(3,4,5-Trimethoxyanilino)-6-fluoro)pyrimidinyl-furo[3,2-c]piperidine.
MS: [M+H]+ = 479.0. MS: [M+H] + = 479.0.
1H-NMR (500 M， DMSO- e) δ 9.66 (s, 1H), 8.57 (s, 1H), 7.38 (s, 2H), 7.27 (s, 1H), 4.28 (s， 2H), 3.81 (s， 6H)， 3.59-3.62 (m， 5H)， 2.97 (s， 3H), 2.89 (s， 2H) ppm。  1H-NMR (500 M, DMSO-e) δ 9.66 (s, 1H), 8.57 (s, 1H), 7.38 (s, 2H), 7.27 (s, 1H), 4.28 (s, 2H), 3.81 (s , 6H), 3.59-3.62 (m, 5H), 2.97 (s, 3H), 2.89 (s, 2H) ppm.
实施例 28: 化合物 28的制备
Figure imgf000034_0001
Example 28: Preparation of Compound 28
Figure imgf000034_0001
1-甲磺酰基 -4- (3- (4-硝基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-methanesulfonyl-4-(3-(4-nitroanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 16中 1-甲磺酰基 -4-( (3-苯胺基）吡咯并 [4，3-b]嘧啶基） -呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4- ( (3-苯胺基） 吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶改为 4- (3- (4-硝基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
MS: [M+H]+ = 429.9. MS: [M+H] + = 429.9.
1H-NMR (500 M， DMSO- e) δ 10.41 (s, 1H), 8.48 (s, 1H), 8.20-8.23 (d, 2H), 8.07-8.09 (d, 2H),7.13(s, 1H)， 4.18 (s, 2H), 3.59-3.60 (m， 2H), 3.39-3.41 (m， 2H), 2.99 (s, 3H), 2.41(s, 3H)ppm。  1H-NMR (500 M, DMSO-e) δ 10.41 (s, 1H), 8.48 (s, 1H), 8.20-8.23 (d, 2H), 8.07-8.09 (d, 2H), 7.13 (s, 1H) , 4.18 (s, 2H), 3.59-3.60 (m, 2H), 3.39-3.41 (m, 2H), 2.99 (s, 3H), 2.41 (s, 3H) ppm.
实施例 29: 化合物 29的制备
Figure imgf000035_0001
Example 29: Preparation of Compound 29
Figure imgf000035_0001
1-甲磺酰基 -4- (3- (4-氟苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-methanesulfonyl-4-(3-(4-fluoroanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 16中 1-甲磺酰基 -4-( (3-苯胺基）吡咯并 [4，3-b]嘧啶基） -呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4- ( (3-苯胺基） 吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶改为 4- (3- (4-氟苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
MS: [M+H]+ = 402.9. MS: [M+H] + = 402.9.
1H-NMR (500 M， CDCI3) δ 8.27 (s, 1Η), 7.61 (s, 2H), 7.07-7.29 (m， 4H)， 4.40 (s, 2H), 3.75 (s， 2H), 2.91-3.00 (m， 2H), 2.88 (s， 3H), 2.44 (s， 3H)ppm。  1H-NMR (500 M, CDCI3) δ 8.27 (s, 1Η), 7.61 (s, 2H), 7.07-7.29 (m, 4H), 4.40 (s, 2H), 3.75 (s, 2H), 2.91-3.00 (m, 2H), 2.88 (s, 3H), 2.44 (s, 3H) ppm.
Figure imgf000035_0002
Figure imgf000035_0002
1-甲磺酰基 -4- (3- (4- (2-氯 -1-乙氧基) 苯胺基） -6-三氟甲基) 嘧啶基-呋喃并 [3,2-c] 哌啶 1-methanesulfonyl-4-(3-(4-(2-chloro-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 15中 1-腈基乙酰基 -4- (3- (4- (2-氯 -1-乙氧基）苯胺基） -6-三氟甲基) 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将氰基乙酸改为甲磺酸。 The preparation method is the same as that in Example 15. 1-cyanoacetyl-4-(3-(4-(2-chloro-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furo[ 3,2-c] Synthesis of piperidine, except that cyanoacetic acid was changed to methanesulfonic acid.
1-甲磺酰基 -4- (3- (4- (2-吡咯浣基小乙氧基）苯胺基） -6-三氟甲基）嘧啶基-呋喃并 [3,2-c] 哌啶  1-methanesulfonyl-4-(3-(4-(2-pyrrolidinyl ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 15中 1-腈基乙酰基 -4- (3- (4- (2-吡咯烷基 1-乙氧基) 苯胺基） -6-三 氟甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 1-腈基乙酰基 -4- (3- (4- (2-氯 -1-乙氧基）苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶改为 1-甲磺酰基 -4- (3- (4- (2-氯 -1-乙氧基） 苯胺基） -6-三氟甲基) 嘧啶基-呋喃并 [3,2-c] 哌啶。 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.
MS: [M+H]+ = 552.2. MS: [M+H] + = 552.2.
1H-NMR (400 M， CDCls) ^8.64(s, 1H), 7.55(s, 1H), 7.48-7.50(d, 2H), 7.20(s, 1H) 6.93-6.96(d, 2H), 4.36(s, 2H), 4.13-4.16(t, 2H), 3.70-3.73(t, 2H), 2.93-2.96(t, 4H)， 2.89(s, 3H), 2.68(s, 4H)， 1.84(s， 4H)ppm。 实施例 31: 化合物 31的制备
Figure imgf000036_0001
1H-NMR (400 M, CDCls) ^8.64 (s, 1H), 7.55 (s, 1H), 7.48-7.50 (d, 2H), 7.20 (s, 1H) 6.93-6.96 (d, 2H), 4.36 ( s, 2H), 4.13-4.16(t, 2H), 3.70-3.73(t, 2H), 2.93-2.96(t, 4H), 2.89(s, 3H), 2.68(s, 4H), 1.84(s, 4H) ppm. Example 31: Preparation of Compound 31
Figure imgf000036_0001
1-甲磺酰基 -4- (3- (4-吗啉基苯胺基）） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-methanesulfonyl-4-(3-(4-morpholinylanilino)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 16中 1-甲磺酰基 -4-( (3-苯胺基）吡咯并 [4，3-b]嘧啶基） -呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4- ( (3-苯胺基） 吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶改为 4- (3- (4-吗啉基苯胺基）） 嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
MS: [M+H]+ =456.1. MS: [M+H] + =456.1.
1H-NMR(400M, CDCls) ^8.38-8.40(d, 1H), 7.54-7.56(d, 2H), 7.23(s, 1H), 7.08(s, 1H)， 6.96-6.99(t, 3H), 4.37(s, 2H), 3.90-3.92(t, 4H)， 3.72-3.75(t, 2H), 3.15-3.17(t, 4H)， 2.95-2.98 (t, 2H), 2.90(s, 3H)ppm。  1H-NMR (400M, CDCls) ^8.38-8.40 (d, 1H), 7.54-7.56 (d, 2H), 7.23 (s, 1H), 7.08 (s, 1H), 6.96-6.99 (t, 3H), 4.37(s, 2H), 3.90-3.92(t, 4H), 3.72-3.75(t, 2H), 3.15-3.17(t, 4H), 2.95-2.98 (t, 2H), 2.90(s, 3H)ppm .
实施例 32: 化合物 32的制备Example 32: Preparation of Compound 32
Figure imgf000036_0002
Figure imgf000036_0002
1-甲磺酰基 -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 16中 1-甲磺酰基 -4-( (3-苯胺基）吡咯并 [4，3-b]嘧啶基） -呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 4- ( (3-苯胺基） 吡咯并 [4，3-b] 嘧啶基） -呋喃并 [3，2-c] 哌啶改为 4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶。 1-Methanesulfonyl-4-(3-(4-morpholinylanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] piperidine is prepared in the same manner as in Example 16 Synthesis of methanesulfonyl-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-morpholinylanilino)-6-trifluoro Methyl)pyrimidinyl-furo[3,2-c] piperidine.
MS: [M+H]+ =524.3. MS: [M+H] + =524.3.
1H-NMR (400 M， DMSO-de) δ 10.05(s， 1H)， 8.72(s, 1H)， 7.61-7.63(d, 2H), 7.33(s, 1H)， 6.93-6.96(d, 2H), 4.29 (s, 2H), 3.73-3.75 (t， 4H)， 3.59(s, 2H), 3.05-3.08(t, 4H)， 2.97(s, 3H), 2.91-2.92(d, 2H) ppm。 33: 化合物 33的制备
Figure imgf000036_0003
1H-NMR (400 M, DMSO-de) δ 10.05 (s, 1H), 8.72 (s, 1H), 7.61-7.63 (d, 2H), 7.33 (s, 1H), 6.93-6.96 (d, 2H) , 4.29 (s, 2H), 3.73-3.75 (t, 4H), 3.59 (s, 2H), 3.05-3.08 (t, 4H), 2.97 (s, 3H), 2.91-2.92 (d, 2H) ppm. 33: Preparation of Compound 33
Figure imgf000036_0003
1-苄基 -4- (3- ( (4- (2-吡咯垸 -1-乙氧基）苯胺基） -6-氟-) 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 23中 1-苄基 -4- (3- ( (4- (2-吡咯烷 -1-乙氧基）苯胺基）） 嘧啶基 -呋喃 并 [3，2-c]哌啶的合成，不同之处在于将 1-苄基 -4- (3- ( (4- (2-氯） -嘧啶基-呋喃并 [3，2-c] 哌啶改为 1-苄基 -4- (3- ( (4- (2-氯 -6-氟） -嘧啶基-呋喃并 [3，2-c] 哌啶。 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.
4- (3- (4- (2-吡咯烷 -1-乙氧基）苯胺基） -6-氟） 嘧啶基-呋喃并 [3,2-c] 哌啶  4-(3- (4-(2-Pyrrolidin-1-ethoxy)anilino)-6-fluoro)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 23中 4- (3- (4- (2-吡咯烷 -1-乙氧基）苯胺基））嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 1-苄基 -4- (3- ( (4- (2-吡咯烷 -1-乙氧基）苯胺基））嘧啶基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)
-呋喃并 [3,2-c] 哌啶改为 1-苄基 -4- (3- ( (4- (2-吡咯烷 -1-乙氧基） 苯胺基） -6善) 嘧 啶基-呋喃并 [3,2-c] 哌啶。 -furo[3,2-c] piperidine is changed to 1-benzyl-4-(3-((4-(2-pyrrolidin-1-ethoxy)anilinyl)-6-pyrimidinyl- Furo[3,2-c] piperidine.
1-甲磺酰基 -4- (3- (4- (2-吡咯垸 -1-乙氧基）苯胺基） -6-氟基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-methanesulfonyl-4-(3-(4-(2-pyrrole-1-enyloxy)anilino)-6-fluoro)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 23中 1-甲磺酰基 -4- (3- (4- (2-吡咯烷 -1-乙氧基） 苯胺基）） 嘧啶基- 呋喃并 [3,2-c] 哌啶的合成， 不同之处在于将 4- (3- (4- (2-吡咯烷 -1-乙氧基） 苯胺基）） 嘧啶基-呋喃并 [3,2-c] 哌啶改为 4- (3- (4- (2-吡咯烷 -1-乙氧基） 苯胺基） -6-氟) 嘧啶 基-呋喃并 [3,2-c] 哌啶。 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.
MS: [M+H]+ =502.3. MS: [M+H] + = 502.3.
1H-NMR (400 M， CDCls) ^8.28-8.29(d, 1H)， 7.49-7.5 l(d, 2H), 7.15-7.15(d, 1H)， 7.08(s, 1H), 6.93-6.95(d, 2H), 4.39-4.41(d, 2H), 4.17-4.19(t, 2H), 3.73-3.76(t, 2H)， 3.00-3.04(m, 4H)， 2.90(s, 3H), 2.76 (s, 4H), 1.88 (s, 4H) ppm。 备
Figure imgf000037_0001
1H-NMR (400 M, CDCls) ^8.28-8.29 (d, 1H), 7.49-7.5 l(d, 2H), 7.15-7.15 (d, 1H), 7.08 (s, 1H), 6.93-6.95 (d , 2,,,, , 4H), 1.88 (s, 4H) ppm. Prepare
Figure imgf000037_0001
1-异丁酰基 -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 制备方法同实施例 8中 1-氰基乙酰基 -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋 喃并 [3，2-c] 哌啶的合成， 不同之处在于将腈基乙酸改为异丁酸。  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.
MS: [M+H]+ =516.2. MS: [M+H] + = 516.2.
1H-NMR (400 M， CDCI3) ^10.04(s, 1H), 8.73(s, 1H), 7.63-7.63(d, 2H), 7.33(s, 1H)， 6.96-6.97(d, 2H), 4.50-4.59(d, 2H), 3.81(s, 2H), 3.76(s, 4H)， 3.08(s, 4H)， 1.24-1.25(m, 3H), 1.03-1.06 (m, 6H) ppm。 备 1H-NMR (400 M, CDCI3) ^10.04 (s, 1H), 8.73 (s, 1H), 7.63-7.63 (d, 2H), 7.33 (s, 1H), 6.96-6.97 (d, 2H), 4.50 -4.59 (d, 2H), 3.81 (s, 2H), 3.76 (s, 4H), 3.08 (s, 4H), 1.24-1.25 (m, 3H), 1.03-1.06 (m, 6H) ppm. Prepare
Figure imgf000038_0001
Figure imgf000038_0001
1- (4-腈基苯甲酰基） -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-(4-cyanobenzoyl)-4-(3-(4-morpholinoanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 8中 1-氰基乙酰基 -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋 喃并 [3，2-c] 哌啶的合成， 不同之处在于将腈基乙酸改为 4-腈基苯甲酸。 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.
MS: [M+H]+ =575.3. MS: [M+H] + =575.3.
1H-NMR (400 M， DMSO- e) δ 10.02-10.05 (d， 1H), 8.73 (s, 1H), 7.95-7.97 (d, 3H), 7.62 -7.7 l(m, 3H), 6.95(s， 2H), 4.68 (s， 2H), 4.38 (s， 1H), 4.03-4.04 (m， 2H), 3.74-3.76 (m， 4H)， 3.06-3.08 (m, 4H), 2.86-2.88 (m, 2H) ppm。 实施例 36: 化合物 36的制备  1H-NMR (400 M, DMSO-e) δ 10.02-10.05 (d, 1H), 8.73 (s, 1H), 7.95-7.97 (d, 3H), 7.62 -7.7 l(m, 3H), 6.95(s , 2H), 4.68 (s, 2H), 4.38 (s, 1H), 4.03-4.04 (m, 2H), 3.74-3.76 (m, 4H), 3.06-3.08 (m, 4H), 2.86-2.88 (m , 2H) ppm. Example 36: Preparation of Compound 36
Figure imgf000038_0002
Figure imgf000038_0002
1- ( 3-腈基苯甲酰基) -4- (3- (4-吗啉基苯胺基) -6-三氟甲基) 嘧啶基-呋喃并 [3,2-c] 哌啶  1-(3-Nitrilebenzoyl)-4-(3-(4-morpholinoanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 8中 1-氰基乙酰基 -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋 喃并 [3，2-c] 哌啶的合成， 不同之处在于将腈基乙酸改为 3-腈基苯甲酸 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
MS: [M+H]+ =575.3. MS: [M+H] + =575.3.
1H-NMR (400 M， DMSO- e) δ 10. 05 (s, 1H), 8.73 (s, 1H), 8.23-8.28 (m， 2H), 8.07-8.09 (d， 2H), 7.97 -7.99(d, 2H), 7.83(s, 1H), 6.96(s， 2H), 4.68 (s, 1H), 4.43 (s, 1H), 4.03 (s, 2H), 3.75 (s， 4H)， 3.07 (s， 4H)， 2.90 (s， 2H) ppm。  1H-NMR (400 M, DMSO-e) δ 10. 05 (s, 1H), 8.73 (s, 1H), 8.23-8.28 (m, 2H), 8.07-8.09 (d, 2H), 7.97 -7.99 ( d, 2H), 7.83(s, 1H), 6.96(s, 2H), 4.68 (s, 1H), 4.43 (s, 1H), 4.03 (s, 2H), 3.75 (s, 4H), 3.07 (s , 4H), 2.90 (s, 2H) ppm.
Figure imgf000038_0003
1- (噻吩 -2-甲酰基） -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌 啶
Figure imgf000038_0003
1-(thiophene-2-formyl)-4-(3-(4-morpholinoanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c]piperidine
制备方法同实施例 8中 1-氰基乙酰基 -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋 喃并 [3，2-c] 哌啶的合成， 不同之处在于将腈基乙酸改为噻吩 -2-甲酸 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
MS: [M+H]+ =556.0. MS: [M+H] + = 556.0.
1H-NMR (400 M， DMSO-de) ^10.03(s, 1H), 8.71(s, 1H), 7.61-7.63(d, 2H), 7.30-7.32(d, 1H), 6.94-6.96(d, 2H), 4.49(s， 2H), 3.78-3.79, 3.83-3.85(dd, 2H), 3.73-3.77(q, 4H)， 3.05-3.08(t, 4H)， 2.86-2.75(dd, 2H), 2.49-2.52(t, 2H), 1.00-1.03(t, 3H)ppm。 实施例 38: 化合物 38的制备
Figure imgf000039_0001
1H-NMR (400 M, DMSO-de) ^10.03 (s, 1H), 8.71 (s, 1H), 7.61-7.63 (d, 2H), 7.30-7.32 (d, 1H), 6.94-6.96 (d, 2H), 4.49(s, 2H), 3.78-3.79, 3.83-3.85(dd, 2H), 3.73-3.77(q, 4H), 3.05-3.08(t, 4H), 2.86-2.75(dd, 2H), 2.49-2.52 (t, 2H), 1.00-1.03 (t, 3H) ppm. Example 38: Preparation of Compound 38
Figure imgf000039_0001
1-丙酰 -4- (3- (4-吗啉基苯胺基） -6-三氟甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-propionyl-4-(3-(4-morpholinoanilino)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c] piperidine
制备方法同实施例 32中 1-甲磺酰基 -4- (3- (4-吗啉基苯胺基） -6-三氟甲基）嘧啶基 -呋喃 并 [3，2-c] 哌啶的合成， 不同之处在于将甲磺酰氯改为丙酰氯。 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.
MS: [M+H]+ =502.3. MS: [M+H] + = 502.3.
1H-NMR (400 M， DMSO-de) ^10.03(s, 1H), 8.71(s, 1H), 7.61-7.63(d, 2H), 7.30-7.32(d, 1H), 6.94-6.96(d, 2H), 4.49(s， 2H), 3.78-3.79, 3.83-3.85(dd, 2H), 3.73-3.77(q, 4H)， 3.05-3.08(t, 4H)， 2.86-2.75(dd, 2H), 2.49-2.5 l(t, 2H), 1.00-1.03(t, 3H)ppm。  1H-NMR (400 M, DMSO-de) ^10.03 (s, 1H), 8.71 (s, 1H), 7.61-7.63 (d, 2H), 7.30-7.32 (d, 1H), 6.94-6.96 (d, 2H), 4.49(s, 2H), 3.78-3.79, 3.83-3.85(dd, 2H), 3.73-3.77(q, 4H), 3.05-3.08(t, 4H), 2.86-2.75(dd, 2H), 2.49-2.5 l(t, 2H), 1.00-1.03 (t, 3H) ppm.
Figure imgf000039_0002
Figure imgf000039_0002
1- ( 3-腈基苯甲酰基） -4- (3- (4- (2-氯小乙氧基） 苯胺基） -6-三氟甲基） 嘧啶基 -呋喃 并 [3,2-c] 哌啶 1-(3-cyanobenzoyl)-4-(3-(4-(2-chlorosuccinyl)anilinyl)-6-trifluoromethyl)pyrimidinyl-furo[3,2- c] piperidine
制备方法同实施例 15中 1-腈基乙酰基 -4- (3- (4- (2-氯 -1-乙氧基）苯胺基） -6-三氟甲基) 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将氰基乙酸改为 3-腈基苯甲酸。 The preparation method is the same as that in Example 15. 1-cyanoacetyl-4-(3-(4-(2-chloro-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furo[ 3,2-c] Synthesis of piperidine, except that cyanoacetic acid was changed to 3-nitrile benzoic acid.
1- (3-腈基苯甲酰基） -4- (3- (4- (2-吡咯浣基 -1-乙氧基）苯胺基） -6-三氟甲基）嘧啶基 -呋喃并 [3,2-c] 哌啶 1-(3-cyanobenzoyl)-4-(3-(4-(2-pyrrolidinyl-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl -furo[3,2-c] piperidine
制备方法同实施例 15中 1-腈基乙酰基 -4- (3- (4- (2-吡咯烷基 1-乙氧基) 苯胺基） -6-三 氟甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 1-腈基乙酰基 -4- (3- (4- (2-氯 -1-乙氧基) 苯胺基） -6-三氟甲基) 嘧啶基-呋喃并 [3,2-c] 哌啶改为 1- (3-腈基苯 甲酰基） —4- (3- (4- (2-氯 -1-乙氧基） 苯胺基） -6-三氟甲基) 嘧啶基-呋喃并 [3,2-c] 哌 啶。 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.
MS: [M+H]+ = 603.3. MS: [M+H] + = 603.3.
1H-NMR (400 M， DMSO- e) δ 10.15 (s， 1H), 8.75 (s， 1H), 7.97-7.99 (d， 2H), 7.82 -7.84(d, 1H)， 7.68-7.72(t, 3H), 7.03 (s， 2H), 4.67 (s， 2H), 4.42 (s， 3H), 4.27 (s， 2H), 2.90 (s， 4H)， 1.95 (s， 4H)， 1.24-1.27 (m， 4H) ppm。 实施例 40: 化合物 40的制备
Figure imgf000040_0001
1H-NMR (400 M, DMSO-e) δ 10.15 (s, 1H), 8.75 (s, 1H), 7.97-7.99 (d, 2H), 7.82 -7.84 (d, 1H), 7.68-7.72 (t, 3H), 7.03 (s, 2H), 4.67 (s, 2H), 4.42 (s, 3H), 4.27 (s, 2H), 2.90 (s, 4H), 1.95 (s, 4H), 1.24-1.27 (m , 4H) ppm. Example 40: Preparation of Compound 40
Figure imgf000040_0001
1- (4-腈基苯甲酰基） -4- (3- (4- (2-氯小乙氧基） 苯胺基） -6-三氟甲基） 嘧啶基 -呋喃 并 [3,2-c] 哌啶  1-(4-cyanobenzoyl)-4-(3-(4-(2-chlorosuccinyl)anilinyl)-6-trifluoromethyl)pyrimidinyl-furo[3,2- c] piperidine
制备方法同实施例 15中 1-腈基乙酰基 -4- (3- (4- (2-氯 -1-乙氧基）苯胺基） -6-三氟甲基) 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将氰基乙酸改为 4-腈基苯甲酸。 The preparation method is the same as that in Example 15. 1-cyanoacetyl-4-(3-(4-(2-chloro-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furo[ 3,2-c] Synthesis of piperidine, except that cyanoacetic acid was changed to 4-nitrile benzoic acid.
1- (4-腈基苯甲酰基） -4- (3- (4- (2-吡咯浣基 -1-乙氧基）苯胺基） -6-三氟甲基）嘧啶基 -呋喃并 [3,2-c] 哌啶 1-(4-cyanobenzoyl)-4-(3-(4-(2-pyrrolidinyl-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furo[ 3,2-c] piperidine
制备方法同实施例 15中 1-腈基乙酰基 -4- (3- (4- (2-吡咯烷基 1-乙氧基) 苯胺基） -6-三 氟甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将 1-腈基乙酰基 -4- (3- (4- (2-氯 -1-乙氧基) 苯胺基） -6-三氟甲基) 嘧啶基-呋喃并 [3,2-c] 哌啶改为 1- (4-腈基苯 甲酰基） —4- (3- (4- (2-氯 -1-乙氧基） 苯胺基） -6-三氟甲基) 嘧啶基-呋喃并 [3,2-c] 哌 啶。 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.
MS: [M+H]+ = 603.3. MS: [M+H] + = 603.3.
1H-NMR (400 M， DMSO- e) δ 10.11 (s， 1H), 8.74 (s， 1H), 7.95-7.97 (d， 2H), 7.68(s, 4H)， 6.96(s， 2H), 4.76 (s, 1H), 4.37 (s, 1H), 4.03-4.12 (m， 4H)， 3.01-3.03 (m， 3H), 2.80-2.86 (m， 2H) 1.78(s, 4H)， 1.23-1.25(m, 4H) ppm。
Figure imgf000041_0001
1H-NMR (400 M, DMSO-e) δ 10.11 (s, 1H), 8.74 (s, 1H), 7.95-7.97 (d, 2H), 7.68 (s, 4H), 6.96 (s, 2H), 4.76 (s, 1H), 4.37 (s, 1H), 4.03-4.12 (m, 4H), 3.01-3.03 (m, 3H), 2.80-2.86 (m, 2H) 1.78(s, 4H), 1.23-1.25 ( m, 4H) ppm.
Figure imgf000041_0001
1- -4- (3- (4-N-甲基哌嗪基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶 1- -4- (3-(4-N-methylpiperazinylphenyl)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine
Figure imgf000041_0002
Figure imgf000041_0002
向反应瓶中加入 1-苄基 -4- ( 3-氯 -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 （2.5g， leq)， 4- (4-N-甲基哌嗪基） 苯胺 （1.4g， leq)， 二氧六环的盐酸溶液 （6M) (2.8mL， 2.2eq), 碘 化钾（0.5g， 0.04eq)， 三氟乙醇 10mL， 170°C微波反应 1小时。停止反应， 加水（10 mL)， 饱和 NaHC03水溶液洗， 二氯甲烷 （10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽 滤， 浓縮， 粗品硅胶柱层析得到 1-苄基 -4- (3- (4-N-甲基哌嗪基苯胺基） -6-甲基） 嘧啶 基-呋喃并 [3,2-c] 哌啶 ( 1.63g To the reaction flask was added 1-benzyl-4-(3-chloro-6-methyl)pyrimidinyl-furo[3,2-c]piperidine (2.5 g, leq), 4- (4-N- Methyl piperazinyl) aniline (1.4g, leq), dioxane in hydrochloric acid (6M) (2.8mL, 2.2eq), potassium iodide (0.5g, 0.04eq), trifluoroethanol 10mL, 170°C microwave Reaction for 1 hour. The reaction was stopped, water (10 mL), washed with saturated aqueous NaHC0 3, (10 mL * 5). The combined methylene chloride organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and the crude product on silica gel column chromatography to give 1- Benzyl-4-(3-(4-N-methylpiperazinylanilide)-6-methyl)pyrimidinyl-furo[3,2-c] piperidine ( 1.63g
MS: [M+H]+ = 495.3. MS: [M+H] + = 495.3.
1H-NMR (400 M， DMSO- e) δ 9.22 (s, 1H), 8.26 (s, 1H), 7.63-7.66 (d, 2H), 7.34 -7.39(m, 4H)， 7.26-7.30(m, 1H)， 7.07 (s, 1H)， 6.87-6.89 (d, 2H), 3.72 (s, 2H), 3.40 (s, 2H), 3.03-3.06 (t， 4H)， 2.82-2.84 (d， 2H), 2.79-2.80 (d， 2H), 2.45-2.47 (t， 4H)， 2.32 (s， 3H), 2.23 (s， 3H)ppm。 实施例 42: 化合物 42的制备
Figure imgf000041_0003
1H-NMR (400 M, DMSO-e) δ 9.22 (s, 1H), 8.26 (s, 1H), 7.63-7.66 (d, 2H), 7.34 -7.39 (m, 4H), 7.26-7.30 (m, 1H), 7.07 (s, 1H), 6.87-6.89 (d, 2H), 3.72 (s, 2H), 3.40 (s, 2H), 3.03-3.06 (t, 4H), 2.82-2.84 (d, 2H) , 2.79-2.80 (d, 2H), 2.45-2.47 (t, 4H), 2.32 (s, 3H), 2.23 (s, 3H) ppm. Example 42: Preparation of Compound 42
Figure imgf000041_0003
1-异丁酰基 -4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3,2-c] 哌啶  1-isobutyryl-4-(3-(4-morpholinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine
向反应瓶中加入 4- (3- (4-吗啉基苯胺基） -6-甲基）嘧啶基-呋喃并 [3，2-c]哌啶 （70mg， leq)， 异丁酸 （15.7mg， leq), 1-羟基-苯并-三氮唑 （60.3mg， 2.5eq)， 1-乙基 -3-(3-二甲 胺丙基)碳二亚胺盐酸盐 （85.6mg， 2.5eq)， 催化量的 DIPEA和二氯甲烷 （15mL)， 室温 反应 4小时， 电磁搅拌。 停止反应， 加水 （20 mL)， 饱和 NaHC03水溶液洗， 二氯甲烷 ( 10 mL*5 ) 萃取， 合并有机相， 无水硫酸钠干燥， 抽滤， 浓縮， 粗品硅胶柱层析得到 1- 异丁酰基 -4- (3- (4-吗啉基苯胺基） -6-甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶 （53.7mg)。 MS: [M+H]+ = 462.3. Ή-NMR (500 M， DMSO- 6) δ 9.26 (s, 1H), 8.29 (s, 1H), 7.66-7.68 (d, 2H), 7.18 (s, 1H): 6.89-6.92 (d, 2H), 4.57 (s, 1H), 4.49 (s, 1H), 3.85-3.87 (t, 2H), 3.73-3.76 (t, 4H)， 3.02-3.05 (t 4H)， 2.88-2.90 (m， 2H), 2.74-2.79 (m， 1H), 2.35 (s, 3H), 0.98-1.07 (m， 6H)ppm。 43: 化合物 43的制备 To the reaction flask was added 4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine (70 mg, leq), isobutyric acid (15.7) Mg, leq), 1-hydroxy-benzo-triazole (60.3 mg, 2.5 eq), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (85.6 mg, 2.5 eq), a catalytic amount of DIPEA and dichloromethane (15 mL) were reacted at room temperature for 4 hours with electromagnetic stirring. The reaction was stopped, water (20 mL), washed with saturated aqueous NaHC0 3, (10 mL * 5). The combined methylene chloride organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and the crude product on silica gel column chromatography to give 1- Isobutyryl-4-(3-(4-morpholinylanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piperidine (53.7 mg). MS: [M+H] + = 462.3. Ή-NMR (500 M, DMSO- 6 ) δ 9.26 (s, 1H), 8.29 (s, 1H), 7.66-7.68 (d, 2H), 7.18 (s, 1H) : 6.89-6.92 (d, 2H) , 4.57 (s, 1H), 4.49 (s, 1H), 3.85-3.87 (t, 2H), 3.73-3.76 (t, 4H), 3.02-3.05 (t 4H), 2.88-2.90 (m, 2H), 2.74-2.79 (m, 1H), 2.35 (s, 3H), 0.98-1.07 (m, 6H) ppm. 43: Preparation of Compound 43
Figure imgf000042_0001
Figure imgf000042_0001
1-腈基乙酰基 -4- ((3-苯胺基） 吡咯并 [4,3-b ]嘧啶基） -呋喃并 [3,2-c] 哌啶  1-cyanoacetyl-4-((3-anilino)pyrrolo[4,3-b]pyrimidinyl)-furo[3,2-c] piperidine
制备方法同实施例 1中 1-腈基酰基 -4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基） 嘧啶基- 呋喃并 [3，2-c]哌啶的合成， 不同之处在于将 4- (3- (3,5-二氟 -4-吗啉基苯胺基） -6-甲基) 嘧啶基-呋喃并 [3，2-c]哌啶改为 4- ( (3-苯胺基）吡咯并 [4，3-b]嘧啶基） -呋喃并 [3，2-c] 哌啶。 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.
MS: [M+H]+ = 399.1. MS: [M+H] + = 399.1.
1H-NMR (500 M， DMSO- e) δ 11.59 (s, 1H), 9.24 (s, 1H), 7.90 -7.92(dd, 2H), 7.28-7.23 (m， 4H)， 6.89-6.91 (t， 1H), 6.75-6.77 (dd， 1H), 4.54 (s, 2H), 4.18-4.20(d, 2H), 3.92-3.70 (dt, 2H), 2.96 -2.82(dt, 2H) ppm。 实施例 44: 化合物 44的制备
Figure imgf000042_0002
1H-NMR (500 M, DMSO-e) δ 11.59 (s, 1H), 9.24 (s, 1H), 7.90 -7.92 (dd, 2H), 7.28-7.23 (m, 4H), 6.89-6.91 (t, 1H), 6.75-6.77 (dd, 1H), 4.54 (s, 2H), 4.18-4.20 (d, 2H), 3.92-3.70 (dt, 2H), 2.96 -2.82 (dt, 2H) ppm. Example 44: Preparation of Compound 44
Figure imgf000042_0002
1-甲磺酰基 -4- (3- (4- (2- (N-甲基-哌嗪基 -1-乙氧基）苯胺基） -6-三氟甲基） 嘧啶基-呋 喃并 [3,2-c] 哌啶  1-Methanesulfonyl-4-(3-(4-(2-(N-methyl-piperazinyl-1-ethoxy)anilinyl)-6-trifluoromethyl)pyrimidinyl-furo[ 3,2-c] piperidine
制备方法同实施例 30中 1-甲磺酰基 -4- (3- (4- (2-吡咯烷基 -1-乙氧基） 苯胺基） -6-三氟 甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将吡咯烷改为 N-甲基哌嗪。 MS: [M+H]+ =581.3. The preparation method is the same as in Example 30, 1-methylsulfonyl-4-(3-(4-(2-pyrrolidinyl-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furan. [3,2-c] Synthesis of piperidine, except that pyrrolidine was changed to N-methylpiperazine. MS: [M+H] + = 581.3.
1H-NMR (500 M， CDCls) ^8.65(s, 1H), 7.50-7.52(d, 2H), 7.31(s, 1H), 7.22(s, 1H), 6.94-6.96 (d: 2H), 4.39(s, 2H), 4.13-4.16(t, 2H), 3.72-3.75(t, 2H), 2.97-3.00(t, 2H), 2.91(s, 3H), 2.84-2.87(t, 2H), 2.59-2.69(m, 8H)， 2.34(s, 3H)ppm。
Figure imgf000043_0001
1H-NMR (500 M, CDCls) ^8.65 (s, 1H), 7.50-7.52 (d, 2H), 7.31 (s, 1H), 7.22 (s, 1H), 6.94-6.96 (d : 2H), 4.39 (s, 2H), 4.13-4.16(t, 2H), 3.72-3.75(t, 2H), 2.97-3.00(t, 2H), 2.91(s, 3H), 2.84-2.87(t, 2H), 2.59 -2.69 (m, 8H), 2.34 (s, 3H) ppm.
Figure imgf000043_0001
1-甲磺酰基 -4- (3- (4- (2- (3, 5-二甲基哌啶基小乙氧基）苯胺基） -6-三氟甲基）嘧啶基 -呋喃并 [3,2-c] 哌啶  1-methanesulfonyl-4-(3-(4-(2-(3,5-dimethylpiperidinyl)ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furo[ 3,2-c] piperidine
制备方法同实施例 30中 1-甲磺酰基 -4- (3- (4- (2-吡咯烷基 -1-乙氧基） 苯胺基） -6-三氟 甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将吡咯烷改为 3， 5-二甲基哌啶 基。 The preparation method is the same as in Example 30, 1-methylsulfonyl-4-(3-(4-(2-pyrrolidinyl-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furan. [3,2-c] Synthesis of piperidine, except that pyrrolidine was changed to 3,5-dimethylpiperidinyl.
MS: [M+H]+ =594.1. MS: [M+H] + =594.1.
1H-NMR (500 M， CDCls) ^8.66(s, 1H), 7.50-7.52(d, 2H), 7.29(s, 1H), 7.22(s, 1H), 6.95-6.97 (d: 2H), 4.39(s, 2H), 4.12-4.15(t, 2H), 3.72-3.75(t, 2H), 3.01-3.03(t, 2H), 2.98-2.99(d, 2H), 2.91(s, 3H), 2.81-2.84(t, 2H), 1.88-1.91(d, 2H), 1.61-1.65(m, 4H)， 0.88-0.90(d, 6H) ppm 46: 化合物 46的制备
Figure imgf000043_0002
1H-NMR (500 M, CDCls) ^8.66 (s, 1H), 7.50-7.52 (d, 2H), 7.29 (s, 1H), 7.22 (s, 1H), 6.95-6.97 (d : 2H), 4.39 (s, 2H), 4.12-4.15(t, 2H), 3.72-3.75(t, 2H), 3.01-3.03(t, 2H), 2.98-2.99(d, 2H), 2.91(s, 3H), 2.81 -2.84(t, 2H), 1.88-1.91(d, 2H), 1.61-1.65 (m, 4H), 0.88-0.90 (d, 6H) ppm 46: Preparation of Compound 46
Figure imgf000043_0002
1-甲磺酰基 -4- (3- (4- (2- (4-环丙基甲酰基哌啶基 -1-乙氧基）苯胺基） -6-三氟甲基）嘧 啶基-呋喃并 [3,2-c] 哌啶  1-Methanesulfonyl-4-(3-(4-(2-(4-cyclopropylformylpiperidinyl-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furan And [3,2-c] piperidine
制备方法同实施例 30中 1-甲磺酰基 -4- (3- (4- (2-吡咯烷基 -1-乙氧基） 苯胺基） -6-三氟 甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将吡咯烷改为 4-环丙基甲酰基 哌啶。 The preparation method is the same as in Example 30, 1-methylsulfonyl-4-(3-(4-(2-pyrrolidinyl-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furan. [3,2-c] Synthesis of piperidine, except that pyrrolidine was changed to 4-cyclopropylformyl piperidine.
MS: [M+H]+ =635.2 MS: [M+H] + =635.2
1H-NMR (500 M， CDCI3) ^8.66(s, 1H), 7.53-7.54(d, 2H), 7.29(s, 1H), 7.22(s, 1H), 6.94-6.97 (d: 2H), 4.38(s, 2H), 4.14-4.17(t, 2H), 3.64-3.75(m, 9H)， 3.40-3.41(d, 2H), 2.98-3.01(t, 2H), 2.91(s: 3H), 2.86-2.89(t, 2H), 2.59-2.66(d, 4H)ppm 实施例 47: 化合物 47的制备
Figure imgf000044_0001
1H-NMR (500 M, CDCI3) ^8.66 (s, 1H), 7.53-7.54 (d, 2H), 7.29 (s, 1H), 7.22 (s, 1H), 6.94-6.97 (d : 2H), 4.38 (s, 2H), 4.14-4.17(t, 2H), 3.64-3.75(m, 9H), 3.40-3.41(d, 2H), 2.98-3.01(t, 2H), 2.91(s : 3H), 2.86 -2.89 (t, 2H), 2.59-2.66 (d, 4H) ppm Example 47: Preparation of Compound 47
Figure imgf000044_0001
1-甲磺酰基 -4- (3- (4- (2- (N-乙基-哌嗪基 -1-乙氧基）苯胺基） -6-三氟甲基） 嘧啶基-呋 喃并 [3,2-c] 哌啶  1-Methanesulfonyl-4-(3-(4-(2-(N-ethyl-piperazinyl-1-ethoxy)anilinyl)-6-trifluoromethyl)pyrimidinyl-furo[ 3,2-c] piperidine
制备方法同实施例 30中 1-甲磺酰基 -4- (3- (4- (2-吡咯烷基 -1-乙氧基） 苯胺基） -6-三氟 甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将吡咯烷改为 N-乙基哌嗪。 MS: [M+H]+ =595.3 The preparation method is the same as in Example 30, 1-methylsulfonyl-4-(3-(4-(2-pyrrolidinyl-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furan. [3,2-c] Synthesis of piperidine, except that pyrrolidine was changed to N-ethylpiperazine. MS: [M+H] + =595.3
1H-NMR (500 M， CDCls) ^8.66(s, 1H), 7.50-7.52(d, 2H), 7.28(s, 1H), 7.22(s, 1H), 6.94-6.96 (d: 2H), 4.39(s, 2H), 4.13-4.16(t, 2H), 3.72-3.75(t, 2H), 2.98-3.01(t, 2H), 2.91(s, 3H), 2.85-2.88(t, 2H), 2.70(bs, 4H)， 2.66(bs, 3H), 2.46-2.5 l(q, 3H), l.ll-1.15(t, 3H)ppm 1H-NMR (500 M, CDCls) ^8.66 (s, 1H), 7.50-7.52 (d, 2H), 7.28 (s, 1H), 7.22 (s, 1H), 6.94-6.96 (d : 2H), 4.39 (s, 2H), 4.13-4.16(t, 2H), 3.72-3.75(t, 2H), 2.98-3.01(t, 2H), 2.91(s, 3H), 2.85-2.88(t, 2H), 2.70 (bs, 4H), 2.66(bs, 3H), 2.46-2.5 l(q, 3H), l.ll-1.15(t, 3H)ppm
Figure imgf000044_0002
Figure imgf000044_0002
1-甲磺酰基 -4- (3- (4- (2- (哌啶基 -1-乙氧基）苯胺基） -6-三氟甲基）嘧啶基-呋喃并 [3,2-c] 哌啶  1-methanesulfonyl-4-(3-(4-(2-(piperidinyl-1-ethoxy)anilinyl)-6-trifluoromethyl)pyrimidinyl-furo[3,2-c Piperidine
制备方法同实施例 30中 1-甲磺酰基 -4- (3- (4- (2-吡咯烷基 -1-乙氧基） 苯胺基） -6-三氟 甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将吡咯烷改为哌啶。 The preparation method is the same as in Example 30, 1-methylsulfonyl-4-(3-(4-(2-pyrrolidinyl-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furan. [3,2-c] Synthesis of piperidine, except that pyrrolidine was changed to piperidine.
哌啶。 Piperidine.
MS: [M+H]+ =566.3 MS: [M+H] + =566.3
1H-NMR (500 M， CDCI3) ^8.65(s, 1H), 7.49-7.52(d, 2H), 7.29(s, 1H), 7.22(s, 1H), 6.94-6.96(d, 2H), 4.39(s, 2H), 4.14-4.17(t, 2H), 3.72-3.75(t, 2H), 2.98-3.00(t, 2H), 2.91(s, 3H), 2.82-2.85(t, 2H), 2.57(s, 4H), 1.63-1.69(q, 4H), 1.48-1.51(t, 2H)ppm 实施例 49: 化合物 49的制备 1H-NMR (500 M, CDCI3) ^8.65 (s, 1H), 7.49-7.52 (d, 2H), 7.29 (s, 1H), 7.22 (s, 1H), 6.94-6.96 (d, 2H), 4.39 (s, 2H), 4.14-4.17(t, 2H), 3.72-3.75(t, 2H), 2.98-3.00(t, 2H), 2.91(s, 3H), 2.82-2.85(t, 2H), 2.57 (s, 4H), 1.63-1.69 (q, 4H), 1.48-1.51 (t, 2H) ppm Example 49: Preparation of Compound 49
H
Figure imgf000044_0003
H
Figure imgf000044_0003
1-甲磺酰基 -4- (3- (4- (2- (4-羟乙基哌啶基 -1-乙氧基）苯胺基） -6-三氟甲基） 嘧啶基- 呋喃并 [3,2-c] 哌啶 制备方法同实施例 30中 1-甲磺酰基 -4- (3- (4- (2-吡咯烷基 -1-乙氧基） 苯胺基） -6-三氟 甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将吡咯烷改为 4-羟乙基哌啶。 MS: [M+H]+ =610.3 1-Methanesulfonyl-4-(3-(4-(2-(4-hydroxyethylpiperidinyl-1-ethoxy)anilinyl)-6-trifluoromethyl)pyrimidinyl-furo[ 3,2-c] piperidine The preparation method is the same as in Example 30, 1-methylsulfonyl-4-(3-(4-(2-pyrrolidinyl-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furan. [3,2-c] Synthesis of piperidine, except that pyrrolidine was changed to 4-hydroxyethylpiperidine. MS: [M+H] + =610.3
1H-NMR (500 M， CDCls) ^8.66(s, 1H), 7.49-7.52(d, 2H), 7.28(s, 1H), 7.21(s, 1H), 6.94-6.96 (d: 2H), 4.39(s, 2H), 4.14-4.17(t, 2H), 3.71-3.75(m, 4H)， 3.03-3.06(d, 2H), 2.98-3.00(t, 3H), 2.91(s, 3H), 2.82-2.85(t, 2H), 2.15(s, 2H), 1.73-1.76(d, 3H), 1.15-1.57(q, 4H)ppm 1H-NMR (500 M, CDCls) ^8.66 (s, 1H), 7.49-7.52 (d, 2H), 7.28 (s, 1H), 7.21 (s, 1H), 6.94-6.96 (d : 2H), 4.39 (s, 2H), 4.14-4.17(t, 2H), 3.71-3.75(m, 4H), 3.03-3.06(d, 2H), 2.98-3.00(t, 3H), 2.91(s, 3H), 2.82 -2.85(t, 2H), 2.15(s, 2H), 1.73-1.76(d, 3H), 1.15-1.57(q, 4H)ppm
Figure imgf000045_0001
Figure imgf000045_0001
1-甲磺酰基 -4- (3- (4- (2- (4-羟基哌啶基 -1-乙氧基） 苯胺基） -6-三氟甲基） 嘧啶基-呋 喃并 [3,2-c] 哌啶  1-methanesulfonyl-4-(3-(4-(2-(4-hydroxypiperidinyl-1-ethoxy)anilinyl)-6-trifluoromethyl)pyrimidinyl-furo[3, 2-c] piperidine
制备方法同实施例 30中 1-甲磺酰基 -4- (3- (4- (2-吡咯烷基 -1-乙氧基） 苯胺基） -6-三氟 甲基） 嘧啶基-呋喃并 [3，2-c] 哌啶的合成， 不同之处在于将吡咯烷改为 4-羟基哌啶。 MS: [M+H]+ =582.2 The preparation method is the same as in Example 30, 1-methylsulfonyl-4-(3-(4-(2-pyrrolidinyl-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furan. [3,2-c] Synthesis of piperidine, except that pyrrolidine was changed to 4-hydroxypiperidine. MS: [M+H] + =582.2
1H-NMR (500 M， CDCI3) ^8.66(s, 1H), 7.50-7.52(d, 2H), 7.28(s, 1H), 7.22(s, 1H), 6.94-6.96 (d: 2H), 4.39(s, 2H), 4.13-4.16(t, 2H), 3.72-3.75(t, 2H), 2.98-3.00(t， 2H), 2.93(s, 2H), 2.91(s, 3H), 2.84-2.87(t, 2H), 2.36(s, 2H), 1.95-1.97(d, 2H), 1.61-1.70(m, 4H)ppm 51: 化合物 51的制备
Figure imgf000045_0002
1H-NMR (500 M, CDCI3) ^8.66 (s, 1H), 7.50-7.52 (d, 2H), 7.28 (s, 1H), 7.22 (s, 1H), 6.94-6.96 (d : 2H), 4.39 (s, 2H), 4.13-4.16(t, 2H), 3.72-3.75(t, 2H), 2.98-3.00(t, 2H), 2.93(s, 2H), 2.91(s, 3H), 2.84-2.87 (t, 2H), 2.36 (s, 2H), 1.95-1.97 (d, 2H), 1.61-1.70 (m, 4H) ppm 51: Preparation of Compound 51
Figure imgf000045_0002
1-甲磺酰基 -4- (3- (4- (2- (4-哌啶基小哌啶基小乙氧基）苯胺基） -6-三氟甲基）嘧啶基 -呋喃并 [3,2-c] 哌啶  1-Methanesulfonyl-4-(3-(4-(2-(4-piperidinylpiperidyl)ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furo[3 ,2-c] piperidine
制备方法同实施例 30中 1-甲磺酰基 -4- (3- (4- (2-吡咯烷基 -1-乙氧基） 苯胺基） -6-三氟 甲基）嘧啶基-呋喃并 [3，2-c]哌啶的合成， 不同之处在于将吡咯烷改为 4-哌啶基 -1-哌啶。 MS: [M+H]+ =648.2 The preparation method is the same as in Example 30, 1-methylsulfonyl-4-(3-(4-(2-pyrrolidinyl-1-ethoxy)anilino)-6-trifluoromethyl)pyrimidinyl-furan. Synthesis of [3,2-c]piperidine, except that pyrrolidine was changed to 4-piperidinyl-1-piperidine. MS: [M+H] + =648.2
1H-NMR (500 M， CDCI3) ^8.65(s, 1H), 7.50-7.52(d, 2H), 7.30(s, 1H), 7.21(s, 1H), 6.93-6.96 (d: 2H), 4.38(s, 2H), 4.11-4.14(t, 2H), 3.72-3.75(t, 2H), 3.10-3.12(d, 2H), 2.97-2.99(t, 2H), 2.91(s, 3H), 2.81-2.83(t, 2H), 2.63(s, 4H)， 2.12-2.18(t, 2H), 1.88-1.91(d, 3H), 1.66-1.74(m, 6H)， 1.491H-NMR (500 M, CDCI3) ^8.65 (s, 1H), 7.50-7.52 (d, 2H), 7.30 (s, 1H), 7.21 (s, 1H), 6.93-6.96 (d : 2H), 4.38 (s, 2H), 4.11-4.14(t, 2H), 3.72-3.75(t, 2H), 3.10-3.12(d, 2H), 2.97-2.99(t, 2H), 2.91(s, 3H), 2.81-2.83(t, 2H), 2.63(s, 4H), 2.12-2.18(t, 2H), 1.88-1.91(d, 3H), 1.66-1.74(m, 6H), 1.49
(m， 2H)ppm (m, 2H) ppm
实施例 52: 体外生化水平抑制 JAK激酶（PK)活性实验 Example 52: In vitro biochemical inhibition JAK kinase (PK) activity assay
材料与方法： JAK2， JAK3 激酶， 来源于 Invitrogen; 384 孔板 （Greiner公司）； HTRF KinEASE ； MgCl2 (sigma)公司； DTT ( Sunshine); PHERAstar FS多功能酶标仪（BMG 公司）； MH-1型低速离心机 （StaiteXiangyi公司）； TD25-W5型恒温箱 （Binder公司）； YG020524/振荡器 （林贝尔公司）； ATP (sigma公司）； 选取的阳性药为 CP-690550, 结 构如下：
Figure imgf000046_0001
Materials and Methods: 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:
Figure imgf000046_0001
化合物溶解及保存：用 DMSO将受试化合物配置成 0.5-10 mmol/L的母液，分装后 -20 Compound dissolution and storage: The test compound was formulated into 0.5-10 mmol/L mother liquor in DMSO, after dispensing -20
°C保存； °C preservation;
化合物工作液的配制： 除 CP-690550外， 其余化合物均为 lOuM起 3倍稀释 10个浓 度， 再加一个零浓度全 DMSO。  Preparation of compound working solution: Except CP-690550, the other compounds were diluted 3 times from lOuM, and a zero concentration of whole DMSO was added.
酶反应步骤： 向 384微孔板的每个孔中加入 4μ1的激酶， 同时加入 4 的 Enzymatic buffer作为阴性对照 （Negative); 向孔加入 2 μΐ的化合物工作液， 同时加入 2 的不含 化合物的缓冲液作为对照 （即阳性对照， Positive); 于 25 V (或 30 V )孵育 5 -lO min; 向孔中加入 2 ATP和 TK Substrate-biotin混合液， 启动酶反应， 于 25°C (或 30°C ) 振 荡反应 15-60 min; 向孔中加入 4 uL TK-Ab-cryptate; 于 25 °C (或 30 °C )孵育 5 -10 min; PHERAstar FS仪器读取 HTRF信号。  Enzyme reaction step: 4 μl of kinase was added to each well of a 384-well plate, and Enzymatic buffer of 4 was added as a negative control; 2 μΐ 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); incubate for 5 -10 min at 25 V (or 30 V); add 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.
对于每孔读出的原始数据， 比值 =665 nm/620 nm;  For raw data read per well, the ratio = 665 nm / 620 nm;
抑制率的计算： 试验组比值 一 阴性对照组比值  Calculation of inhibition rate: ratio of test group to ratio of negative control group
抑制率 ％ = ( 1- ) l 00 %  Inhibition rate % = ( 1- ) l 00 %
^阳性对照组比值 一阴性对照组比值 ~  ^ Positive control ratio - negative control ratio -
计算 IC50:  Calculate IC50:
以 log [给药浓度] 为横坐标， 抑制率为纵坐标， 在 Graphpad PriSm 5中拟合出一条剂 量反应曲线， 得出其 50 %抑制率时的药物浓度， 即为此化合物在酶水平的 IC5Q值。 实验结果： JAK激酶活性半数抑制浓度 （IC5Q nM) With log [dose concentration] as the abscissa and inhibition rate as the ordinate, a dose response curve was fitted in Graphp a d Pri S m 5 to obtain the drug concentration at 50% inhibition rate. IC 5Q values at the enzyme level. Experimental results: JAK kinase activity half inhibitory concentration (IC 5Q nM)
本发明提供结构如式 I所示化合物对 JAK激酶活性的半数抑制浓度 （IC5Q) 见表 1 : 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:
表 1 化合物对 JAK2激酶活性的半数抑制浓度 （IC5())
Figure imgf000047_0001
Table 1 Half-inhibitory concentration of compound on JAK2 kinase activity (IC 5() )
Figure imgf000047_0001
表示 IC50< 500nM; 表示 IC50范围为 500-5000nM; +表示 IC50范围为 5000ηΜ-50μΜ; -表示:木 It represents a IC 50 <500nM; represents the range of IC 50 of 500-5000nM; + represents the range of IC 50 of 5000ηΜ-50μΜ; - represents: Wood
表 2化合物对 JAK3激酶活性的半数抑制浓度 aC5o)Table 2 Compounds have a half-inhibitory concentration of JAK3 kinase activity aC 5 o)
Figure imgf000047_0002
活性强度 +++ +++ ++ +++ +++ +++ +++ +++ +++ +++ 化合物 51 CP-690550
Figure imgf000047_0002
Activity intensity +++ +++ ++ +++ +++ +++ +++ +++ +++ +++ Compound 51 CP-690550
活性强度 +++ +++ Activity intensity +++ +++
表示 IC50< 500nM; 表示 IC50范围为 500-5000nM; +表示 IC50范围为 5000ηΜ-50μΜ; -表示未 It represents a IC 50 <500nM; represents the range of IC 50 of 500-5000nM; + represents the range of IC 50 of 5000ηΜ-50μΜ; - indicates no
实验结果：本发明化合物对 JAK2， JAK3激酶生化水平的抑制活性与阳性药 CP-690550 相当. 以上所述仅是本发明的优选实施方式， 应当指出， 对于本技术领域的普通技术人员来 说， 在不脱离本发明原理的前提下， 还可以做出若干改进和润饰， 这些改进和润饰也应视 为本发明的保护范围。 Experimental results: The inhibitory activity of the compound of the present invention on the biochemical level of JAK2, JAK3 kinase is comparable to that of the positive drug CP-690550. The above description is only a preferred embodiment of the present invention, and it should be noted that one of ordinary skill in the art will recognize A number of modifications and refinements can also be made without departing from the principles of the invention, and such modifications and refinements are also considered to be within the scope of the invention.

Claims

权利要求书 Claim
1、 结构如式 I所示的化合物、 其药学上可接受的等价物或盐: 1. A compound of the formula I, a pharmaceutically acceptable equivalent thereof or a salt thereof:
Figure imgf000049_0001
Figure imgf000049_0001
其巾：  Its towel:
R1为任意取代的烷基、 环烷基、 酰基、 磺酰基； R 1 is an optionally substituted alkyl group, a cycloalkyl group, an acyl group or a sulfonyl group;
R2为氢、 卤素、 C1-C6直链或支链烷基、 环烷基、 卤代 C1-C6直链或支链烷基； R3为氢、 卤素； R 2 is hydrogen, halogen, C1-C6 straight or branched alkyl, cycloalkyl, halogenated C1-C6 straight or branched alkyl; R 3 is hydrogen, halogen;
或者 R2与 R3以及与连接它们的碳原子一起形成一个 5元的杂芳环； Or R 2 and R 3 together with the carbon atom to which they are attached form a 5-membered heteroaryl ring;
Z独立的选自 N或 CR4; Z is independently selected from N or CR 4 ;
n为 0-3整数；  n is an integer of 0-3;
R4独立地选自氢、卤素、 R5、 -OR5、 -OH、 R6、 -CN、 -CF3、 -(CH2)nN(R5)2、 -N02、 -R5R6、 -OR5R6或者两个 R4取代基与它们连接的碳原子共同形成饱和或不饱和的 5或 6元杂环基; 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;
R5是氢、取代或未取代的 C1-C4烷基、或者取代或未取代的 C1-C4亚烷基、其中至多 两个碳原子可以任选地被 CO、 S、 S02、 或 O替代； R 5 is hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C1-C4 alkylene, wherein up to two carbon atoms may be optionally replaced by CO, S, S0 2 , or O ;
R6是 NH2、 NHR5、 N(R5)2、 N(R4)2、 取代或未取代的吗啉基、 取代或未取代的硫代吗 啉基、取代或未取代的哌嗪基、取代或未取代的哌啶基、取代或未取代的吡咯烷基、取代 或未取代的吡咯基、 取代或未取代的噁唑基、 取代或未取代的咪唑基。 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.
2、 如权利要求 1所述的化合物， 其中 R1为下列基团：
Figure imgf000049_0002
2. The compound according to claim 1, wherein R 1 is the following groups:
Figure imgf000049_0002
R7为 C1-6直链或支链烷基、 -CN、 -NHS02R12、 -NHOH、 -NHCOR12、 -CON(R12); R 7 is C1-6 straight or branched alkyl, -CN, -NHS0 2 R 12 , -NHOH, -NHCOR 12 , -CON(R 12 ) ;
-N(R1 )2、 -ORl 、 -CF:
Figure imgf000049_0003
R8为 Cl-6直链或支链烷基、 C3-C7环烷基、 V 或
Figure imgf000050_0001
-N(R 1 ) 2 , -OR l , -CF:
Figure imgf000049_0003
R 8 is a C 6 straight or branched alkyl group, a C 3 -C 7 cycloalkyl group, V or
Figure imgf000050_0001
R9、 R1Q或 R11相同或不同， 各自独立选自卤素、 氢、 C1-C6直链或支链烷基、 C3-C7 环烷基、
Figure imgf000050_0002
R 9 , R 1Q or R 11 are the same or different and are each independently selected from halogen, hydrogen, C1-C6 straight or branched alkyl, C3-C7 cycloalkyl,
Figure imgf000050_0002
R12选自氢、 -CN、 -NHS02R5、 卤素、 -N(R5)2、 -OR5、 -CF3或 C1-C3直链或支链烷基;R 12 is selected from the group consisting of hydrogen, -CN, -NHS0 2 R 5 , halogen, -N(R 5 ) 2 , -OR 5 , -CF 3 or a C1-C3 straight or branched alkyl group;
X选自 S、 NH或 0; X is selected from S, NH or 0;
m为 0-3整数。  m is an integer of 0-3.
3、 如权利要求 2所述的化合物， 其中 R1为下列基团：
Figure imgf000050_0003
3. A compound according to claim 2, wherein R 1 is the following groups:
Figure imgf000050_0003
R7为 C1-C4直链或支链烷基、 -CN、
Figure imgf000050_0004
R 7 is a C1-C4 linear or branched alkyl group, -CN,
Figure imgf000050_0004
R8为 C1-C4直链或支链烷基； R 8 is a C1-C4 straight or branched alkyl group;
R9、 R1Q或 R11相同或不同， 各自独立选自卤素、 氢或
Figure imgf000050_0005
R 9 , R 1Q or R 11 are the same or different and are each independently selected from halogen, hydrogen or
Figure imgf000050_0005
R12选自卤素、 -CN或氢； R 12 is selected from the group consisting of halogen, -CN or hydrogen;
X为 S;  X is S;
m为 0或 1。  m is 0 or 1.
4、 如权利要求 3所述的化合物， 其中 4. The compound of claim 3, wherein
R7为 -CN、
Figure imgf000050_0006
、 X 或~ R 7 is -CN,
Figure imgf000050_0006
, X or ~
R8为甲基； R9或 R1Q为氢； R 8 is methyl; R 9 or R 1Q is hydrogen;
R11为 ^ ； R 11 is ^ ;
R12为 -CN或氢； R 12 is -CN or hydrogen;
X为 S;  X is S;
m为 0或 1。  m is 0 or 1.
5、 如权利要求 1所述的化合物， 其中 R2为氢、 卤素、 C1-C4直链或支链烷基或卤代 C1-C4直链或支链烷基； R3为氢； 5. The compound of claim 1 wherein R 2 is hydrogen, halogen, C1-C4 straight or branched alkyl or halogenated C1-C4 straight or branched alkyl; R 3 is hydrogen;
或者 R2、 R3 与连接它们的碳原子一起组成以下杂环：
Figure imgf000051_0001
Or R 2 and R 3 together with the carbon atom to which they are attached constitute the following heterocyclic ring:
Figure imgf000051_0001
6、 如权利要求 5所述的化合物， 其中  6. The compound of claim 5, wherein
R2为氢、 -F、 -CH3或 -CF3 ; R3为氢； 或 R2、 R3 与连接它们的碳原子一起组成 ^NH。R 2 is hydrogen, -F, -CH 3 or -CF 3 ; R 3 is hydrogen; or R 2 , R 3 together with the carbon atom to which they are attached constitutes NH .
7、 如权利要求 1所述的化合物， 其中 7. The compound of claim 1 wherein
Z为 CR4。 Z is CR 4 .
8、 如权利要求 1或 7所述的化合物， 其中  8. The compound of claim 1 or 7, wherein
R4为氢、 卤素、 -N02、 -OH、 C1-C6直链或支链烷氧基、 取代或非取代的饱和或不饱 和的 5或 6元饱和或不饱和杂环基或 -OR5R6; R 4 is hydrogen, halogen, -N0 2 , -OH, C1-C6 straight or branched alkoxy, substituted or unsubstituted saturated or unsaturated 5 or 6 membered saturated or unsaturated heterocyclic group or -OR 5 R 6 ;
R5是取代或未取代的 C1-C3亚烷基； R 5 is a substituted or unsubstituted C1-C3 alkylene group;
R6是 NH2、 C1-C6直链或支链烷氨基、 取代或未取代的吗啉基、 取代或未取代的硫代 吗啉基、取代或未取代的哌嗪基、取代或未取代的哌啶基、取代或未取代的吡咯烷基、取 代或未取代的吡咯基、 取代或未取代的噁唑基、 取代或未取代的咪唑基； R 6 is NH 2 , C1-C6 straight or branched alkylamino, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted Piperidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted imidazolyl;
R4、 R5和 R6中的取代基分别独立地为卤素、羟基、 C1-C6直链或支链烷基、羟基取代 的 C1-C6直链或支链烷基、 C3-C7环烷基、 C3-C7环烷甲酰基、 二恶烷基或哌啶基。The substituents in R 4 , R 5 and R 6 are each independently halogen, hydroxy, C1-C6 straight or branched alkyl, hydroxy-substituted C1-C6 straight or branched alkyl, C3-C7 naphthenic Base, C3-C7 cycloalkanoyl, dioxoalkyl or piperidinyl.
9、 如权利要求 8所述的化合物， 其中 9. The compound of claim 8 wherein
R4为氢、 -F、 -N02、 -OH、 C1-C4直链或支链烷氧基、 吡咯烷基、 C1-C6烷基取代的 吡咯烷基、 哌啶基、 C1-C6烷基取代的哌啶基、 哌嗪基、 C1-C6烷基取代的哌嗪基、 吗啉 基、 C1-C6烷基取代的吗啉基、 咪唑基、 C1-C6烷基取代的咪唑基或 -OR5R6。 R 4 is hydrogen, -F, -N0 2 , -OH, C1-C4 straight or branched alkoxy, pyrrolidinyl, C1-C6 alkyl substituted pyrrolidinyl, piperidinyl, C1-C6 alkane Substituted piperidinyl, piperazinyl, C1-C6 alkyl-substituted piperazinyl, morpholinyl, C1-C6 alkyl-substituted morpholinyl, imidazolyl, C1-C6 alkyl-substituted imidazolyl or -OR 5 R 6 .
10、 如权利要求 9所述的化合物， 其中  10. The compound of claim 9, wherein
、 〔 〕 〔〕
R4为氢、 -F、 -N02、 -OH、 -OCH3、
Figure imgf000051_0002
、 丫或 -OR5R6。 R 4 is hydrogen, -F, -N0 2 , -OH, -OCH 3 ,
Figure imgf000051_0002
, 丫 or -OR 5 R 6 .
11、 如权利要求 8、 9或 10所述的化合物， 其中  11. A compound according to claim 8, 9 or 10 wherein
^为 〜 或¾^^/、。 ^ is ~ or 3⁄4^^/,.
12、 如权利要求 8、 9或 10所述的化合物， 其中 12. A compound according to claim 8, 9 or 10 wherein
R6是取代或未取代的吗啉基、 取代或未取代的硫代吗啉基、 取代或未取代的哌嗪基、 取代或未取代的哌啶基、取代或未取代的吡咯烷基、取代或未取代的吡咯基、取代或未取 代的噁唑基、取代或未取代的咪唑基； 所述取代基为羟基、 C1-C6直链或支链烷基、羟基 取代的 C1-C6直链或支链烷基、 C1-C6烷基酰基、 C3-C7环烷甲酰基或哌啶基。 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 or branched alkyl group, a hydroxy-substituted C1-C6 straight A chain or branched alkyl group, a C1-C6 alkyl acyl group, a C3-C7 cycloalkylene group or a piperidinyl group.
13、 如权利要求 12所述的化合物， 其中  13. The compound of claim 12, wherein
Figure imgf000052_0001
Figure imgf000052_0001
14、 如权利要求 1所述的化合物， 其中  14. The compound of claim 1 wherein
n为 0、 1或 2。  n is 0, 1, or 2.
15、 如权利要求 14所述的化合物， 其中  15. The compound of claim 14, wherein
当 n为 1时， R4为苯环上氨基的对位取代基； When n is 1, R 4 is a para-substituent of an amino group on the phenyl ring;
当 n为 2时， R4为苯环上氨基的间位和对位取代基。 When n is 2, R 4 is a meta and para substituent of the amino group on the phenyl ring.
16、 如权利要求 1所述的化合物或其药学上可接受的盐， 所述化合物选自 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of
- Z - - Z -
Figure imgf000053_0001
Figure imgf000053_0001
8TCS.0/M0Z OAV 8TCS.0/M0Z OAV
Figure imgf000054_0001
Figure imgf000054_0001
17、一种药物组合物， 其包含药学上可接受的载体、赋形剂或稀释剂， 以及作为活性成分 的权利要求 1或 16中任一项所述的化合物。 A pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent, and the compound according to any one of claims 1 or 16 as an active ingredient.
18、权利要求 1或 16中任一项所述的化合物在制备治疗 JAK介导的病症药物方面的应用， 该病症选自： 真性红细胞增多、 自发性血小板增多、慢性特发性骨髓纤维化、伴有骨髓纤 维化的骨髓性组织转化、 慢性特骨髓性白血病、 慢性骨髓单核细胞性白血病、 变态反应、 哮喘、 自身免疫疾病如抑制移植排斥、类风湿性关节炎、肌肉縮性侧索硬化、 多发性硬化 或实体或血液恶性肿瘤。  18. Use of a compound according to any one of claims 1 or 16 for the manufacture of a medicament for the treatment of a JAK-mediated disorder selected from the group consisting of: true erythrocytosis, spontaneous thrombocytosis, chronic idiopathic myelofibrosis, Bone marrow tissue transformation with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, allergies, asthma, autoimmune diseases such as inhibition of transplant rejection, rheumatoid arthritis, muscle contraction lateral sclerosis , multiple sclerosis or solid or hematological malignancies.
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