WO2017133630A1 - Inhibitor of bruton's tyrosine kinase - Google Patents

Inhibitor of bruton's tyrosine kinase Download PDF

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WO2017133630A1
WO2017133630A1 PCT/CN2017/072716 CN2017072716W WO2017133630A1 WO 2017133630 A1 WO2017133630 A1 WO 2017133630A1 CN 2017072716 W CN2017072716 W CN 2017072716W WO 2017133630 A1 WO2017133630 A1 WO 2017133630A1
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group
substituted
amino
thiophen
nitrogen
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PCT/CN2017/072716
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French (fr)
Chinese (zh)
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孟坤
张建存
王永钢
唐勇
林庆聪
王骏
王宗惠
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北京盛诺基医药科技有限公司
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Priority to CN201780009992.6A priority Critical patent/CN108602834B/en
Publication of WO2017133630A1 publication Critical patent/WO2017133630A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a Bruton tyrosine kinase inhibitor, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or N-oxide belongs to the field of medicine.
  • Btk Bruton's tyrosine kinase
  • Btk Bruton's tyrosine kinase
  • Btk inhibitors can also inhibit Fc-mediated cytokine release from monocytes as well as macrophages, as well as FcR-mediated cell degranulation.
  • the lack of Btk has been shown to block B cell antigen receptor signaling, so compounds with Btk inhibitory activity can act as blocking B cell and/or mast cell-mediated related diseases such as cancer, autoimmune diseases, An effective treatment for thromboembolic diseases and inflammatory diseases, International Reviews of Immunology, 2012, 31, 119-132; Arthritis Research & Therapy, 2011, 13, R115; "Clin. Exp. Immunol.” 1993, 94, 459; Chem. "MedChem.” 2007, 2, 58-61.
  • a Btk inhibitor having the following formula (i) is disclosed in International Publication No. WO2008121742:
  • Ibrutinib is a FDA-approved treatment for the treatment of mantle cell lymphoma on November 13, 2013. In addition, ibrutinib has shown great potential in the treatment of chronic lymphocytic leukemia and multiple myeloma.
  • the compound having such a structure has excellent Btk selective inhibitory activity and is a compound which is excellent in metabolic stability and can avoid hepatotoxicity, and thus can be used as a safety-preserving B cell and/or hypertrophy with non-Hodgkin's lymphoma.
  • a therapeutic agent for cell-related diseases is a compound which is excellent in metabolic stability and can avoid hepatotoxicity, and thus can be used as a safety-preserving B cell and/or hypertrophy with non-Hodgkin's lymphoma.
  • B-cell non-Hodgkin's lymphoma preferably diffuse large B-cell lymphoma, human B lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia (WM) and B-cell chronic lymphocytic leukemia Has a good inhibitory effect.
  • One aspect of the present invention provides a compound having the formula (I), a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, and the like. Racemate or N-oxide:
  • W is a 4-6 membered nitrogen-containing saturated heterocyclic group, a benzylidene (C 3 -C 6 )cycloalkyl group or a [3.3-5] nitrogen-containing saturated heterospirocyclic group;
  • R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 ) Haloalkoxy, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, phenyl (C 1 -C 4 )alkyl, benzylidene (C 3 -C 6 )cycloalkyl, substituted benzene C 1 -C 4 )alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 - C 4 ) alkenyl, substituted benzene (C 2 -C 4 ) alkenyl, nitrogen-containing heterophenyl, substitute
  • R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring
  • W is a 4-6 membered nitrogen-containing saturated heterocyclic group, a benzylidene (C 3 -C 6 )cycloalkyl group or a [3.3-5] nitrogen-containing saturated heterospirocyclic group;
  • R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 ) Haloalkoxy, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, phenyl (C 1 -C 4 )alkyl, benzylidene (C 3 -C 6 )cycloalkyl, phenoxy a substituted phenoxyalkyl group, a benzene (C 1 -C 4 ) alkoxy group, a substituted benzene (C 1 -C 4 ) alkoxy group, a benzene (C 2 -C 4 ) alkenyl group, a substituted benzene group (C 2 - C 4 ) alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heteropheny
  • R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring
  • R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C) 4 ) haloalkoxy, phenyl, substituted phenyl, benzene (C 1 -C 4 )alkyl, benzylidene (C 3 -C 6 )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy group, benzene (C 2 -C 4 ) alkenyl group, substituted benzene (C 2 -C 4 ) alkenyl group, nitrogen-containing heterophenyl group, substituted nitrogen-containing heterophenyl group, nitrogen-containing hetero a phenyl-substituted (C 1 -C 4 )alkyl group, a nitrogen-containing heterophenyl
  • R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring
  • R 2 is selected from the group consisting of phenyl, substituted phenyl, phenyl (C 1 -C 4 ) alkyl, substituted benzene (C 1 -C 4 ) alkyl, substituted benzene (C 1 -C 4 ) alkoxy a benzylidene (C 3 -C 6 )cycloalkyl group, a phenoxyalkyl group, a substituted phenoxyalkyl group, a benzene (C 1 -C 4 ) alkoxy group, a benzene (C 2 -C 4 )alkenyl group, Substituted benzene (C 2 -C 4 ) alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, nitrogen-containing heterophenyl substituted ( C 1 -C 4 ) alkoxy and
  • R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring
  • X and Y are each independently selected from CH or N, and R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 - C 4 ) one of a haloalkyl group, a carbamoyl group, an acetamide group, and a (C 1 -C 4 )haloalkoxy group.
  • R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, carbamoyl, acetamide One of a (C 1 -C 4 )haloalkoxy group.
  • R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, carbamoyl, acetamide One of a (C 1 -C 4 )haloalkoxy group.
  • R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
  • R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
  • X, Y and Z are each independently selected from CH or N; and R 5 and R 6 are each independently selected from H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl One or more of a cyano group, a (C 1 -C 4 )haloalkyl group, and a (C 1 -C 4 )haloalkoxy group.
  • R 1 is selected from the group consisting of phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, phenyl (C 1 -C 4 )alkyl, substituted benzene (C 1 -C 4 )alkyl, substituted benzene ( C 1 -C 4 ) alkoxy, benzylidene (C 3 -C 6 )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 )alkenyl, substituted benzene (C 2 -C 4 )alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, a nitrogen-containing heterophenyl-substituted (C 1 -C
  • R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring
  • the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XII) shows:
  • X and Y are each independently selected from CH or N, and R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 - C 4 ) one of a haloalkyl group, a carbamoyl group, an acetamide group, and a (C 1 -C 4 )haloalkoxy group.
  • R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
  • R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
  • X, Y and Z are each independently selected from CH or N; and R 5 and R 6 are each independently selected from H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl One or more of a cyano group, a (C 1 -C 4 )haloalkyl group, and a (C 1 -C 4 )haloalkoxy group.
  • R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, carbamoyl, acetamide One of a (C 1 -C 4 )haloalkoxy group.
  • the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X VII) shows:
  • R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, carbamoyl, acetamide One of a (C 1 -C 4 )haloalkoxy group.
  • R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C) 4 ) haloalkoxy, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, benzene (C 1 -C 4 )alkyl, substituted benzene (C 1 -C 4 )alkyl, benzene methylene (C 3 -C 6 )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 )alkenyl, substituted benzene (C 2 -C 4 )alkenyl, nitrogen-containing hetero
  • R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring
  • the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X IX) shows:
  • R 2 is selected from the group consisting of phenyl, substituted phenyl, phenyl(C 1 -C 4 )alkyl, benzylidene(C 3 -C 6 )cycloalkyl, substituted benzene(C 1 -C 4 )alkyl, Benzene (C 1 -C 4 )alkoxy, substituted benzene (C 1 -C 4 )alkoxy, phenoxyalkyl, substituted phenoxyalkyl, phenyl(C 2 -C 4 )alkenyl, substituted benzene C 2 -C 4 )alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, nitrogen-containing heterophenyl substituted (C 1 - C 4 ) alkoxy and One or more of the following; wherein R" is selected from one or more of the following
  • R 1 is selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl or (C 1 -C 4 )haloalkoxy;
  • R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring
  • the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X X) shows:
  • R 2 is selected from the group consisting of phenyl, substituted phenyl, phenyl(C 1 -C 4 )alkyl, benzylidene(C 3 -C 6 )cycloalkyl, substituted benzene(C 1 -C 4 )alkyl, Benzene (C 1 -C 4 )alkoxy, substituted benzene (C 1 -C 4 )alkoxy, phenoxyalkyl, substituted phenoxyalkyl, phenyl(C 2 -C 4 )alkenyl, substituted benzene C 2 -C 4 )alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, nitrogen-containing heterophenyl substituted (C 1 - C 4 ) alkoxy and One or more of the following; wherein R" is selected from one or more of the following
  • R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring
  • the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X XI) shows:
  • R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
  • the compound its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X XII)
  • R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
  • the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X X III) shows:
  • R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
  • X, Y and Z are each independently selected from CH or N; and R 5 and R 6 are each independently selected from H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl One or more of a cyano group, a (C 1 -C 4 )haloalkyl group, and a (C 1 -C 4 )haloalkoxy group.
  • the compound is selected from one or more of the following compounds:
  • the present invention also provides a compound represented by the following formula (X X V) or a salt of the compound,
  • R 1 or R 2 is selected from the group consisting of H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkane Oxyl, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, benzene (C 1 -C 4 )alkyl, phenylmethylene (C 3 -C 6 )cycloalkyl, substituted benzene (C 1 -C 4 )alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 ) alkenyl, substituted benzene (C 2 -C 4 ) alkenyl, nitrogen
  • R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C) 4 ) haloalkoxy, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, benzene (C 1 -C 4 )alkyl, benzyl (C 3 -C 6 )cycloalkyl, substituted Benzene (C 1 -C 4 )alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 )alkenyl, substituted benzene (C 2 -C 4 )alkenyl, nitrogen-containing heterophenyl
  • R 1 is selected from the group consisting of H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy, Phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, benzene (C 1 -C 4 )alkyl, benzylidene (C 3 -C 6 )cycloalkyl, substituted benzene (C 1 -C 4 ) alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 ) olefin a substituted benzene (C 2 -C 4 )alkenyl group, a nitrogen-
  • the present invention also provides a compound represented by the following formula (X X VIII), wherein the compound is as follows:
  • R 8 is selected from H, Br or a boronic acid group
  • R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido.
  • the compound of the formula (X X VIII) is an intermediate compound of the compound of the formula (I)-formula (X X IV).
  • R 8 is selected from H, Br or a boronic acid group
  • R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido.
  • R 8 is selected from H, Br or a boronic acid group
  • R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido.
  • R 8 is selected from H, Br or a boronic acid group
  • R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido.
  • R 8 is selected from H, Br or a boronic acid group
  • R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido.
  • the invention also provides a compound of the invention, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation.
  • a compound of the invention a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation.
  • the malignant tumor comprises one or more of lymphoma, plasmacytoma and leukemia.
  • the lymphoma comprises non-Hodgkin's lymphoma, follicular lymphoma, and sheath
  • lymphoma small lymphocytic lymphoma, mantle cell lymphoma, intravascular large cell B-cell lymphoma, Burkitt's lymphoma, AIDS-associated lymphoma, and marginal B-cell lymphoma .
  • said non-Hodgkin's lymphoma comprises B-cell non-Hodgkin's lymphoma.
  • the B-cell non-Hodgkin's lymphoma comprises one or more of diffuse large B-cell lymphoma and human B-lymphoma.
  • the autoimmune diseases include one or more of arthritis, rheumatism, inflammatory bowel disease, and lupus erythematosus.
  • a further aspect of the invention provides a Bruton tyrosine kinase inhibitor composition
  • a Bruton tyrosine kinase inhibitor composition comprising a compound of the invention, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, A mixture of enantiomers, a racemate or an N-oxide.
  • Fig. 1 shows the improvement of the disease in mice by the action of the compound of the present invention on rheumatoid arthritis mice.
  • the term "bruton tyrosine kinase inhibitor” is provided herein to include having formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI). , (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (X) VI), formula (XVII), formula (XVIII), formula (X IX), formula (X X), formula (X X I), formula (X X II), formula (XXIII), formula (X X IV) Compounds of the formula, each of which includes different stereoisomers having the same structural formula, wherein the stereoisomers also include optical isomers and geometric isomers, and optical isomers are also referred to as enantiomers. Geometric isomers are also known as cis and trans isomers.
  • Optical enantiomers are optical enantiomers that have mirror images of each other.
  • a mixture of optical enantiomers refers to a mixture of two optical enantiomers which are chiral with each other in different molar ratios.
  • Racemic refers to the mixing of two optical enantiomers that are chiral with each other in the same molar ratio. Since the intermolecular action causes the optical rotation to cancel out, the resulting mixture is called a racemate.
  • the cis-trans isomer means that the same atom is located on the same side and the opposite side of the carbon-carbon double bond.
  • the same atom is located on the same side of the carbon-carbon double bond, called cis, and the same atom is located on the carbon-carbon.
  • the opposite side of the double bond is called trans.
  • heterocyclyl refers to one or more of the carbon atoms of the cycloalkyl group constituting the ring being replaced by a heteroatom other than carbon to form a heterocyclic group, including but not limited to A nitrogen atom, an oxygen atom, a sulfur atom, and the like.
  • cycloalkyl group includes, without limitation, phenyl, cyclohexane, and the like.
  • nitrogen-containing heterocyclic group refers to a carbon atom constituting a ring which is substituted by one or more nitrogen atoms to form a heterocyclic group, and when the heterocyclic group formed is a saturated heterocyclic group, it is referred to as "saturated nitrogen-containing”.
  • Heterocyclic group when the heterocyclic group formed is an unsaturated heterocyclic group, it is referred to as "nitrogen-containing unsaturated heterocyclic group”.
  • benzimid (C 3 -C 6 )cycloalkyl refers to a hydrogen atom of a methyl group on a benzyl group substituted by a (C 3 -C 6 )cycloalkyl group.
  • the structure of a benzylidene cycloalkyl group in which two groups attached to a cycloalkyl group include, without being limited to, adjacent, interphase and relative positions.
  • nitrogen-containing saturated heterospiro refers to two saturated cycloalkyl groups sharing one carbon atom to form a saturated spiro ring.
  • a carbon atom (unshared carbon atom) on a saturated spiro ring is bonded to a nitrogen atom, and a saturated spiro ring is bonded to its adjacent group to form a nitrogen-containing saturated heterospinyl group, wherein the saturated heterospiro ring is named after the atom
  • the number is determined by the number of carbon atoms or nitrogen atoms forming each ring skeleton, and does not contain two carbon atoms common to the ring.
  • phenyl (C 1 -C 4) alkyl refers to a hydrogen atom on the phenyl ring is substituted (C 1 -C 4) alkyl, phenyl formation (C 1 -C 4 ) Alkyl structures, including but not limited to benzyl, phenethyl, phenylpropyl, phenylisopropyl and phenylbutyl.
  • phenyl (C 2 -C. 4) alkynyl group refers to a hydrogen atom on the benzene ring is (C 2 -C. 4) substituted alkynyl group, formed by benzene (C 2 -C 4 ) alkynyl structures including, but not limited to, phenylacetylene, phenylpropyne, phenylbutyne, and the like.
  • substituted phenyl refers to a substituted phenyl group substituted by a hydrogen atom on a phenyl group other than a hydrogen atom or a group.
  • phenoxyalkyl refers to a group formed by the attachment of a phenyl group and an alkyl group through an oxygen group, and the group is attached to the other groups externally via an alkyl group, including Limited to: phenoxymethyl, phenoxyethyl, phenoxypropyl and the like.
  • substituted phenoxyalkyl as used herein means that the phenyl group of the phenoxyalkyl group is substituted with an atom or group other than a hydrogen atom to form a substituted phenoxyalkyl group.
  • amino substituted (C 2 -C 4 )alkenyl refers to one or more hydrogen atoms of a (C 2 -C 4 )alkenyl group substituted by one or more amine groups.
  • the atom, the "amine group” is an organic amine group formed by replacing a hydrogen atom of ammonia with a hydrocarbon group.
  • benzene (C 2 -C 4 )alkenyl means that one hydrogen atom on the phenyl ring is substituted with a (C 2 -C 4 ) alkenyl group to give a benzene ring (C 2 -C) 4 ) Alkenyl group, including but not limited to: styryl group, phenylpropenyl group, benzoisopropenyl group, phenylbutenyl group and the like.
  • nitrogen-containing heterophenyl means that one or more carbon atoms on the phenyl group are replaced by a nitrogen atom to form a phenyl group bearing a nitrogen heteroatom, including but not limited to: pyridine Base, m-diazaphenyl, p-diazaphenyl and the like.
  • plasma cell tumor is a group of neoplastic diseases caused by proliferation of monoclonal plasma cells, including multiple myeloma, primary macroglobulinemia.
  • a subject of the invention may be a mammal, such as a dog, cat, cow, sheep, horse or human, preferably a human.
  • the necessary therapeutic amount of the medicament of the present invention will vary depending on the particular disease and can be readily determined by one of ordinary skill in the art.
  • one or more compounds of the invention may be used in combination with each other, and the compounds of the invention may be optionally used in combination with any other active agent for the preparation of Bruton's tyrosine kinase inhibition.
  • Agents, if a group of compounds are used, these compounds can be administered to the subject simultaneously, separately or sequentially.
  • the compounds of the invention may be used in combination with one or more other anticancer agents.
  • Anticancer agents that can be used include, but are not limited to, ibrutinib, statinidin, erlotinib, lapatinib, neratinib, lapatinib, cediranib, axitinib , pazopanib, sorafenib, aboxicept, rituximab, alemtuzumab, bevacizumab, panitumumab, trastuzumab, alkylating agent, nitrogen-based Drugs, folic acid antagonists, sputum antagonists, pyrimidine antagonists, spindle toxins, topoisomerase inhibitors, apoptosis inducers, angiogenesis inhibitors, podophyllotoxin, nitrosourea, antimetabolites, protein synthesis Inhibitors, kinase inhibitors, antiestrogens, cis
  • the pharmaceutical compositions of the invention are also useful for treating diseases in animals.
  • a general veterinarian can administer a compound of the invention, or a veterinary salt thereof, or a veterinary solvent or prodrug thereof, in a suitable acceptable formulation, based on experience in the art. The veterinarian can determine the most appropriate route of administration for an animal.
  • the compounds of the invention are prepared by the following route 1:
  • the compound 4' is a raw material having a chiral property, and therefore, in the course of the synthesis, the compound 4' having an appropriate optical rotation can be selected as a raw material according to the optical rotation property of the target compound, whereby the obtained reaction intermediate compound also has a compound compound. 4' identical optical properties.
  • the starting material 5-amino-1H-pyrazole-4-cyano CAS No. 16617-46-2 was purchased from Shanghai Haiqu Chemical Co., Ltd.
  • Compound 4' is 1-tert-butoxycarbonyl-3-hydroxypiperidine CAS No. 85275-45-2, (S)-1-tert-butoxycarbonyl-3-hydroxypiperidine CAS No. 143900-44-1 or (R)-1-tert-Butoxycarbonyl-3-hydroxypiperidine CAS No. 143900-43-0 was purchased from Shanghai Yuyuan Reagent Co., Ltd.
  • the reaction accompanying the heating can be carried out using a water bath or an oil bath.
  • the reaction product can be purified by a usual purification means such as a fraction obtained by normal or reduced pressure distillation using high performance liquid chromatography, thin layer chromatography, washing or the like using silica gel. Purification can be carried out in each reaction or after multiple steps of the reaction.
  • Compound 5' is: tert-butyl-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
  • Et 3 N represents triethylamine and EDCl represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • ring 1 is benzene
  • L 1 is a methoxy group, wherein the methyl moiety is bonded to the thiophene, the oxy group is bonded to the benzene, L 1 is bonded to the 5-position of the thiophene, and the boron and the thiophene are 2 Linked to the compound 6' is: (5-(phenoxymethyl)thiophen-2-yl)boronic acid.
  • the intermediate compound was changed 6' in the same manner as in Example 4 to give the following compound, wherein the intermediate compound 6' may be selected from the following compounds:
  • the above synthesis method of the boric acid compound is similar to the preparation method of the compound 6' of Example 4 as (5-(phenoxymethyl)thiophen-2-yl)boronic acid.
  • R 5 and R 6 are both H, ring 1 is toluene, L 1 is a single bond, benzene ring is bonded to the 5-position of thiophene, 1H-pyrazole [3,4-d]pyrimidin-1-yl and thiophene 3
  • the compound 6' is: ((5-(3-methylphenyl))thiophen-3-yl)boronic acid, the preparation method is:
  • the reaction was carried out at minus 70 ° C for 2 hours, then trimethyl borate (4 g, 40 mmol) was added (CAS No.: 121-43-7, available from Best Reagent, trade name Trimethyl borate, commercial number: B00269101)
  • the reaction was continued at minus 70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol/L hydrochloric acid (30 mL), and stirred for 10 minutes. After extracting with ethyl acetate, the organic layer was dried over anhydrous Na 2 SO 4 and then evaporated. The refining is used directly in the next reaction.
  • the method for synthesizing the above boric acid compound is the same as the method for preparing (4-(3-tolyl)thiophen-2-yl)boronic acid.
  • R 5 and R 6 are both H, ring 1 is 3-tolyl, L 1 is a single bond, 3-tolyl is attached to the 5-position of thiophene, 1H-pyrazole [3,4-d]pyrimidin-1- The base is attached to the 2-position of the thiophene, and the compound 6' is (5-(m-tolyl)thiophen-2-yl)boronic acid by the preparation of 2,5-dibromothiophene (4 g, 16 mmol) (purchased from Qingdao).
  • the method for synthesizing the above boric acid compound is the same as the method for preparing (5-(m-tolyl)thiophen-2-yl)boronic acid.
  • ring 1 is a styryl group
  • L 1 is a single bond
  • the styryl group is linked to the thiophene at the 2-position by a single bond
  • the preparation method is: 4-bromo-2-thiophene - Formaldehyde (4g, 21mmol) (CAS18791-75-8, available from Best Reagent Co., Ltd.) and benzyltriphenylphosphonium chloride (10.9g, 25mmol) dissolved in 50mL of isopropanol, then lithium hydroxide Monohydrate (1.32 g, 32 mmol).
  • R 5 and R 6 are both H
  • ring 1 is phenethyl
  • L 1 is a single bond
  • phenethyl is attached to the 2-position of thiophene
  • 1H-pyrazole [3,4-d]pyrimidin-1-yl and The thiophene is attached at the 4-position
  • m 0
  • ring 2 is piperidine
  • compound 6' is (2-(phenethyl)thiophen-4-yl)boronic acid.
  • the crude product is 1.20g. Since the product is easily decomposed, it can be directly used in the next reaction without purification.
  • the reaction of the step 1 in the reaction scheme 3 is well known, and in the above synthetic route, the compound 5' as a starting material is prepared by the same method as in the route 1.
  • Compound 5' and compound 10' in an organic solvent in metal palladium, for example : including tetrakis(triphenylphosphine)palladium Pd(PPh 3 ) 4 , bisphenylphosphine dichloropalladium Pd(PPh 3 ) 2 Cl 2 and [1,1'-bis(diphenylphosphino)ferrocene]
  • the compound 11' is obtained by a coupling reaction at 60-80 ° C under the catalysis of any one or more of palladium dichloride Pd(dppf)Cl 2 .
  • TEMPO 2,2,6,6-tetramethylpiperidine-nitrogen oxide
  • NaClO 2 sodium chlorite
  • NaClO sodium hypochlorite
  • step 4 in Scheme 2 is well known, compound 13', in an organic solvent (dichloromethane or dimethylformamide), in the condensing agent 1-ethyl-(3-dimethylaminopropyl) Carbodiimide hydrochloride (EDCL) (CAS No. 25952-53-8, purchased from Jinan Panuo Chemical Co., Ltd.), 2-(7-azobenzotriazole)-N, N, N' , N'-tetramethylurea hexafluorophosphate (HATU) (CAS No.
  • compound 148893-10-1 purchased from Shanghai Ziyi Reagent Factory
  • O-benzotriazole-N, N, N', N' - Tetramethylurea tetrafluoroborate (TBTU) (CAS No. 125700-67-6, purchased from Nanjing Peptide Biotechnology Co., Ltd.) reacts with compound 14' at room temperature, thereby performing condensation The reaction gives compound 15'.
  • compound 14' can be selected from the group consisting of 2-aminopyridine, 3-aminopyridine, 4-aminopyridine or aniline.
  • the reaction of the step 5 in the reaction scheme 3 is known to be the same as the operation of the step 5 in the reaction scheme 1.
  • the reaction of the step 6 in the reaction scheme 3 is known to be the same as the operation of the step 6 in the reaction scheme 1, wherein the starting aminopyridine is purchased from Beijing Vinda Chemical Co., Ltd., wherein the 3-aminopyridine product number is 462- 08-8, 2-aminopyridine commercial number is 504-29-0, 4-aminopyridine commercial number is 504-24-5.
  • step 1 of Scheme 3 when compound 10' is ((5-tert-butyldimethylsiloxymethylene)thiophen-2-yl)boronic acid, tert-butyldimethylsilyloxide in compound 11'
  • the methyl group is attached to the 5-position of the thiophene
  • the 1H-pyrazole [3,4-d]pyrimidin-1-yl group is attached to the 2-position of the thiophene
  • m 0
  • the ring 2 is piperidine
  • the compound 11' is a tert-butyl group- 3-(4-Amino-3-(5-(tert-butyldimethylsilyloxy)methylthiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)piperidin Pyridine-1-carboxylate.
  • the preparation method is as follows: (R) tert-butyl-3-(-4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- (5-(tert-Butyldimethylsiloxymethylene))thiophene-2- was added to a solution of formic acid ester (300 mg, 0.68 mmol) in ethylene glycol dimethyl ether (5 mL) and water (2 mL). Boric acid (345 mg, 1.35 mmol), tetratriphenylphosphine palladium (39 mg, 0.03 mmol), Na 2 CO 3 (215 mg, 2.1 mmol).
  • the tert-butyldimethylsiloxymethylene group of compound 11' in step 2 of Reaction Scheme 3 is linked to the 5-position of thiophene, 1H-pyrazole [3,4-d]pyrimidin-1-yl and thiophene
  • compound 11' is (R) tert-butyl-3-(4-amino-3-(5-(tert-butyldimethylsiloxane) Methyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
  • compound 12' is (R) tert-butyl-3- (4-Amino-3-(5-(hydroxymethylene)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
  • the preparation method is:
  • the compound of the compound 13' in the step 4 of the reaction scheme 3 is (R) tert-butyl-3-(3-(5-carboxylic acid thiophen-2-yl)-4-amino-1H-pyrazole [3, 4 -d]pyrimidin-1-yl)piperidine-1-carboxylate, compound 14' is (R)-2-aminopyridine, and compound 15' is (R)-3-(4-amino-3-(5) -(2-Pyridinylcarbonyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester, which is prepared by:
  • HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Ester) (154 mg, 0.41 mmol) (CAS No.: 148893-10-1, purchased from Shanghai Shuo Biotech Co., Ltd.) and N,N-diisopropylethylamine (172 mg, 1.1 mmol). Then, it was reacted for 10 hours at room temperature, and a saturated ammonium chloride solution (20 mL) was added thereto, and the mixture was extracted with ethyl acetate.
  • Compound 16' in step 5 of Scheme 3 is (R)-3-(4-amino-3-(5-(2-pyridylaminocarbonyl)thiophen-2-yl)-1H-pyrazole [3 , 4-d]pyrimidin-1-yl)-1-piperidine, which is prepared by the method of 15', (R) tert-butyl-3-(4-amino-3-(5-) at room temperature.
  • the compound 17' in the step 6 of the scheme 3 is (R)-1-(3-(4-amino-3-(5-(2-pyridylcarbamoyl)thiophen-2-yl)-1H-pyridyl Azole [3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, which is prepared by:
  • the compound 10' was changed in a similar manner to Example 6 to give the compound 51-62 shown in the following Table 1, wherein the compound 10' may be selected from the following compounds:
  • the organic layer was washed twice with water (100 mL), and then the organic phase was dried over anhydrous sodium sulfate.
  • the liquid chromatography was carried out on a silica gel column.
  • the eluting solvent was ethyl acetate: petroleum ether (1:30->1:15) to give 2-bromo-(5-tert-butyldimethylsiloxymethylene)thiophene) (5.5 g, yield: 90%).
  • the above-described method for synthesizing a boric acid compound is the same as the method for producing the compound 10' (5-(tert-butyldimethylsiloxymethylene)thiophen-2-yl)boronic acid.
  • ring 1 is 2-pyridyl
  • L 1 is a single bond
  • 2-pyridyl is attached to the 5-position of thiophene
  • the preparation method is as follows: 2- at room temperature Water (30 mL), (thiophene-) was added to a solution of bromopyridine (3 g, 19.1 mmol) (CAS No.: 109-04-6, available from Best Reagent, commercial number B012654) in ethylene glycol dimethyl ether (60 mL). 2-yl)boronic acid (3.4 g, 26.7 mmol), tetratriphenylphosphine palladium (454 mg, 3.8 mmol) and Na 2 CO 3 (6.1 g, 57.3 mmol).
  • the reaction was carried out at 80 ° C for 6 hours, cooled to room temperature, poured into 50 mL of water, extracted with ethyl acetate, and the organic layer was extracted with anhydrous Na 2 SO 4 and then evaporated.
  • the crude product was separated by chromatography on silica gel column eluting eluting elution elution elution elution .
  • R 7 is selected from methyl, cyano, formylamino or acetylamino, and R 7 may be at the 5- or 6-position of the pyridyl group.
  • the pyridyl group and the thienyl group to which the position is desired can be obtained by selecting a thiophene boric acid substituted at a different position and selecting a bromopyridyl group at a different position.
  • the above synthesis methods of the boronic acid compound are similar to the preparation method of the compound 6'(5-(2-pyridyl)thiophen-2-yl)boronic acid.
  • BTK Bruton kinase inhibitor
  • Cisbio product number 62TK0PEJ
  • test compound and the positive compound Ibrutinib were diluted 3 times with dimethyl sulfoxide (DMSO) for a total of 11 concentrations, and the final system concentration was from 10 ⁇ M to 0.17 nM.
  • DMSO dimethyl sulfoxide
  • EDTA ethylenediaminetetraacetic acid
  • TK thymidine Btk-deficient antibody
  • SA-XL665 purchased from Shanghai Baili Biotechnology Co., Ltd. (cisbio)
  • the fluorescence intensity of each well at 445 nm and 520 nm was measured using a fluorescent plate reader/capacitor and a universal microplate reader.
  • the ratio of phosphorylation was determined by the coloration ratio at 445 nm (coumarin color development) relative to 520 nm (fluorescein color development) according to the instructions attached to the kit.
  • the inhibition rate (%) of the test compound was calculated using the following formula:
  • Phosphorylation inhibition rate (%) 1 - ⁇ (A C - A X ) / (A C - A B ) ⁇ X 100
  • a B Phosphorylation rate when ATP (blank) is added
  • the value (IC 50 value) of the 50% inhibition rate of the test compound was calculated from the inhibition curve based on the inhibition rate at each concentration of the test compound.
  • IgM EC 80 The cells were collected, containing 0.1% FBS (fetal bovine serum) 1640 medium and resuspended cells were adjusted to a concentration of 5x10 6 / mL. A 20 L/well cell suspension was added to the cell plate, and 40 L of Fluo-4 loading dye was added and incubated at 37 ° C for 50 minutes. IgM was serially diluted 3 fold to a final concentration of 10 g/mL to 0.0046 g/mL, and 10 L of IgM was transferred to the cell plate using a high throughput cell level screening system (FLIPR) and the fluorescence values were read. The drug concentration of IgM (EC 80 ) was calculated.
  • FBS fetal bovine serum
  • Compound IC 50 detection Cells were harvested with 0.1% FBS containing medium cells were resuspended in 1640 and adjusted to a concentration of 5x10 6 / mL. A 20 L/well cell suspension was added to the cell plate. The test compound and the positive compound Ibrutinib were diluted 3 fold to a final concentration of 10 M to 0.0046 M, and 10 L of the compound was transferred to a cell plate and incubated at 37 ° C for 60 minutes. Add 40 L of Fluo-4 loading dye and incubate for 50 min at 37 °C. 10 L of 8 x EC 80 IgM was transferred to the cell plates using a high-throughput cell transfer screening system (FLIPR) and the fluorescence values were read. Using graphics software (Prism) GraphPad Software) Production inhibition rate graph, the compound is calculated IC 50.
  • FLIPR high-throughput cell transfer screening system
  • HBL-1 human diffuse large B lymphoma cells
  • DOHH-2 human follicular lymphoma cells
  • JeKo-1 human mantle cell lymphoma cells
  • SU-DHL-4 human diffuse large B lymphoma cells
  • SU-DHL-10 human diffuse large B lymphoma cells
  • WSU-DLCL2 human follicular lymphoma cells
  • the cells were collected, and the cells were resuspended in 1640 medium containing 10% FBS (fetal calf serum) and the concentration was adjusted to 3 x 10 4 /mL. 50 ⁇ L/well of cell suspension was added to the cell plate. The test compound and the positive compound Ibrutinib were diluted 3-fold, and 5 ⁇ L of the compound solution was transferred to a cell plate to a final concentration of 50 ⁇ M or 1 ⁇ M to 0.128 nM or 0.0026 nM, and incubated at 37 ° C for 72 hours.
  • FBS fetal calf serum
  • Collagen-induced arthritis is an experimental animal model induced by species-specific collagen type II immunization. Because its genetic background and immunopathological changes are very similar to clinical rheumatoid arthritis, it is an ideal animal model for studying rheumatoid arthritis.
  • Model making method DBA/1J mice, 7 weeks old, weighing 18-22 g, male, (purchased from Jinan Ono Bioengineering Co., Ltd., trade name DBA/1J mice, model: DBA/1J).
  • DBA/1J mice 7 weeks old, weighing 18-22 g, male, (purchased from Jinan Ono Bioengineering Co., Ltd., trade name DBA/1J mice, model: DBA/1J).
  • acetic acid 4mg collagen/ml
  • complete Freund's adjuvant in an ice bath environment
  • the emulsion was intradermally injected at the base of the tail.
  • the same amount of collagen was emulsified by incomplete Freund's adjuvant, and the immunization was boosted once.
  • DBA/1J mice were induced by oral administration of type II collagen-induced arthritis once daily at a dose of 25 mg/kg.
  • Arthritis index score The arthritis index score was scored according to Wood's arthritis scoring criteria. 0 points, normal; 1 point, redness involves 1 finger joint; 2 points, redness involves more than 2 knuckles or the entire foot is slightly red and swollen; 3 points, the feet are red and swollen; 4 points, the feet are severely red and swollen, The joints are stiff and inelastic. The damage of each of the 4 paws was divided into 0-4 to calculate the total score of the limbs. The number of limbs in each group of rats with arthritis was expressed as a percentage, and the scores at different times (arthritis index) were also recorded. The incidence of arthritis and the onset of arthritis. As shown in Fig. 1, it can be seen from Fig. 1 that the arthritis condition of the mice is improved as the time of administration increases.
  • Leukemia K562 cells were derived from ATCC and maintained at 37 ° C in a 5% CO 2 atmosphere as well as in Dulbecco's medium (IMDM) and 10% fetal bovine serum. The cells were seeded at a density of 6*10 3 cells/well in 96-well plates, and the test compound was dissolved in DMSO at concentrations of 0 ⁇ M, 0.3 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 2 ⁇ M, 3 ⁇ M, 5 ⁇ M, 10 ⁇ M, 20 ⁇ M, K562 cells were treated with 30 ⁇ M, 50 ⁇ M and 100 ⁇ M for 72 hours, and then the cells treated with the compound were detected using the CellTiter-Glo luminescence cell viability assay kit, and luminescence values were recorded.
  • IMDM Dulbecco's medium

Abstract

The present invention relates to an inhibitor of Bruton's tyrosine kinase. A structure of the inhibitor is represented by formula (I). The inhibitor has a good selective inhibitory effect.

Description

一种布鲁顿酪氨酸激酶抑制剂Bruton tyrosine kinase inhibitor 技术领域Technical field
本发明涉及一种布鲁顿酪氨酸激酶抑制剂、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，属于医药领域。The present invention relates to a Bruton tyrosine kinase inhibitor, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or N-oxide belongs to the field of medicine.
背景技术Background technique
布鲁顿酪氨酸激酶(Bruton′s tyrosine kinase，以下简称为Btk)是属于非受体酪氨酸激酶Tec家族的一员。它在除了T淋巴细胞、自然杀伤细胞和浆细胞之外的所有造血细胞类型，如B细胞、肥大细胞和巨噬细胞中都有表达，是至少三种关键B细胞生存机制的重要介质。Btk也担负着向经由B细胞抗原受体(B-cell antigen receptor，即BCR)的B细胞信号传递通路的一部分的作用。Btk的这种多重作用可以使其指挥B细胞恶性肿瘤进入淋巴组织，使肿瘤细胞能够接触必要的微环境而得以生存。实验数据表明Btk在单核细胞、巨噬细胞、中性粒细胞和肥大细胞的信号通路中也有作用。Btk抑制剂也可以抑制单核细胞以及巨噬细胞由Fc介导的细胞因子释放，也可抑制由FcR介导的细胞脱颗粒。Btk的缺乏已经显示可以阻断B细胞抗原受体信号传导，因此具有Btk的抑制活性的化合物可以作为阻断B细胞和/或肥大细胞介导的相关疾病，例如：癌症、自身免疫性疾病、血栓栓塞性疾病和炎性疾病等的有效治疗方法《国际免疫综述(International Reviews of Immunology)》，2012年，31，119-132；《关节炎研究和治疗(Arthritis Research& Therapy)》，2011年，13，R115；《临床免疫(Clin.Exp.Immunol.)》1993，94，459；Chem.《药物化学(MedChem.)》2007，2，58-61。在国际公开号为WO2008121742公开了具有如下式(i)的Btk抑制剂： Bruton's tyrosine kinase (Btk, hereinafter referred to as Btk) is a member of the Tec family of non-receptor tyrosine kinases. It is expressed in all hematopoietic cell types except T lymphocytes, natural killer cells and plasma cells, such as B cells, mast cells and macrophages, and is an important mediator of at least three key B cell survival mechanisms. Btk also acts as part of the B cell signaling pathway via the B-cell antigen receptor (BCR). This multiple action of Btk allows it to direct B-cell malignancies into lymphoid tissues, allowing tumor cells to survive the necessary microenvironment. Experimental data suggest that Btk also plays a role in the signaling pathways of monocytes, macrophages, neutrophils and mast cells. Btk inhibitors can also inhibit Fc-mediated cytokine release from monocytes as well as macrophages, as well as FcR-mediated cell degranulation. The lack of Btk has been shown to block B cell antigen receptor signaling, so compounds with Btk inhibitory activity can act as blocking B cell and/or mast cell-mediated related diseases such as cancer, autoimmune diseases, An effective treatment for thromboembolic diseases and inflammatory diseases, International Reviews of Immunology, 2012, 31, 119-132; Arthritis Research & Therapy, 2011, 13, R115; "Clin. Exp. Immunol." 1993, 94, 459; Chem. "MedChem." 2007, 2, 58-61. A Btk inhibitor having the following formula (i) is disclosed in International Publication No. WO2008121742:
Figure PCTCN2017072716-appb-000001
Figure PCTCN2017072716-appb-000001
当式(i)结构中的L选自O，Ar选自苯，Y选自哌啶，Z选自羰基，Ri、Rii和Riii均选自H时，得到已有的化合物依鲁替尼(Ibrutinib；商品名：Imbruvica)，其具有如下式(ii)所示的结构：When L in the structure of formula (i) is selected from O, Ar is selected from benzene, Y is selected from piperidine, Z is selected from carbonyl, and R i , R ii and R iii are each selected from H, and an existing compound is obtained. Ibrutinib (trade name: Imbruvica) having the structure shown by the following formula (ii):
Figure PCTCN2017072716-appb-000002
Figure PCTCN2017072716-appb-000002
依鲁替尼是2013年11月13日，美国FDA批准的治疗用于治疗套细胞淋巴瘤。除此之外，依鲁替尼在治疗慢性淋巴细胞白血病和多发性骨髓瘤方面还表现出很大的潜力。Ibrutinib is a FDA-approved treatment for the treatment of mantle cell lymphoma on November 13, 2013. In addition, ibrutinib has shown great potential in the treatment of chronic lymphocytic leukemia and multiple myeloma.
在公开号为CN102918040公开了另外一种Btk抑制剂，其具有如下式(iii)所示的结构： Another Btk inhibitor having the structure shown by formula (iii) below is disclosed in the publication No. CN102918040:
Figure PCTCN2017072716-appb-000003
Figure PCTCN2017072716-appb-000003
具有该结构的化合物除了具有Btk选择性抑制活性以外，还是代谢稳定性优异、可避免肝脏毒性等的化合物，因此可用作安全性优异、与非霍奇金淋巴瘤等B细胞和/或肥大细胞相关疾病的治疗剂。The compound having such a structure has excellent Btk selective inhibitory activity and is a compound which is excellent in metabolic stability and can avoid hepatotoxicity, and thus can be used as a safety-preserving B cell and/or hypertrophy with non-Hodgkin's lymphoma. A therapeutic agent for cell-related diseases.
在公开号为WO2015048689的专利申请中公开了具有以下式(iv)的Btk抑制剂：A Btk inhibitor having the following formula (iv) is disclosed in the patent application published as WO 2015048689:
Figure PCTCN2017072716-appb-000004
Figure PCTCN2017072716-appb-000004
文中还公开了该化合物用于治疗自动免疫、异常免疫和癌症等疾病的用途。The use of the compounds for the treatment of diseases such as autoimmunity, abnormal immunity and cancer is also disclosed herein.
随着研究的不断深入，Btk抑制剂的结构及其适应症范围也有着更深的变化。As the research progresses, the structure of Btk inhibitors and the range of their indications have also undergone deeper changes.
发明内容Summary of the invention
本发明的目的在于提供一种布鲁顿酪氨酸激酶抑制剂，该抑制剂具有选择性的抑制效果，对于非霍奇金淋巴瘤，其中优选B细胞性非霍奇金淋巴瘤， 例如：弥漫性大B细胞淋巴瘤、人体B淋巴细胞瘤、套细胞淋巴瘤、小淋巴细胞淋巴瘤，瓦尔登斯特伦(氏)巨球蛋白血症(WM)和B细胞慢性淋巴细胞白血病具有良好的抑制效果。It is an object of the present invention to provide a Bruton's tyrosine kinase inhibitor which has a selective inhibitory effect, and for non-Hodgkin's lymphoma, preferably B-cell non-Hodgkin's lymphoma, For example: diffuse large B-cell lymphoma, human B lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia (WM) and B-cell chronic lymphocytic leukemia Has a good inhibitory effect.
本发明一方面提供了一种具有通式(I)所示的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物：One aspect of the present invention provides a compound having the formula (I), a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, and the like. Racemate or N-oxide:
Figure PCTCN2017072716-appb-000005
Figure PCTCN2017072716-appb-000005
其中：W为4-6元的含氮饱和杂环基、苯亚甲(C3-C6)环烷基或[3.3-5]含氮饱和杂螺环基；Wherein: W is a 4-6 membered nitrogen-containing saturated heterocyclic group, a benzylidene (C 3 -C 6 )cycloalkyl group or a [3.3-5] nitrogen-containing saturated heterospirocyclic group;
R1或R2各自独立地选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基、(C1-C4)卤代烷氧基、苯基、取代苯基、苯(C2-C4)炔基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、取代苯(C1-C4)烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
Figure PCTCN2017072716-appb-000006
中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；取代苯基或取代含氮杂苯基上的取代基可各自独立地选自卤素、(C1-C4)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基、胺甲酰基、乙酰胺基和(C1-C4)卤代烷氧基中的一种或多种；R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 ) Haloalkoxy, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, phenyl (C 1 -C 4 )alkyl, benzylidene (C 3 -C 6 )cycloalkyl, substituted benzene C 1 -C 4 )alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 - C 4 ) alkenyl, substituted benzene (C 2 -C 4 ) alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, nitrogen-containing Heterophenyl substituted (C 1 -C 4 ) alkoxy group and
Figure PCTCN2017072716-appb-000006
One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; a substituted phenyl group or a substituted nitrogen-containing heterophenyl group The substituents above may each independently be selected from the group consisting of halogen, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, carbamoyl, One or more of an acetamide group and a (C 1 -C 4 )haloalkoxy group;
n＝0-4之间的任一个整数；Any integer between n=0-4;
R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对 映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(II)所示：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical pair a mixture, a mixture of enantiomers, a racemate or an N-oxide, as shown in formula (II):
Figure PCTCN2017072716-appb-000007
Figure PCTCN2017072716-appb-000007
其中，W为4-6元的含氮饱和杂环基、苯亚甲(C3-C6)环烷基或[3.3-5]含氮饱和杂螺环基；Wherein W is a 4-6 membered nitrogen-containing saturated heterocyclic group, a benzylidene (C 3 -C 6 )cycloalkyl group or a [3.3-5] nitrogen-containing saturated heterospirocyclic group;
R1或R2各自独立地选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基、(C1-C4)卤代烷氧基、苯基、取代苯基、苯(C2-C4)炔基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
Figure PCTCN2017072716-appb-000008
中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 ) Haloalkoxy, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, phenyl (C 1 -C 4 )alkyl, benzylidene (C 3 -C 6 )cycloalkyl, phenoxy a substituted phenoxyalkyl group, a benzene (C 1 -C 4 ) alkoxy group, a substituted benzene (C 1 -C 4 ) alkoxy group, a benzene (C 2 -C 4 ) alkenyl group, a substituted benzene group (C 2 - C 4 ) alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, nitrogen-containing heterophenyl substituted (C 1 -C 4 ) Alkoxy and
Figure PCTCN2017072716-appb-000008
One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group;
n＝0-4之间的任一个整数；Any integer between n=0-4;
R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(III)所示： Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (III):
Figure PCTCN2017072716-appb-000009
Figure PCTCN2017072716-appb-000009
其中，R1或R2各自独立地选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基、(C1-C4)卤代烷氧基、苯基、取代苯基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
Figure PCTCN2017072716-appb-000010
中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；Wherein R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C) 4 ) haloalkoxy, phenyl, substituted phenyl, benzene (C 1 -C 4 )alkyl, benzylidene (C 3 -C 6 )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy group, benzene (C 2 -C 4 ) alkenyl group, substituted benzene (C 2 -C 4 ) alkenyl group, nitrogen-containing heterophenyl group, substituted nitrogen-containing heterophenyl group, nitrogen-containing hetero a phenyl-substituted (C 1 -C 4 )alkyl group, a nitrogen-containing heterophenyl-substituted (C 1 -C 4 ) alkoxy group, and
Figure PCTCN2017072716-appb-000010
One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group;
n＝0-4之间的任一个整数；Any integer between n=0-4;
R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(IV)所示：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (IV):
Figure PCTCN2017072716-appb-000011
Figure PCTCN2017072716-appb-000011
其中，所述的R2选自苯基、取代苯基、苯(C1-C4)烷基、取代苯(C1-C4)烷基、取代苯(C1-C4)烷氧基、苯亚甲(C3-C6)环烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷 氧基和
Figure PCTCN2017072716-appb-000012
中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；Wherein R 2 is selected from the group consisting of phenyl, substituted phenyl, phenyl (C 1 -C 4 ) alkyl, substituted benzene (C 1 -C 4 ) alkyl, substituted benzene (C 1 -C 4 ) alkoxy a benzylidene (C 3 -C 6 )cycloalkyl group, a phenoxyalkyl group, a substituted phenoxyalkyl group, a benzene (C 1 -C 4 ) alkoxy group, a benzene (C 2 -C 4 )alkenyl group, Substituted benzene (C 2 -C 4 ) alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, nitrogen-containing heterophenyl substituted ( C 1 -C 4 ) alkoxy and
Figure PCTCN2017072716-appb-000012
One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group;
n＝0-4之间的任一个整数；Any integer between n=0-4;
R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(V)所示：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (V):
Figure PCTCN2017072716-appb-000013
Figure PCTCN2017072716-appb-000013
其中，X、Y各自独立地选自CH或N，R4选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基、胺甲酰基、乙酰胺基和(C1-C4)卤代烷氧基中的一种。Wherein X and Y are each independently selected from CH or N, and R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 - C 4 ) one of a haloalkyl group, a carbamoyl group, an acetamide group, and a (C 1 -C 4 )haloalkoxy group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(VI)所示： Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (VI):
Figure PCTCN2017072716-appb-000014
Figure PCTCN2017072716-appb-000014
其中，R4选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基、胺甲酰基、乙酰胺基和(C1-C4)卤代烷氧基中的一种。Wherein R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, carbamoyl, acetamide One of a (C 1 -C 4 )haloalkoxy group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(VII)所示：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (VII):
Figure PCTCN2017072716-appb-000015
Figure PCTCN2017072716-appb-000015
其中，R4选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基、胺甲酰基、乙酰胺基和(C1-C4)卤代烷氧基中的一种。Wherein R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, carbamoyl, acetamide One of a (C 1 -C 4 )haloalkoxy group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(VIII)所示： Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (VIII):
Figure PCTCN2017072716-appb-000016
Figure PCTCN2017072716-appb-000016
其中，R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(IX)所示：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (IX):
Figure PCTCN2017072716-appb-000017
Figure PCTCN2017072716-appb-000017
其中，R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X)所示： Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X):
Figure PCTCN2017072716-appb-000018
Figure PCTCN2017072716-appb-000018
其中，X、Y和Z各自独立地选自CH或N；R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或几种。Wherein X, Y and Z are each independently selected from CH or N; and R 5 and R 6 are each independently selected from H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl One or more of a cyano group, a (C 1 -C 4 )haloalkyl group, and a (C 1 -C 4 )haloalkoxy group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XI)所示：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XI):
Figure PCTCN2017072716-appb-000019
Figure PCTCN2017072716-appb-000019
其中，R1选自苯基、取代苯基、苯(C2-C4)炔基、苯(C1-C4)烷基、取代苯(C1-C4)烷基、取代苯(C1-C4)烷氧基、苯亚甲(C3-C6)环烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
Figure PCTCN2017072716-appb-000020
中的一种或几种；其中R”选自苯基、取代苯基、 含氮杂苯基和取代含氮杂苯基中的一种或几种；Wherein R 1 is selected from the group consisting of phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, phenyl (C 1 -C 4 )alkyl, substituted benzene (C 1 -C 4 )alkyl, substituted benzene ( C 1 -C 4 ) alkoxy, benzylidene (C 3 -C 6 )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 )alkenyl, substituted benzene (C 2 -C 4 )alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, a nitrogen-containing heterophenyl-substituted (C 1 -C 4 ) alkoxy group and
Figure PCTCN2017072716-appb-000020
One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group;
R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XII)所示：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XII) shows:
Figure PCTCN2017072716-appb-000021
Figure PCTCN2017072716-appb-000021
其中，X、Y各自独立地选自CH或N，R4选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基、胺甲酰基、乙酰胺基和(C1-C4)卤代烷氧基中的一种。Wherein X and Y are each independently selected from CH or N, and R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 - C 4 ) one of a haloalkyl group, a carbamoyl group, an acetamide group, and a (C 1 -C 4 )haloalkoxy group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X III)所示： Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X III):
Figure PCTCN2017072716-appb-000022
Figure PCTCN2017072716-appb-000022
其中，R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X IV)所示：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X IV):
Figure PCTCN2017072716-appb-000023
Figure PCTCN2017072716-appb-000023
其中，R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X V)所示： Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X V):
Figure PCTCN2017072716-appb-000024
Figure PCTCN2017072716-appb-000024
其中，X、Y和Z各自独立地选自CH或N；R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein X, Y and Z are each independently selected from CH or N; and R 5 and R 6 are each independently selected from H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl One or more of a cyano group, a (C 1 -C 4 )haloalkyl group, and a (C 1 -C 4 )haloalkoxy group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X VI)所示：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X VI):
Figure PCTCN2017072716-appb-000025
Figure PCTCN2017072716-appb-000025
其中，R4选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基、胺甲酰基、乙酰胺基和(C1-C4)卤代烷氧基中的一种。Wherein R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, carbamoyl, acetamide One of a (C 1 -C 4 )haloalkoxy group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X VII)所示： Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X VII) shows:
Figure PCTCN2017072716-appb-000026
Figure PCTCN2017072716-appb-000026
其中，R4选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基、胺甲酰基、乙酰胺基和(C1-C4)卤代烷氧基中的一种。Wherein R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, carbamoyl, acetamide One of a (C 1 -C 4 )haloalkoxy group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X VIII)所示：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X VIII):
Figure PCTCN2017072716-appb-000027
Figure PCTCN2017072716-appb-000027
其中，R1或R2各自独立地选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基、(C1-C4)卤代烷氧基、苯基、取代苯基、苯(C2-C4)炔基、苯(C1-C4)烷基、取代苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
Figure PCTCN2017072716-appb-000028
中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种； Wherein R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C) 4 ) haloalkoxy, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, benzene (C 1 -C 4 )alkyl, substituted benzene (C 1 -C 4 )alkyl, benzene methylene (C 3 -C 6 )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 )alkenyl, substituted benzene (C 2 -C 4 )alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, a nitrogen-containing heterophenyl-substituted (C 1 -C 4 ) alkoxy group and
Figure PCTCN2017072716-appb-000028
One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group;
n＝0-4之间的任一个整数；Any integer between n=0-4;
R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X IX)所示：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X IX) shows:
Figure PCTCN2017072716-appb-000029
Figure PCTCN2017072716-appb-000029
其中，R2选自苯基、取代苯基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、取代苯(C1-C4)烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯氧烷基、取代苯氧烷基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
Figure PCTCN2017072716-appb-000030
中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；Wherein R 2 is selected from the group consisting of phenyl, substituted phenyl, phenyl(C 1 -C 4 )alkyl, benzylidene(C 3 -C 6 )cycloalkyl, substituted benzene(C 1 -C 4 )alkyl, Benzene (C 1 -C 4 )alkoxy, substituted benzene (C 1 -C 4 )alkoxy, phenoxyalkyl, substituted phenoxyalkyl, phenyl(C 2 -C 4 )alkenyl, substituted benzene C 2 -C 4 )alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, nitrogen-containing heterophenyl substituted (C 1 - C 4 ) alkoxy and
Figure PCTCN2017072716-appb-000030
One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group;
R1选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基或(C1-C4)卤代烷氧基；R 1 is selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl or (C 1 -C 4 )haloalkoxy;
R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X X)所示： Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X X) shows:
Figure PCTCN2017072716-appb-000031
Figure PCTCN2017072716-appb-000031
其中，R2选自苯基、取代苯基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、取代苯(C1-C4)烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯氧烷基、取代苯氧烷基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
Figure PCTCN2017072716-appb-000032
中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；Wherein R 2 is selected from the group consisting of phenyl, substituted phenyl, phenyl(C 1 -C 4 )alkyl, benzylidene(C 3 -C 6 )cycloalkyl, substituted benzene(C 1 -C 4 )alkyl, Benzene (C 1 -C 4 )alkoxy, substituted benzene (C 1 -C 4 )alkoxy, phenoxyalkyl, substituted phenoxyalkyl, phenyl(C 2 -C 4 )alkenyl, substituted benzene C 2 -C 4 )alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, nitrogen-containing heterophenyl substituted (C 1 - C 4 ) alkoxy and
Figure PCTCN2017072716-appb-000032
One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group;
R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X XI)所示：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X XI) shows:
Figure PCTCN2017072716-appb-000033
Figure PCTCN2017072716-appb-000033
其中，R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X XII)所示Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X XII)
其中，R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X X III)所示：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X X III) shows:
Figure PCTCN2017072716-appb-000035
Figure PCTCN2017072716-appb-000035
其中，R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X X IV)所示：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X X IV):
Figure PCTCN2017072716-appb-000036
Figure PCTCN2017072716-appb-000036
其中，X、Y和Z各自独立地选自CH或N；R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或几种。Wherein X, Y and Z are each independently selected from CH or N; and R 5 and R 6 are each independently selected from H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl One or more of a cyano group, a (C 1 -C 4 )haloalkyl group, and a (C 1 -C 4 )haloalkoxy group.
优选地，所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，其中所述的化合物选自如下化合物中的一种或几种：Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, The compound is selected from one or more of the following compounds:
1-(3-(4-氨基-3-(5-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)piperidin-1- Propyl-2-en-1-one;
1-(3-(4-氨基-3-(5-苯基噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(5-phenylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)propane- 2-en-1-one;
1-(3-(4-氨基-3-(4-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(4-(phenoxymethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- Propyl-2-en-1-one;
1-(3-(4-氨基-3-(5-甲基-4-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮； 1-(3-(4-Amino-3-(5-methyl-4-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
1-(3-(4-氨基-3-(5-(苯氧甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(5-(phenoxymethyl)thiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- Propyl-2-en-1-one;
1-(3-(4-氨基-3-(4-((2-甲基)苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(4-(2-methyl)phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
1-(3-(4-氨基-3-(4-((间-甲基)苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(4-((m-methyl)phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
1-(3-(4-氨基-3-(4-((对-甲基)苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(4-((p-methyl)phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
1-(3-(4-氨基-3-(4-((2-甲氧基)苯氧基甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(4-((2-methoxy)phenoxymethyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidine-1 -yl)piperidin-1-yl)prop-2-en-1-one;
1-(3-(4-氨基-3-(4-((3-甲氧基)苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(4-((3-methoxy)phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
1-(3-(4-氨基-3-(4-((4-甲氧基)苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(4-(4-methoxy)phenoxymethyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
1-(3-(4-氨基-3-(2-((2-氰基)苯氧甲基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(2-((2-cyano)phenoxymethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
1-(3-(4-氨基-3-(2-((4-氰基)苯氧甲基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(2-(4-cyano)phenoxymethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
1-(3-(4-氨基-3-(2-((3-氰基)苯氧甲基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(2-((3-cyano)phenoxymethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
1-(3-(4-氨基-3-(2-(2-甲氧基苯)氧甲基噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(2-(2-methoxyphenyl)oxymethylthiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
1-(3-(4-氨基-3-(2-(3-甲氧基苯)氧甲基噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(2-(3-methoxyphenyl)oxymethylthiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-苯噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-phenylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl )prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(苯氧甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(phenoxymethyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)piperidin Pyridin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-((嘧啶-4-基氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]-嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮； (R)-1-(3-(4-Amino-3-(5-((pyrimidin-4-yloxy)methyl)thiophen-3-yl)-1H-pyrazole [3,4-d] -pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;
1-(3-(4-氨基-3-(5-((2-甲氧基-4-甲基苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(5-((2-methoxy-4-methylphenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3,4- d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;
1-(3-(4-氨基-3-(5-((2-甲氧基-4-氯苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(5-((2-methoxy-4-chlorophenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3,4-d Pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-((2-甲氧基-4-氰基苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((2-methoxy-4-cyanophenoxy)methyl)thiophen-3-yl)-1H-pyrazole [ 3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-((2-氯-5-甲氧基苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((2-chloro-5-methoxyphenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3 , 4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-((3-氯-5-甲氧基苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((3-chloro-5-methoxyphenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3 , 4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-((3-甲氧基-4-氰基苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((3-methoxy-4-cyanophenoxy)methyl)thiophen-3-yl)-1H-pyrazole [ 3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(2-甲基苯氧甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(2-methylphenoxymethyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidine-1 -yl)piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(4-甲苯氧基甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(4-methyloxymethyl)thiophen-3-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(3-甲基苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3-methylphenyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(3，4-二甲基苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3,4-dimethylphenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidine- 1-yl)piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(3-甲氧基苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3-methoxyphenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(4-甲氧基苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(4-methoxyphenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(4-苯基噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(4-phenylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- Propyl-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-苯基噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-phenylthiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- Propyl-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(4-三氟甲基苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮； (R)-1-(3-(4-Amino-3-(5-(4-trifluoromethylphenyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidine-1 -yl)piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(3-三氟甲苯)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3-trifluorotoluene)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(3，5-二甲苯)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3,5-dimethylphenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-苯基噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-phenylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- Propyl-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(2-氟苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(2-fluorophenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(3-氟苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3-fluorophenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(4-氟苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(4-fluorophenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(2-(3-甲基苯基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(2-(3-methylphenyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(2-(4-甲氧基苯基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(2-(4-methoxyphenyl)thiophen-4-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(3-甲氧基苯基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3-methoxyphenyl)thiophen-3-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-((2-氟苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((2-fluorophenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3,4-d]pyrimidine -1-yl)piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-((3-氟苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((3-fluorophenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3,4-d]pyrimidine -1-yl)piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-((4-氟苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((4-fluorophenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3,4-d]pyrimidine -1-yl)piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(苯氧基甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)-哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(phenoxymethyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl) -piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(2-(苯乙基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)-哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(2-(phenylethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)-per Pyridin-1-yl)prop-2-en-1-one;
(R)反-1-(3-(4-氨基-3-(2-苯乙烯噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮； (R) trans-1-(3-(4-amino-3-(2-styrenethiophen-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -yl)prop-2-en-1-one;
1-(3-(4-氨基-3-(2-((3-甲基苯)氧甲基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(2-(3-methylphenyl)oxymethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(2-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(2-pyridylcarbamoyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(3-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3-pyridylcarbamoyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(4-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(4-pyridylcarbamoyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(苯胺基甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(anilinoyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)piperidin Pyridin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(2-(2-吡啶胺基甲酰基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(2-(2-pyridylaminocarbonyl)thiophen-4-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(2-(3-吡啶胺基甲酰基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(2-(3-pyridylaminocarbonyl)thiophen-4-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(2-(4-吡啶胺基甲酰基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(2-(4-pyridylaminocarbonyl)thiophen-4-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(2-(苯胺基甲酰基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(2-(anilinoyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)piperidin Pyridin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(4-(2-吡啶胺基甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(4-(2-pyridylaminocarbonyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(4-(3-吡啶胺基甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(4-(3-pyridylaminocarbonyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(4-(4-吡啶胺基甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(4-(4-pyridylaminocarbonyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(4-(苯胺基甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(4-(anilinoyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)piperidin Pyridin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(吡啶-2-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(pyridin-2-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(吡啶-3-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮； (R)-1-(3-(4-Amino-3-(5-(pyridin-3-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(4-(吡啶-2-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(4-(pyridin-2-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(4-(吡啶-3-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(4-(pyridin-3-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(吡啶-2-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(pyridin-2-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(6-氰基吡啶-2-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(6-cyanopyridin-2-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidine- 1-yl)piperidin-1-yl)prop-2-en-1-one;
(R)-6-(5-(1-(1-丙烯酰哌啶-3-基)-4-氨基-1H-吡唑[3，4-d]嘧啶-3-基)噻吩-2-基)-吡啶酰胺；(R)-6-(5-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene-2- Base)-pyridine amide
(R)-6-(5-(1-(1-丙烯酰哌啶-3-基)-4-氨基-1H-吡唑[3，4-d]嘧啶-3-基)噻吩-2-基)-3-吡啶甲酰胺；(R)-6-(5-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene-2- Base)-3-pyridinecarboxamide;
(R)-N-(6-(5-(1-(1-丙烯酰哌啶-3-基)-4-氨基-1H-吡唑[3，4-d]嘧啶-3-基)噻吩-2-基)吡啶-2-基)乙酰胺；(R)-N-(6-(5-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene -2-yl)pyridin-2-yl)acetamide;
(R)-N-(6-(5-(1-(1-丙烯酰哌啶-3-基)-4-氨基-1H-吡唑[3，4-d]嘧啶-3-基)噻吩-2-基)吡啶-3-基)乙酰胺；(R)-N-(6-(5-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene -2-yl)pyridin-3-yl)acetamide;
(R)-1-(3-(4-氨基-3-(5-(6-甲基吡啶-2-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(6-methylpyridin-2-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidine- 1-yl)piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(4-氨基-3-(5-(5-甲基吡啶-2-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮。(R)-1-(3-(4-Amino-3-(5-(5-methylpyridin-2-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidine- 1-yl)piperidin-1-yl)prop-2-en-1-one.
本发明还提供了一种如下式(X X V)所示的化合物或该化合物的盐，The present invention also provides a compound represented by the following formula (X X V) or a salt of the compound,
Figure PCTCN2017072716-appb-000037
Figure PCTCN2017072716-appb-000037
其中，R1或R2选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基、(C1-C4)卤代烷氧基、苯基、取代苯基、苯(C2-C4)炔基、苯(C1-C4)烷基、苯亚 甲(C3-C6)环烷基、取代苯(C1-C4)烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
Figure PCTCN2017072716-appb-000038
中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；R7选自H或者
Figure PCTCN2017072716-appb-000039
其中R3选自三氟甲基、叔丁氧基和苄氧基中的一种；当R7为H时，式(X X V)化合物的盐可以为盐酸盐、硫酸盐、乙酸盐和三氟乙酸盐中的一种。式(X X V)化合物或其盐为本发明式(I)-式(X X IV)化合物的中间体化合物。Wherein R 1 or R 2 is selected from the group consisting of H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkane Oxyl, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, benzene (C 1 -C 4 )alkyl, phenylmethylene (C 3 -C 6 )cycloalkyl, substituted benzene (C 1 -C 4 )alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 ) alkenyl, substituted benzene (C 2 -C 4 ) alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, aza-containing Phenyl substituted (C 1 -C 4 ) alkoxy and
Figure PCTCN2017072716-appb-000038
One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R 7 is selected from H or
Figure PCTCN2017072716-appb-000039
Wherein R 3 is selected from the group consisting of trifluoromethyl, tert-butoxy and benzyloxy; when R 7 is H, the salt of the compound of formula (XXV) may be hydrochloride, sulfate, acetate and One of the trifluoroacetate salts. The compound of the formula (X X V) or a salt thereof is an intermediate compound of the compound of the formula (I) to the formula (X X IV).
优选地，其中所述化合物如下所示：Preferably, wherein the compound is as follows:
Figure PCTCN2017072716-appb-000040
Figure PCTCN2017072716-appb-000040
其中，R1或R2各自独立地选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基、(C1-C4)卤代烷氧基、苯基、取代苯基、苯(C2-C4)炔基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、取代苯(C1-C4)烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
Figure PCTCN2017072716-appb-000041
中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；R7选自H或者
Figure PCTCN2017072716-appb-000042
其中R3选自三氟甲基，叔丁氧基和苄氧基中的一种；当R7为H时，式(X X VI)化合物的盐可以为盐酸盐、硫酸盐、乙酸盐和三氟乙酸盐中的一种。 Wherein R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C) 4 ) haloalkoxy, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, benzene (C 1 -C 4 )alkyl, benzyl (C 3 -C 6 )cycloalkyl, substituted Benzene (C 1 -C 4 )alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 )alkenyl, substituted benzene (C 2 -C 4 )alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, a nitrogen-containing heterophenyl-substituted (C 1 -C 4 ) alkoxy group and
Figure PCTCN2017072716-appb-000041
One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R 7 is selected from H or
Figure PCTCN2017072716-appb-000042
Wherein R 3 is selected from the group consisting of trifluoromethyl, tert-butoxy and benzyloxy; when R 7 is H, the salt of the compound of formula (XX VI) may be hydrochloride, sulfate or acetate. And one of the trifluoroacetate salts.
优选地，其中所述化合物如下所示：Preferably, wherein the compound is as follows:
Figure PCTCN2017072716-appb-000043
Figure PCTCN2017072716-appb-000043
其中，R1选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基、(C1-C4)卤代烷氧基、苯基、取代苯基、苯(C2-C4)炔基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、取代苯(C1-C4)烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
Figure PCTCN2017072716-appb-000044
中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；R7选自H或者
Figure PCTCN2017072716-appb-000045
其中R3选自三氟甲基，叔丁氧基和苄氧基中的一种；当R7为H时，式(X X VII)化合物的盐可以为盐酸盐、硫酸盐、乙酸盐和三氟乙酸盐中的一种。Wherein R 1 is selected from the group consisting of H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy, Phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, benzene (C 1 -C 4 )alkyl, benzylidene (C 3 -C 6 )cycloalkyl, substituted benzene (C 1 -C 4 ) alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 ) olefin a substituted benzene (C 2 -C 4 )alkenyl group, a nitrogen-containing heterophenyl group, a substituted nitrogen-containing heterophenyl group, a nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl group, a nitrogen-containing heterophenyl group substituted (C 1 -C 4 ) alkoxy group and
Figure PCTCN2017072716-appb-000044
One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R 7 is selected from H or
Figure PCTCN2017072716-appb-000045
Wherein R 3 is selected from the group consisting of trifluoromethyl, tert-butoxy and benzyloxy; when R 7 is H, the salt of the compound of formula (XX VII) may be hydrochloride, sulfate or acetate. And one of the trifluoroacetate salts.
本发明还提供了一种如下式(X X VIII)所示的化合物，其中所述的化合物如下所示：The present invention also provides a compound represented by the following formula (X X VIII), wherein the compound is as follows:
Figure PCTCN2017072716-appb-000046
Figure PCTCN2017072716-appb-000046
其中，R8选自H、Br或者硼酸基，R9选自H、甲基、氰基、胺甲酰基或者乙酰胺基。式(X X VIII)化合物为式(I)-式(X X IV)化合物的中间体化合物。Wherein R 8 is selected from H, Br or a boronic acid group, and R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido. The compound of the formula (X X VIII) is an intermediate compound of the compound of the formula (I)-formula (X X IV).
优选地，其中所述的化合物如下式(X X IX)所示：Preferably, wherein the compound is represented by the following formula (X X IX):
Figure PCTCN2017072716-appb-000047
Figure PCTCN2017072716-appb-000047
其中，R8选自H、Br或者硼酸基，R9选自H、甲基、氰基、胺甲酰基或者乙酰胺基。Wherein R 8 is selected from H, Br or a boronic acid group, and R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido.
优选地，其中所述的化合物如下式(X X X)所示：Preferably, wherein the compound is represented by the following formula (X X X):
Figure PCTCN2017072716-appb-000048
Figure PCTCN2017072716-appb-000048
其中，R8选自H、Br或者硼酸基，R9选自H、甲基、氰基、胺甲酰基或者乙酰胺基。Wherein R 8 is selected from H, Br or a boronic acid group, and R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido.
优选地，其中所述的化合物如下式(X X XI)所示：Preferably, wherein the compound is represented by the following formula (X X XI):
Figure PCTCN2017072716-appb-000049
Figure PCTCN2017072716-appb-000049
其中，R8选自H、Br或者硼酸基，R9选自H、甲基、氰基、胺甲酰基或者乙酰胺基。Wherein R 8 is selected from H, Br or a boronic acid group, and R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido.
优选地，其中所述的化合物如下式(X X XII)所示：Preferably, wherein the compound is represented by the following formula (X X XII):
Figure PCTCN2017072716-appb-000050
Figure PCTCN2017072716-appb-000050
其中，R8选自H、Br或者硼酸基，R9选自H、甲基、氰基、胺甲酰基或者乙酰胺基。Wherein R 8 is selected from H, Br or a boronic acid group, and R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido.
本发明还提供了本发明所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物在制备用于治疗与包括恶性肿瘤、自身免疫性疾病和过敏性疾病相关药物中的用途。The invention also provides a compound of the invention, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation. Use in the preparation of a medicament for the treatment of a medicament associated with malignant tumors, autoimmune diseases and allergic diseases.
优选地，其中所述的恶性肿瘤包括淋巴瘤、浆细胞瘤和白血病中的一种或几种。Preferably, the malignant tumor comprises one or more of lymphoma, plasmacytoma and leukemia.
优选地，其中所述的淋巴瘤包括非霍奇金淋巴瘤、滤泡性淋巴瘤、套细 胞淋巴瘤、小淋巴细胞淋巴瘤、外套细胞淋巴瘤、血管内大细胞型B细胞淋巴瘤、伯基特淋巴瘤、艾滋病相关性淋巴瘤和边缘区B细胞淋巴瘤中的一种或几种。Preferably, wherein the lymphoma comprises non-Hodgkin's lymphoma, follicular lymphoma, and sheath One or more of lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, intravascular large cell B-cell lymphoma, Burkitt's lymphoma, AIDS-associated lymphoma, and marginal B-cell lymphoma .
优选地，所述的非霍奇金淋巴瘤包括B细胞性非霍奇金淋巴瘤。Preferably, said non-Hodgkin's lymphoma comprises B-cell non-Hodgkin's lymphoma.
更优选地，所述的B细胞性非霍奇金淋巴瘤包括弥漫性大B细胞淋巴瘤和人体B淋巴细胞瘤中的一种或几种。More preferably, the B-cell non-Hodgkin's lymphoma comprises one or more of diffuse large B-cell lymphoma and human B-lymphoma.
优选地，其中所述的自身免疫性疾病包括关节炎、风湿、炎性肠炎和红斑狼疮中的一种或几种。Preferably, the autoimmune diseases include one or more of arthritis, rheumatism, inflammatory bowel disease, and lupus erythematosus.
本发明再一方面提供了一种布鲁顿酪氨酸激酶抑制剂组合物，其中包括本发明的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物。A further aspect of the invention provides a Bruton tyrosine kinase inhibitor composition comprising a compound of the invention, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, A mixture of enantiomers, a racemate or an N-oxide.
说明书附图Instruction sheet
图1表示通过本发明化合物对风湿性关节炎小鼠作用时间的增长，小鼠的疾病改善情况。Fig. 1 shows the improvement of the disease in mice by the action of the compound of the present invention on rheumatoid arthritis mice.
具体实施方式Detailed ways
以下实施例仅用于对本发明进行示例性说明，不用于限制本发明，在本发明保护范围内所做的修改、改变、变型等都在本发明的保护范围内。The following examples are intended to exemplify the invention, and are not intended to limit the invention, and modifications, changes, variations and the like are possible within the scope of the invention.
除非另外说明，本文中术语“布鲁顿酪氨酸激酶抑制剂”中提供包括具有式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(IX)、式(X)、式(XI)、式(XII)、式(XIII)、式(XIV)、式(XV)、式(X VI)、式(XVII)、式(XVIII)、式(X IX)、式(X X)、式(X X I)、式(X X II)、式(XXIII)、式(X X IV)结构式的化合物，每种化合物均包括具有相同结构式的不同立体异构体，其中的立体异构体还包括光学异构体和几何异构体，光学异构体也称为对映异构体，几何异构体也称为顺反异构体。Unless otherwise indicated, the term "bruton tyrosine kinase inhibitor" is provided herein to include having formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI). , (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (X) VI), formula (XVII), formula (XVIII), formula (X IX), formula (X X), formula (X X I), formula (X X II), formula (XXIII), formula (X X IV) Compounds of the formula, each of which includes different stereoisomers having the same structural formula, wherein the stereoisomers also include optical isomers and geometric isomers, and optical isomers are also referred to as enantiomers. Geometric isomers are also known as cis and trans isomers.
光学对映异构体为具有手性中心互为镜像的光学对映异构体。Optical enantiomers are optical enantiomers that have mirror images of each other.
光学对映异构体的混合物指的是互为手性的两种光学对映异构体以不同的摩尔比例混合，得到的混合物。A mixture of optical enantiomers refers to a mixture of two optical enantiomers which are chiral with each other in different molar ratios.
外消旋体指的是互为手性的两种光学对映异构体以相同摩尔比例混合， 因为分子间作用导致旋光性抵消，得到的混合物称为外消旋体。Racemic refers to the mixing of two optical enantiomers that are chiral with each other in the same molar ratio. Since the intermolecular action causes the optical rotation to cancel out, the resulting mixture is called a racemate.
顺反异构体指的是：相同的原子分别位于碳碳双键同侧和异侧的两种异构体，相同的原子位于碳碳双键同侧称为顺式，相同原子位于碳碳双键异侧称为反式。The cis-trans isomer means that the same atom is located on the same side and the opposite side of the carbon-carbon double bond. The same atom is located on the same side of the carbon-carbon double bond, called cis, and the same atom is located on the carbon-carbon. The opposite side of the double bond is called trans.
除非另外说明，本文中的术语“杂环基”指的是环烷基的一个或多个构成环的碳原子通过碳以外的杂原子替代形成杂环基，所述的杂原子包括而不限于氮原子、氧原子和硫原子等。所述的“环烷基”包括而不限于苯基、环己烷等。所述的“含氮杂环基”指的是构成环的碳原子通过一或者多个氮原子替代形成杂环基，当形成的杂环基为饱和杂环基时，称为“含氮饱和杂环基”；当形成的杂环基为不饱和杂环基时，称为“含氮不饱和杂环基”。The term "heterocyclyl" as used herein, unless otherwise indicated, refers to one or more of the carbon atoms of the cycloalkyl group constituting the ring being replaced by a heteroatom other than carbon to form a heterocyclic group, including but not limited to A nitrogen atom, an oxygen atom, a sulfur atom, and the like. The "cycloalkyl group" includes, without limitation, phenyl, cyclohexane, and the like. The "nitrogen-containing heterocyclic group" refers to a carbon atom constituting a ring which is substituted by one or more nitrogen atoms to form a heterocyclic group, and when the heterocyclic group formed is a saturated heterocyclic group, it is referred to as "saturated nitrogen-containing". Heterocyclic group"; when the heterocyclic group formed is an unsaturated heterocyclic group, it is referred to as "nitrogen-containing unsaturated heterocyclic group".
除非另外说明，本文中的术语“苯亚甲(C3-C6)环烷基”指的是苯甲基上甲基的一个氢原子由(C3-C6)环烷基取代，形成苯亚甲环烷基的结构，其中与环烷基相连的两个基团包括而不限于相邻、相间和相对的位置。Unless otherwise stated, the term "benzimid (C 3 -C 6 )cycloalkyl" as used herein refers to a hydrogen atom of a methyl group on a benzyl group substituted by a (C 3 -C 6 )cycloalkyl group. The structure of a benzylidene cycloalkyl group in which two groups attached to a cycloalkyl group include, without being limited to, adjacent, interphase and relative positions.
除非另外说明，本文中的术语“含氮饱和杂螺环基”指的是两个饱和环烷基共用一个碳原子，形成饱和螺环。饱和螺环上的一个碳原子(非共用的碳原子)被氮原子，并且饱和螺环与其相邻基团连接形成了含氮饱和杂螺环基，其中饱和杂螺环命名时涉及到的原子数目根据形成每个环骨架的碳原子或氮原子的数目确定，不含两个环公共的碳原子。The term "nitrogen-containing saturated heterospiro" as used herein, unless otherwise indicated, refers to two saturated cycloalkyl groups sharing one carbon atom to form a saturated spiro ring. A carbon atom (unshared carbon atom) on a saturated spiro ring is bonded to a nitrogen atom, and a saturated spiro ring is bonded to its adjacent group to form a nitrogen-containing saturated heterospinyl group, wherein the saturated heterospiro ring is named after the atom The number is determined by the number of carbon atoms or nitrogen atoms forming each ring skeleton, and does not contain two carbon atoms common to the ring.
除非另外说明，本文中的术语“苯(C1-C4)烷基”指的是苯环上的一个氢原子被(C1-C4)烷基取代，形成的苯(C1-C4)烷基结构，包括而不限于苯甲基、苯乙基、苯丙基、苯异丙基和苯丁基等。Unless otherwise indicated, the term of "phenyl (C 1 -C 4) alkyl" refers to a hydrogen atom on the phenyl ring is substituted (C 1 -C 4) alkyl, phenyl formation (C 1 -C 4 ) Alkyl structures, including but not limited to benzyl, phenethyl, phenylpropyl, phenylisopropyl and phenylbutyl.
除非另外说明，本文中的术语“苯(C2-C4)炔基”指的是苯环上的一个氢原子被(C2-C4)炔基取代，形成的苯(C2-C4)炔基结构，包括而不限于苯乙炔、苯丙炔、苯丁炔等。除非另外说明，本文中的术语“取代苯基”指的是由氢原子以外的其他原子或者基团取代苯基上的氢原子，得到的带有取代基的苯基。Unless otherwise indicated, the term of "phenyl (C 2 -C. 4) alkynyl group" refers to a hydrogen atom on the benzene ring is (C 2 -C. 4) substituted alkynyl group, formed by benzene (C 2 -C 4 ) alkynyl structures including, but not limited to, phenylacetylene, phenylpropyne, phenylbutyne, and the like. Unless otherwise stated, the term "substituted phenyl" as used herein refers to a substituted phenyl group substituted by a hydrogen atom on a phenyl group other than a hydrogen atom or a group.
除非另外说明，本文中的术语“苯氧烷基”指的是苯基和烷基通过氧相连接，形成的基团，并且该基团通过烷基与外界其他基团相连接，包括而不限于：苯氧甲基、苯氧乙基、苯氧丙基等。Unless otherwise stated, the term "phenoxyalkyl" as used herein refers to a group formed by the attachment of a phenyl group and an alkyl group through an oxygen group, and the group is attached to the other groups externally via an alkyl group, including Limited to: phenoxymethyl, phenoxyethyl, phenoxypropyl and the like.
除非另外说明，本文中的术语“取代苯氧烷基”指的是苯氧烷基的苯基由氢原子以外的其他原子或者基团取代，形成带有取代基的苯氧烷基。 Unless otherwise stated, the term "substituted phenoxyalkyl" as used herein means that the phenyl group of the phenoxyalkyl group is substituted with an atom or group other than a hydrogen atom to form a substituted phenoxyalkyl group.
除非另外说明，本文中的“胺基取代的(C2-C4)烯基”指的是(C2-C4)烯基的一个或多个氢原子被一个或一个以上胺基取代后得到的带有胺基的(C2-C4)烯基，其中的“氢原子”既包括烯基上的氢原子也包括非烯基如：甲基、亚甲基等基团上的氢原子，所述的“胺基”是氨的氢原子被烃基替代后形成的有机胺基。Unless otherwise stated, "amino substituted (C 2 -C 4 )alkenyl" as used herein refers to one or more hydrogen atoms of a (C 2 -C 4 )alkenyl group substituted by one or more amine groups. The resulting (C 2 -C 4 ) alkenyl group having an amine group, wherein the "hydrogen atom" includes both a hydrogen atom on the alkenyl group and a hydrogen group on a non-alkenyl group such as a methyl group or a methylene group. The atom, the "amine group" is an organic amine group formed by replacing a hydrogen atom of ammonia with a hydrocarbon group.
除非另外说明，“苯(C2-C4)烯基”指的是苯环上的一个氢原子被(C2-C4)的烯基取代，得到带有苯环的(C2-C4)烯基，其中包括而不限于：苯乙烯基、苯丙烯基、苯异丙烯基、苯丁烯基等。Unless otherwise stated, "benzene (C 2 -C 4 )alkenyl" means that one hydrogen atom on the phenyl ring is substituted with a (C 2 -C 4 ) alkenyl group to give a benzene ring (C 2 -C) 4 ) Alkenyl group, including but not limited to: styryl group, phenylpropenyl group, benzoisopropenyl group, phenylbutenyl group and the like.
除非另外说明，本文中的术语“含氮杂苯基”指的是苯基上的一个或者一个以上的碳原子被氮原子取代，形成带有氮杂原子的苯基，包括而不限于：吡啶基、间二氮杂苯基、对二氮杂苯基等。Unless otherwise stated, the term "nitrogen-containing heterophenyl" as used herein means that one or more carbon atoms on the phenyl group are replaced by a nitrogen atom to form a phenyl group bearing a nitrogen heteroatom, including but not limited to: pyridine Base, m-diazaphenyl, p-diazaphenyl and the like.
除非另外说明，本文中的术语“浆细胞瘤”是单克隆浆细胞增生引起的一组肿瘤性疾病，包括多发性骨髓瘤、原发性巨球蛋白血症。Unless otherwise stated, the term "plasma cell tumor" herein is a group of neoplastic diseases caused by proliferation of monoclonal plasma cells, including multiple myeloma, primary macroglobulinemia.
在某些实施例中，本发明的受试对象可以为哺乳动物，如狗、猫、牛、羊、马或人，优选人。本发明的药物的必需治疗量根据具体疾病的变化并且可由本领域普通技术人员容易地确定。In certain embodiments, a subject of the invention may be a mammal, such as a dog, cat, cow, sheep, horse or human, preferably a human. The necessary therapeutic amount of the medicament of the present invention will vary depending on the particular disease and can be readily determined by one of ordinary skill in the art.
在某些实施方式中，本发明的一种或多种化合物可以彼此间联合使用，也可以选择将本发明的化合物与任何其它的活性试剂结合使用，用于制备布鲁顿酪氨酸激酶抑制剂，如果使用的是一组化合物，则可将这些化合物同时、分别或者有序地对受试对象进行给药。In certain embodiments, one or more compounds of the invention may be used in combination with each other, and the compounds of the invention may be optionally used in combination with any other active agent for the preparation of Bruton's tyrosine kinase inhibition. Agents, if a group of compounds are used, these compounds can be administered to the subject simultaneously, separately or sequentially.
在某些实施方式中，本发明的化合物可以与一种或多种其它抗癌剂联合使用。可联用的抗癌剂包括但不限于依鲁替尼、来他替尼、厄洛替尼、拉帕替尼、来那替尼、拉帕替尼、西地尼布、阿西替尼、帕唑帕尼、索拉非尼、阿柏西普、利妥昔单抗、阿仑单抗、贝伐单抗、帕尼单抗、曲妥珠单抗、烷化剂、氮介类药物、叶酸拮抗剂、嘌呤拮抗剂、嘧啶拮抗剂、纺锤体毒素、拓扑异构酶抑制剂、凋亡诱导剂、血管生成抑制剂、鬼臼毒素、亚硝基脲、抗代谢物、蛋白合成抑制剂、激酶抑制剂、抗***药、顺铂、卡铂、干扰素、天冬酰胺酶、亮丙瑞林、氟他胺、甲地孕酮、丝裂霉素、博莱霉素、阿霉素、依立替康和紫杉醇。在某一个实施方式中，所述的抗癌剂是抗***药物，诸如他莫昔芬和氟维司群(ICI182，780)。 In certain embodiments, the compounds of the invention may be used in combination with one or more other anticancer agents. Anticancer agents that can be used include, but are not limited to, ibrutinib, statinidin, erlotinib, lapatinib, neratinib, lapatinib, cediranib, axitinib , pazopanib, sorafenib, aboxicept, rituximab, alemtuzumab, bevacizumab, panitumumab, trastuzumab, alkylating agent, nitrogen-based Drugs, folic acid antagonists, sputum antagonists, pyrimidine antagonists, spindle toxins, topoisomerase inhibitors, apoptosis inducers, angiogenesis inhibitors, podophyllotoxin, nitrosourea, antimetabolites, protein synthesis Inhibitors, kinase inhibitors, antiestrogens, cisplatin, carboplatin, interferon, asparaginase, leuprolide, flutamide, megestrol, mitomycin, bleomycin, Doxorubicin, irinotecan and paclitaxel. In one embodiment, the anticancer agent is an antiestrogen drug such as tamoxifen and fulvestrant (ICI 182, 780).
在某些实施方式中，本发明的药物组合物也可用于治疗动物疾病。普通的兽医可根据从业经验将本发明的一种化合物、或其可兽用的盐、或其可兽用的溶剂或前药以合适的可接受的制剂形式给药。兽医可决定对某一动物最适合的给药途径。In certain embodiments, the pharmaceutical compositions of the invention are also useful for treating diseases in animals. A general veterinarian can administer a compound of the invention, or a veterinary salt thereof, or a veterinary solvent or prodrug thereof, in a suitable acceptable formulation, based on experience in the art. The veterinarian can determine the most appropriate route of administration for an animal.
本发明的化合物通过以下路线1进行制备：The compounds of the invention are prepared by the following route 1:
Figure PCTCN2017072716-appb-000051
Figure PCTCN2017072716-appb-000051
在以上的合成路线中，作为起始原料的5-胺基-1H-吡唑-4-氰基(化合物1’)与甲脒盐酸盐在70-90℃，优选80℃条件下反应得到1H-吡唑[3，4-d]嘧啶-4-胺(化合物2’)，在有机溶剂(例如，二甲基甲酰胺，乙酸)中与N-碘代丁二酰亚胺或氯化碘在80℃下反应，由此进行，发生碘代反应得到3-碘-1H-吡唑[3，4-d]嘧啶-4-胺(化合物3’)。In the above synthetic route, 5-amino-1H-pyrazole-4-cyano (compound 1') as a starting material is reacted with formamidine hydrochloride at 70-90 ° C, preferably 80 ° C. 1H-pyrazole [3,4-d]pyrimidin-4-amine (Compound 2') in N-iodosuccinimide or chlorinated in an organic solvent (eg dimethylformamide, acetic acid) Iodine is reacted at 80 ° C to carry out an iodo reaction to obtain 3-iodo-1H-pyrazole [3,4-d]pyrimidin-4-amine (compound 3').
反应路线1中步骤3中的反应是公知的，3-碘-1H-吡唑[3，4-d]嘧啶-4-胺(化合物3’)在有机溶剂中，如四氢呋喃(THF)中与羟基化合物4’，在三苯基膦和偶氮二甲酸二异丙酯的存在下，在50-70℃下反应，由此发生双分子亲核取代(Mitsunobu取代)反应，得到化合物5’。化合物4’是具有手性性质的原料，因此，在合成的过程中，可以根据目标化合物的旋光性质，选择适当旋光性的化合物4’作为原料，从而得到的反应中间体化合物也具有了和化合物4’相同的旋光性质。化合物5’与化合物6’，在有机溶剂(二甲基甲 酰胺、乙二醇二甲醚、四氢呋喃和1，4-二氧六环(1，4-dioxane))中，在金属钯，例如：包括四(三苯基膦)钯Pd(PPh3)4、双苯基磷二氯钯Pd(Pd(PPh3)2Cl2和[1，1′-双(二苯基磷)二茂铁]二氯化钯Pd(dppf)Cl2中任意一种或几种的催化下，在60-80℃下反应，由此进行发生偶联反应得到化合物7’。The reaction in the step 3 of Reaction Scheme 1 is well known, and 3-iodo-1H-pyrazole [3,4-d]pyrimidin-4-amine (Compound 3') is in an organic solvent such as tetrahydrofuran (THF). The hydroxy compound 4' is reacted at 50-70 ° C in the presence of triphenylphosphine and diisopropyl azodicarboxylate, whereby a bimolecular nucleophilic substitution (Mitsunobu substitution) reaction occurs to obtain a compound 5'. The compound 4' is a raw material having a chiral property, and therefore, in the course of the synthesis, the compound 4' having an appropriate optical rotation can be selected as a raw material according to the optical rotation property of the target compound, whereby the obtained reaction intermediate compound also has a compound compound. 4' identical optical properties. Compound 5' and compound 6' in an organic solvent (dimethylformamide, ethylene glycol dimethyl ether, tetrahydrofuran and 1,4-dioxane) in metallic palladium, for example : including tetrakis(triphenylphosphine)palladium Pd(PPh 3 ) 4 , bisphenylphosphine dichloropalladium Pd (Pd(PPh 3 ) 2 Cl 2 and [1,1'-bis(diphenylphosphino)) The compound 7' is obtained by a coupling reaction at 60-80 ° C under the catalysis of any one or more of iron]palladium dichloride Pd(dppf)Cl 2 .
反应路线1中步骤5的反应是公知的，化合物7’，在有机溶剂(二氯甲烷、四氢呋喃)中，在三氟乙酸或盐酸的存在下，在0℃到室温下反应，由此进行，进行脱保护反应得到化合物8’。The reaction of the step 5 in the reaction scheme 1 is known, and the compound 7' is reacted in an organic solvent (dichloromethane or tetrahydrofuran) in the presence of trifluoroacetic acid or hydrochloric acid at 0 ° C to room temperature, thereby proceeding, Deprotection is carried out to give compound 8'.
反应路线1中的步骤5的反应是公知的，化合物8’，在有机溶剂(二氯甲烷或二甲基甲酰胺)中，与对应的羧酸，或酰氯在0℃到室温下反应，由此进行，发生缩合反应得到化合物9’。The reaction of the step 5 in the reaction scheme 1 is well known, and the compound 8' is reacted with the corresponding carboxylic acid or acid chloride in an organic solvent (dichloromethane or dimethylformamide) at 0 ° C to room temperature. This proceeds, and a condensation reaction takes place to give compound 9'.
起始原料5-氨基-1H-吡唑-4-氰基CAS号为16617-46-2购自上海海曲化工有限公司。The starting material 5-amino-1H-pyrazole-4-cyano CAS No. 16617-46-2 was purchased from Shanghai Haiqu Chemical Co., Ltd.
化合物4’是1-叔丁氧羰基-3-羟基哌啶CAS号为85275-45-2，(S)-1-叔丁氧羰基-3-羟基哌啶CAS号为143900-44-1或(R)-1-叔丁氧羰基-3-羟基哌啶CAS号为143900-43-0购自上海韶远试剂有限公司。Compound 4' is 1-tert-butoxycarbonyl-3-hydroxypiperidine CAS No. 85275-45-2, (S)-1-tert-butoxycarbonyl-3-hydroxypiperidine CAS No. 143900-44-1 or (R)-1-tert-Butoxycarbonyl-3-hydroxypiperidine CAS No. 143900-43-0 was purchased from Shanghai Yuyuan Reagent Co., Ltd.
化合物6’按照以下方法制得：把相应的溴代取代噻吩化合物的四氢呋喃溶液在氮气环境下滴加到零下70℃的正丁基锂(nBuLi)的四氢呋喃(THF)溶液中。在零下70℃下反应2小时，然后加入硼酸甲酯(B(OMe)3)，在零下70℃下继续反应30分钟，升至室温导入1mol/L的盐酸中搅拌10分钟。用乙酸乙酯萃取得到的有机相干燥，减压浓缩得到目标硼酸化合物粗品，因其不稳定，不用精制直接用于下一步反应。Compound 6' was obtained by the following method: a solution of the corresponding bromo substituted thiophene compound in tetrahydrofuran was added dropwise to a solution of n-butyllithium (nBuLi) in tetrahydrofuran (THF) at 70 ° C under nitrogen. The reaction was carried out at -70 ° C for 2 hours, then methyl borate (B(OMe) 3 ) was added, the reaction was continued at minus 70 ° C for 30 minutes, and the mixture was introduced to 1 mol/L hydrochloric acid at room temperature for 10 minutes. The organic phase obtained by extraction with ethyl acetate was dried and concentrated under reduced pressure to give a crude compound of the title compound, which was used for the next reaction without purification.
在本说明书中的反应中，伴随加热的反应，如在本技术领域内常见的可使用水浴或油浴来进行。在本说明书中的反应中，反应产物可用通常的纯化手段，例如将常压或减压蒸馏得到的馏分，使用硅胶的高效液相色谱，薄层色谱，洗涤等的方法来纯化。纯化即可在每个反应中进行，也可在多步反应之后进行操作。In the reaction in the present specification, the reaction accompanying the heating, as is common in the art, can be carried out using a water bath or an oil bath. In the reaction in the present specification, the reaction product can be purified by a usual purification means such as a fraction obtained by normal or reduced pressure distillation using high performance liquid chromatography, thin layer chromatography, washing or the like using silica gel. Purification can be carried out in each reaction or after multiple steps of the reaction.
实施例1Example 1
1H-吡唑[3，4-d]嘧啶-4-胺(化合物2’)的制备Preparation of 1H-pyrazole [3,4-d]pyrimidin-4-amine (Compound 2')
在室温下向5-氨基-1H-吡唑-4-氰基(化合物1’)(20g，185.2mmol)的 乙醇(500mL)溶液中加入甲脒盐酸盐(16.4g，203.7mmol)，然后在80℃下反应10小时，冷却至室温，通过减压浓缩溶剂，得到的固体产物用水洗涤后真空干燥得到目标产物(21.3g，85％收率)，即1H-吡唑[3，4-d]嘧啶-4-胺(化合物2’)。To 5-amino-1H-pyrazole-4-cyano (compound 1') (20 g, 185.2 mmol) at room temperature To a solution of ethanol (500 mL), formazan hydrochloride (16.4 g, 203.7 mmol) was added, and then reacted at 80 ° C for 10 hours, cooled to room temperature, and the solvent was concentrated under reduced pressure. Product (21.3 g, 85% yield), 1H-pyrazole [3,4-d]pyrimidine-4-amine (Compound 2').
薄层色谱(TLC)检测：Rf 0.5(二氯甲烷∶甲醇＝5∶1，展开相)Thin layer chromatography (TLC) detection: R f 0.5 (dichloromethane:methanol = 5:1, unfolded phase)
质谱检测：MS(ESI)m/z 136(M+1)；Mass spectrometry: MS (ESI) m/z 136 (M + 1);
核磁共振：1HNMR(400MHz，DMSO-d6)、6.96(br s，2H)、7.68(s，1H)、8.35(s，1H)、13.24(s，1H)。Nuclear magnetic resonance: 1H NMR (400 MHz, DMSO-d6), 6.96 (br s, 2H), 7.68 (s, 1H), 8.35 (s, 1H), 13.24 (s, 1H).
实施例2：3-碘-1H-吡唑[3，4-d]嘧啶-4-胺(化合物3’)的制备Example 2: Preparation of 3-iodo-1H-pyrazole [3,4-d]pyrimidin-4-amine (Compound 3')
在室温下向1H-吡唑[3，4-d]嘧啶-4-胺(20g，148mmol)的乙酸(500mL)溶液中加入氯化碘ICl(24g，148mmol)，然后在80℃下反应10小时，冷却至室温，通过减压浓缩溶剂，得到的固体产物依次用Na2CO3饱和溶液，Na2SO3饱和溶液和水洗涤后真空干燥得到3-碘-1H-吡唑[3，4-d]嘧啶-4-胺(化合物3’，30.9g、80％收率)。薄层色谱检测：TLC：Rf 0.5(二氯甲烷∶甲醇＝5∶1)To a solution of 1H-pyrazole [3,4-d]pyrimidin-4-amine (20 g, 148 mmol) in acetic acid (500 mL) was added EtOAc (1 g, 148 mmol) and then reacted at 80 ° C. After cooling to room temperature, the solvent was concentrated under reduced pressure, and the obtained solid product was washed successively with Na 2 CO 3 saturated solution, Na 2 SO 3 saturated solution and water, and dried in vacuo to give 3-iodo-1H-pyrazole [3,4 -d]pyrimidine-4-amine (compound 3', 30.9 g, 80% yield). Thin layer chromatography: TLC: R f 0.5 (dichloromethane:methanol = 5:1)
质谱检测：MS(ESI)m/z 262(M+1)；Mass spectrometry: MS (ESI) m/z 262 (M + 1);
核磁共振检测：1HNMR(400MHz，DMSO-d6)、6.98(br s，2H)、8.35(s，1H)，13.20(s，1H)。Nuclear magnetic resonance detection: 1H NMR (400 MHz, DMSO-d6), 6.98 (br s, 2H), 8.35 (s, 1H), 13.20 (s, 1H).
实施例3(化合物4’)的制备Preparation of Example 3 (Compound 4')
当环2为哌啶、m＝0时，化合物4’为：1-叔丁氧羰基-3-羟基哌啶When ring 2 is piperidine, m = 0, compound 4' is: 1-tert-butoxycarbonyl-3-hydroxypiperidine
化合物5’为：叔-丁基-3-(4-氨基-3-碘-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯Compound 5' is: tert-butyl-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
在室温下向3-碘-1H-吡唑[3，4-d]嘧啶-4-胺(化合物3’)(10g，38.3mmol)的四氢呋喃(150mL)溶液中依次加入1-叔丁氧羰基-3-羟基哌啶(化合物4’)，(9.25g，46mmol)(根据具体需要，选择适合旋光性的1-叔丁氧羰基-3-羟基哌啶)、偶氮二甲酸二异丙酯(9.30g，46mmol)和三苯基膦(12.06mmol，46mmol)。然后在60℃下反应5小时，冷却至室温，通过减压浓缩溶剂得到的粗品用硅胶柱的液相色谱分离，洗脱溶剂为二氯甲烷∶甲醇(40∶1-＞10∶1)得到目标产物叔-丁基-3-(4-氨基-3-碘-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸 酯(化合物5’，2.8g，收率：75％)。To a solution of 3-iodo-1H-pyrazol[3,4-d]pyrimidin-4-amine (Compound 3') (10 g, 38.3 mmol) in tetrahydrofuran (150 mL) 3-hydroxypiperidine (Compound 4'), (9.25 g, 46 mmol) (optionally suitable for optically active 1-tert-butoxycarbonyl-3-hydroxypiperidine), diisopropyl azodicarboxylate (9.30 g, 46 mmol) and triphenylphosphine (12.06 mmol, 46 mmol). Then, the reaction was carried out at 60 ° C for 5 hours, and the mixture was cooled to room temperature. The target product tert-butyl-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid Ester (Compound 5', 2.8 g, yield: 75%).
薄层色谱检测：TLC：Rf0.5(二氯甲烷∶甲醇＝10∶1)质谱检测：MS(ESI)m/z 445(M+1)；核磁共振检测：1HNMR(400MHz，CDCl3)1.67(s，9H)；1.70-2.40(m，4H)，2.95-4.95(m，5H)，6.95(br s，2H)，8.31(s，1H)。实施例4TLC: R f 0.5 (dichloromethane:methanol = 10:1) Mass spectrometric detection: MS (ESI) m/z 445 (M+1); NMR detection: 1H NMR (400 MHz, CDCl 3 ) 1.67 (s, 9H); 1.70-2.40 (m, 4H), 2.95-4.95 (m, 5H), 6.95 (br s, 2H), 8.31 (s, 1H). Example 4
反应路线1中的产物9’中，当R5、R6均为H，环1为苯，L1为甲氧基，其中甲基部分与噻吩相连，氧基与苯相连，L1与噻吩的5位相连，噻吩的2位与吡唑环的3位相连，m＝0，环2为哌啶环，哌啶环的3位与吡唑环的1位氮素相连，哌啶环的1位氮素与羰基相连，R3为乙烯基，其制备如下Scheme 1 product 9 ', where R 5, R 6 are H, a benzene ring, L 1 is a methoxy group, wherein the methyl moiety is connected thiophene, connected with benzene group, L 1 and thienyl The 5 positions are linked, the 2 position of the thiophene is linked to the 3 position of the pyrazole ring, m=0, the ring 2 is the piperidine ring, and the 3 position of the piperidine ring is linked to the nitrogen of the pyrazole ring, the piperidine ring The nitrogen in the 1-position is bonded to the carbonyl group, and the R 3 is a vinyl group, which is prepared as follows
反应路线2：Reaction route 2:
Figure PCTCN2017072716-appb-000052
Figure PCTCN2017072716-appb-000052
其中Et3N表示三乙胺，EDCl表示1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。Wherein Et 3 N represents triethylamine and EDCl represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
当R5、R6均为H，环1为苯，L1为甲氧基，其中甲基部分与噻吩相连，氧基与苯相连，L1与噻吩的5位相连，硼与噻吩的2位相连，化合物6’为：(5-(苯氧甲基)噻吩-2-基)硼酸。When R 5 and R 6 are both H, ring 1 is benzene, and L 1 is a methoxy group, wherein the methyl moiety is bonded to the thiophene, the oxy group is bonded to the benzene, L 1 is bonded to the 5-position of the thiophene, and the boron and the thiophene are 2 Linked to the compound 6' is: (5-(phenoxymethyl)thiophen-2-yl)boronic acid.
化合物6’(5-(苯氧甲基)噻吩-2-基)硼酸到化合物1：1-(3-(4-氨基Compound 6'(5-(phenoxymethyl)thiophen-2-yl)boronic acid to compound 1:1-(3-(4-amino) -3-(5-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2--3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)propan-2- 烯-1-酮的制备Preparation of ene-1-one
I.(5-(苯氧甲基)噻吩-2-基)硼酸制备方法I. (5-(phenoxymethyl)thiophen-2-yl)boronic acid preparation method
在室温下向2-溴噻吩-5-甲醇(2g，10mmol)(CAS为79387-71-6购于上海泰坦科技股份有限公司)的四氢呋喃(50mL)溶液中依次加入苯酚(1.46g，15mmol)，偶氮二甲酸二异丙酯(3.1g，15mmol)和三苯基膦(4g，15mmol)。然后在室温下反应10小时，通过减压浓缩溶剂得到的粗品用硅胶柱的液相色谱分离，洗脱溶剂为乙酸乙酯∶石油醚(1∶20-＞1∶10)得到2-溴-5-(苯氧甲基)噻吩1.95g，收率：70％)。To a solution of 2-bromothiophene-5-methanol (2 g, 10 mmol) (CAS 79387-71-6 from Shanghai Titan Technology Co., Ltd.) in tetrahydrofuran (50 mL) was added phenol (1.46 g, 15 mmol) at room temperature. Diisopropyl azodicarboxylate (3.1 g, 15 mmol) and triphenylphosphine (4 g, 15 mmol). Then, the reaction was carried out for 10 hours at room temperature, and the crude product obtained by concentrating the solvent under reduced pressure was subjected to liquid chromatography on silica gel column eluting solvent ethyl acetate: petroleum ether (1:20 -> 1:10) to give 2-bromo- 5-(phenoxymethyl)thiophene 1.95 g, yield: 70%).
薄层色谱检测：TLC：Rf0.5(乙酸乙酯∶石油醚＝1∶15)Thin layer chromatography: TLC: R f 0.5 (ethyl acetate: petroleum ether = 1:15)
质谱检测：MS(ESI)m/z 269(M+1)；Mass spectrometry: MS (ESI) m/z 269 (M+1);
核磁共振检测：1HNMR(400MHz，CDCl3)5.20(s，2H)，6.50-6.75(m，2H)，7.00-7.45(m，5H)。Nuclear magnetic resonance detection: 1H NMR (400 MHz, CDCl 3 ) 5.20 (s, 2H), 6.50-6.75 (m, 2H), 7.0-7.45 (m, 5H).
2-溴-5-(苯氧甲基)噻吩(1.90g，7mmol)溶于四氢呋喃(10mL)在氮气环境下滴加到零下70℃的正丁基锂(5.6mL，2.5mol/L的正己烷溶液)的四氢呋喃(15mL)溶液中。在-70℃下反应2小时，然后加入硼酸甲酯(3.67g，35mmol)，在-70℃下继续反应30分钟，升至室温导入1mol/L的盐酸(30mL)中搅拌10分钟。用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩得到(5-(苯氧甲基)噻吩-2-基)硼酸粗品1.25g，由于产品易分解，不用精制直接用于下一步反应。2-Bromo-5-(phenoxymethyl)thiophene (1.90 g, 7 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to n-butyllithium (5.6 mL, 2.5 mol/L) at 70 ° C under nitrogen. A solution of the alkane in tetrahydrofuran (15 mL). After reacting at -70 ° C for 2 hours, methyl borate (3.67 g, 35 mmol) was added, and the reaction was continued at -70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol / L hydrochloric acid (30 mL), and stirred for 10 minutes. After extracting with ethyl acetate, the organic layer was dried over anhydrous Na 2 SO 4 and then concentrated under reduced pressure to give 1.25 g of crude (5-(phenoxymethyl)thiophen-2-yl)boronic acid. The refining is used directly in the next reaction.
薄层色谱检测：TLC：Rf0.5(乙酸乙酯∶石油醚＝1∶5)质谱检测：MS(ESI)m/z 235(M+1)；TLC: R f 0.5 (ethyl acetate: petroleum ether = 1 : 5) mass spectroscopy: MS (ESI) m/z 235 (M+1);
II.叔-丁基-3-(4-氨基-3-(5-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]II. Tert-Butyl-3-(4-amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole [3,4-d] 嘧啶-1-基)哌啶-1-甲酸酯的制备方法Method for preparing pyrimidin-1-yl) piperidine-1-carboxylate
在室温下向叔丁基-3-(4-氨基-3-碘-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯(200mg，0.45mmol)的乙二醇二甲醚(5mL)、水(2mL)的溶液中依次加入(5-(苯氧甲基)噻吩-2-基)硼酸(211mg，0.90mmol)，四(三苯基磷)鈀(26mg，0.02mmol)，Na2CO3(143mg，1.35mmol)。然后在80℃下反应16小时，冷却至室温，倒入50mL水中，用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩溶剂得到的粗品用硅胶柱的液相色谱分离，洗脱溶剂为石油醚∶乙酸乙酯(8∶1→2∶1)得到目标产物叔丁基3-(4-氨基-3-(5-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1- 基)哌啶-1-甲酸酯(160mg，收率75％)。To tert-butyl-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (200 mg, 0.45 mmol) at rt (5-(phenoxymethyl)thiophen-2-yl)boronic acid (211 mg, 0.90 mmol), tetrakis(triphenylphosphine), was added to a solution of ethylene glycol dimethyl ether (5 mL) in water (2 mL). palladium (26mg, 0.02mmol), Na 2 CO 3 (143mg, 1.35mmol). Then, the reaction was carried out at 80 ° C for 16 hours, cooled to room temperature, poured into 50 mL of water, and extracted with ethyl acetate. The organic layer was extracted with anhydrous Na 2 SO 4 and then evaporated. Chromatography and elution solvent: petroleum ether: ethyl acetate (8:1→2:1) to give the desired product tert-butyl 3-(4-amino-3-(5-(phenoxymethyl)thiophene-2 -yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (160 mg, yield 75%).
薄层色谱：(TLC)检测：Rf0.5(石油醚∶乙酸乙酯＝2∶1展开相)Thin layer chromatography: (TLC) detection: R f 0.5 (petroleum ether: ethyl acetate = 2:1 unfolded phase)
质谱检测：MS(ESI)m/z 507(M+1)；Mass spectrometry: MS (ESI) m/z 507 (M + 1);
核磁共振：1HNMR(400MHz，CDCl3)、1.68(s，9H)、0(m，1H)、2.28-2.45(m，2H)、2.90-3.25(m，1H)、3.40-3.80(m，1H)、4.05-4.25(m，2H)、4.65-4.90(m，2H)、5.31(s，2H)、6.30-6.40(m，1H)、6.60-6.70(m，1H)、7.05-7.15(m，2H)、7.20-7.25(m，1H)、7.30-7.40(m，4H)、8.41(s，1H)。Nuclear Magnetic Resonance: 1H NMR (400MHz, CDCl 3 ), 1.68 (s, 9H), 0 (m, 1H), 2.28-2.45 (m, 2H), 2.90-3.25 (m, 1H), 3.40-3.80 (m, 1H) ), 4.05-4.25 (m, 2H), 4.65-4.90 (m, 2H), 5.31 (s, 2H), 6.30-6.40 (m, 1H), 6.60-6.70 (m, 1H), 7.05-7.15 (m , 2H), 7.20-7.25 (m, 1H), 7.30-7.40 (m, 4H), 8.41 (s, 1H).
III.3-(4-氨基-3-(5-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1- 基)哌啶的制备方法 III. Preparation method of 3-(4-amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1 -yl)piperidine
在0℃向叔丁基3-(4-氨基-3-(5-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯(160mg，0.32mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(2mL)，然后升至室温反应4小时，得到3-(4-氨基-3-(5-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶的三氟乙酸盐，也可以在溶液中加入盐酸、硫酸或者乙酸，得到相应的盐酸盐、硫酸盐或者乙酸盐。通过减压浓缩溶剂得到的粗品溶于乙酸乙酯(20mL)，用Na2CO3饱和溶液洗涤然后用无水Na2SO4干燥后，通过减压浓缩溶剂得到3-(4-氨基-3-(5-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶的粗品80mg，直接用于下一步的反应，得到相应的盐酸盐、硫酸盐或者乙酸盐。To tert-butyl 3-(4-amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazo[3,4-d]pyrimidin-1-yl)piperidin at 0 °C Trifluoroacetic acid (2 mL) was added to a solution of the pyridine-1-carboxylate (160 mg, 0.32 mmol) in dichloromethane (4 mL), and then warmed to room temperature for 4 hours to give 3-(4-amino-3-(5) -(phenoxymethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine trifluoroacetate, can also be added hydrochloric acid, sulfuric acid or Acetic acid gives the corresponding hydrochloride, sulfate or acetate. To give 3- (4-amino-3 by concentrating the solvent under reduced pressure to give the crude product was dissolved in ethyl acetate (20mL), washed with a saturated solution of Na 2 CO 3 followed by drying with anhydrous Na 2 SO 4, the solvent was concentrated under reduced pressure -(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine crude product 80mg, directly used in the next reaction, corresponding Hydrochloride, sulfate or acetate.
薄层色谱检测：TLC：Rf0.5(二氯甲烷∶甲醇＝5∶1)Thin layer chromatography: TLC: R f 0.5 (dichloromethane:methanol = 5:1)
质谱检测：MS(ESI)m/z 407(M+1)；Mass spectrometry: MS (ESI) m/z 407 (M+1);
IV.3-(4-氨基-3-(5-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-IV. 3-(4-Amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1- 基)哌啶到化合物1：1-(3-(4-氨基-3-(5-(苯氧甲基)噻吩-2-基)-1H-Piperidine to the compound 1:1-(3-(4-amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H- 吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮制备方法Preparation method of pyrazole [3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one
在0℃下向3-(4-氨基-3-(5-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)-1-哌啶(80mg，0.20mmol)的二氯甲烷(5mL)溶液中依次加入丙烯酸(23mg，0.30mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(64mg，0.30mmol)(CAS号25952-53-8，购买厂家：上海倍卓生物科技有限公司)，4-二甲基胺吡啶(DMAP)(13mg，0.10mmol)，然后在室温反应2小时，用水洗涤然后用无水Na2SO4干燥后，通过减压浓缩溶剂得到的粗品，通过薄层色谱(乙酸乙酯∶甲醇＝40∶1)纯化，得到化合物1： 1-(3-(4-氨基-3-(5-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮(54mg，收率60％)。To 3-(4-amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)-1- at 0 °C To a solution of piperidine (80 mg, 0.20 mmol) in dichloromethane (5 mL), EtOAc (EtOAc <RTI ID=0.0> (64mg, 0.30mmol) (CAS No. 25952-53-8, purchased by: Shanghai Bezoo Biotechnology Co., Ltd.), 4-dimethylaminopyridine (DMAP) (13mg, 0.10mmol), then reacted at room temperature for 2 hours , washed with water and then dried over anhydrous Na 2 SO 4, the solvent under reduced pressure the crude product obtained by thin layer chromatography was concentrated: purification (ethyl acetate methanol = 40) to give compound 1: 1- (3- ( 4-amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)propan-2- En-1-one (54 mg, yield 60%).
TLC：Rf0.5(乙酸乙酯∶甲醇＝30∶1)MS(ESI)m/z 461(M+1)；1HNMR(400MHz，CDCl3)(m，1H)，2.27-2.41(m，2H)，2.89-3.24(m，1H)，3.40-3.78(m，1H)，4.07-4.28(m，2H)，4.65-4.91(m，2H)，5.31(s，2H)，5.70-5.77(m，1H)，5.83(s，2H)，6.31-6.40(m，1H)，6.59-6.67(m，1H)，7.04-7.10(m，2H)，7.19-7.25(m，1H)，7.30-7.32(m，2H)，7.33-7.40(m，2H)，8.41(s，1H)。TLC: R f 0.5 (ethyl acetate: methanol = 30:1) MS (ESI) m / z 461 (M + 1); 1 HNMR (400MHz, CDCl 3) (m, 1H), 2.27-2.41 (m, 2H), 2.89-3.24 (m, 1H), 3.40-3.78 (m, 1H), 4.07-4.28 (m, 2H), 4.65-4.91 (m, 2H), 5.31 (s, 2H), 5.70-5.77 ( m,1H), 5.83 (s, 2H), 6.31-6.40 (m, 1H), 6.59-6.67 (m, 1H), 7.04-7.10 (m, 2H), 7.19-7.25 (m, 1H), 7.30- 7.32 (m, 2H), 7.33-7.40 (m, 2H), 8.41 (s, 1H).
V.中间体化合物及其制备方法V. Intermediate compound and preparation method thereof
按照与实施例4类似的方法将中间产物化合6’进行改变，可以得到如下表化合物，其中中间产物化合物6’可以选自如下化合物：The intermediate compound was changed 6' in the same manner as in Example 4 to give the following compound, wherein the intermediate compound 6' may be selected from the following compounds:
(4-(苯氧甲基)噻吩-2-基)硼酸(4-(phenoxymethyl)thiophen-2-yl)boronic acid
(4-((5-甲基苯氧基)甲基)噻吩-2-基)硼酸(4-((5-Methylphenoxy)methyl)thiophen-2-yl)boronic acid
(5-(苯氧甲基)噻吩-3-基)硼酸(5-(phenoxymethyl)thiophen-3-yl)boronic acid
(4-((邻-甲苯氧基)甲基)噻吩-2-基)硼酸(4-((o-tolyloxy)methyl)thiophen-2-yl)boronic acid
(4-((间-甲苯氧基)甲基)噻吩-2-基)硼酸(4-((m-tolyloxy)methyl)thiophen-2-yl)boronic acid
(4-((对-甲苯氧基)甲基)噻吩-2-基)硼酸(4-((p-tolyloxy)methyl)thiophen-2-yl)boronic acid
(4-((邻-甲氧苯氧基)甲基)噻吩-2-基)硼酸(4-((o-methoxyphenoxy)methyl)thiophen-2-yl)boronic acid
(4-((间-甲氧苯氧基)甲基)噻吩-2-基)硼酸(4-((m-methoxyphenoxy)methyl)thiophen-2-yl)boronic acid
(4-((对-甲氧苯氧基)甲基)噻吩-2-基)硼酸(4-((p-methoxyphenoxy)methyl)thiophen-2-yl)boronic acid
(5-((邻-氰基苯氧基)甲基)噻吩-3-基)硼酸(5-((o-Cyanophenoxy)methyl)thiophen-3-yl)boronic acid
(5-((对-氰基苯氧基)甲基)噻吩-3-基)硼酸(5-((p-Cyanophenoxy)methyl)thiophen-3-yl)boronic acid
(5-((间-氰基苯氧基)甲基)噻吩-3-基)硼酸(5-((m-Cyanophenoxy)methyl)thiophen-3-yl)boronic acid
(5-((邻-甲氧苯氧基)甲基)噻吩-3-基)硼酸(5-((o-methoxyphenoxy)methyl)thiophen-3-yl)boronic acid
(5-((间-甲氧苯氧基)甲基)噻吩-3-基)硼酸(5-((m-methoxyphenoxy)methyl)thiophen-3-yl)boronic acid
(5-((嘧啶-4-基氧基)甲基)噻吩-3-基)硼酸(5-((pyrimidin-4-yloxy)methyl)thiophen-3-yl)boronic acid
(5-((2-甲氧基-4-甲基苯氧基)甲基)噻吩-3-基)硼酸(5-((2-methoxy-4-methylphenoxy)methyl)thiophen-3-yl)boronic acid
(5-((2-甲氧基-4-氯苯氧基)甲基)噻吩-3-基)硼酸(5-((2-methoxy-4-chlorophenoxy)methyl)thiophen-3-yl)boronic acid
(5-((2-甲氧基-4-氰基苯氧基)甲基)噻吩-3基)硼酸(5-((2-methoxy-4-cyanophenoxy)methyl)thiophen-3-yl)boronic acid
(5-((2-氯-5-甲氧基苯氧基)甲基)噻吩-3基)硼酸(5-((2-chloro-5-methoxyphenoxy)methyl)thiophen-3-yl)boronic acid
(5-((3-氯-5-甲氧基苯氧基)甲基)噻吩-3基)硼酸 (5-((3-chloro-5-methoxyphenoxy)methyl)thiophen-3-yl)boronic acid
(5-((3-甲氧基-4-氰基苯氧基)甲基)噻吩-3基)硼酸(5-((3-Methoxy-4-cyanophenoxy)methyl)thiophen-3-yl)boronic acid
(5-((邻-甲苯氧基)甲基)噻吩-3-基)硼酸(5-((o-tolyloxy)methyl)thiophen-3-yl)boronic acid
(5-((对-甲苯氧基)甲基)噻吩-3-基)硼酸(5-((p-tolyloxy)methyl)thiophen-3-yl)boronic acid
(5-((邻-氟苯氧基)甲基)噻吩-3-基)硼酸(5-((o-fluorophenoxy)methyl)thiophen-3-yl)boronic acid
(5-((间-氟苯氧基)甲基)噻吩-3-基)硼酸(5-((m-Fluorophenoxy)methyl)thiophen-3-yl)boronic acid
(5-((对-氟苯氧基)甲基)噻吩-3-基)硼酸(5-((p-Fluorophenoxy)methyl)thiophen-3-yl)boronic acid
((5-苯氧基甲基)噻吩-3-基)硼酸((5-phenoxymethyl)thiophen-3-yl)boronic acid
上述硼酸化合物的合成方法均类似于实施例4化合物6’为(5-(苯氧甲基)噻吩-2-基)硼酸的制备方法。The above synthesis method of the boric acid compound is similar to the preparation method of the compound 6' of Example 4 as (5-(phenoxymethyl)thiophen-2-yl)boronic acid.
实施例5Example 5
当R5、R6均为H，环1为苯，L1为单键，苯环与噻吩的5位相连，1H-吡唑[3，4-d]嘧啶-1-基与噻吩的3位相连，化合物6’为：((5-苯基)噻吩-3-基)硼酸When R 5 and R 6 are both H, ring 1 is benzene, L 1 is a single bond, benzene ring is bonded to the 5-position of thiophene, 1H-pyrazole [3,4-d]pyrimidin-1-yl and thiophene 3 Linked to a compound 6': ((5-phenyl)thiophen-3-yl)boronic acid
5.1中间体((5-苯基)噻吩-3-基)硼酸制备方法：5.1 Preparation of intermediate ((5-phenyl)thiophen-3-yl)boronic acid :
3-溴-5-(苯基)噻吩(CAS号为38071-58-8，购于上海毕得医药科技有限公司)(2g，8.3mmol)溶于四氢呋喃(10mL)在氩气环境下滴加到零下70℃的正丁基锂(6.7mL，2.5mol/L的正己烷溶液)的四氢呋喃(15mL)溶液中。在零下70℃下反应2小时，然后加入硼酸甲酯(4.35g，42mmol)，在零下70℃下继续反应30分钟，升至室温导入1mol/L的盐酸(30mL)中搅拌10分钟。用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩得到(5-(苯基)噻吩-3-基)硼酸粗品1.30g，由于产品易分解，不用精制直接用于下一步反应。3-bromo-5-(phenyl)thiophene (CAS No. 38071-58-8, purchased from Shanghai Bied Pharmaceutical Technology Co., Ltd.) (2g, 8.3mmol) dissolved in tetrahydrofuran (10mL) and added dropwise under argon To a solution of n-butyllithium (6.7 mL, 2.5 mol/L in n-hexane) in tetrahydrofuran (15 mL) at 70 ° C. The reaction was carried out at -70 ° C for 2 hours, then methyl borate (4.35 g, 42 mmol) was added, and the reaction was continued at minus 70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol/L hydrochloric acid (30 mL) and stirred for 10 minutes. After extracting with ethyl acetate, the organic layer was dried over anhydrous Na 2 SO 4 and then evaporated to dryness to give the crude (5-(phenyl)thiophen-3-yl)boronic acid 1.30 g. Used for the next reaction.
薄层色谱检测：TLC：Rf0.5(乙酸乙酯∶石油醚＝1∶5)TLC: TLC: R f 0.5 (ethyl acetate: petroleum ether = 1:5)
质谱检测：MS(ESI)m/z 205(M+1)；Mass spectrometry: MS (ESI) m/z 205 (M + 1);
5.2中间体((5-苯基)噻吩-2-基)硼酸和((4-苯基)噻吩-2-基)硼酸的5.2 intermediates ((5-phenyl)thiophen-2-yl)boronic acid and ((4-phenyl)thiophen-2-yl)boronic acid 制备方法Preparation
((5-苯基)噻吩-2-基)硼酸和((4-苯基)噻吩-2-基)硼酸的合成方法同于为(5-(苯基)噻吩-3-基)硼酸的制备方法。 The synthesis method of ((5-phenyl)thiophen-2-yl)boronic acid and ((4-phenyl)thiophen-2-yl)boronic acid is the same as (5-(phenyl)thiophen-3-yl)boronic acid Preparation.
5.32-溴-4-(间-甲苯基)噻吩的制备方法Method for preparing 5.32-bromo-4-(m-tolyl)thiophene
当R5、R6均为H，环1为甲苯，L1为单键，苯环与噻吩的5位相连，1H-吡唑[3，4-d]嘧啶-1-基与噻吩的3位相连，化合物6’为：((5-(3-甲基苯基))噻吩-3-基)硼酸，制备方法为：When R 5 and R 6 are both H, ring 1 is toluene, L 1 is a single bond, benzene ring is bonded to the 5-position of thiophene, 1H-pyrazole [3,4-d]pyrimidin-1-yl and thiophene 3 The compound 6' is: ((5-(3-methylphenyl))thiophen-3-yl)boronic acid, the preparation method is:
向2，4-二溴噻吩(4g，16mmol)(购自西亚试剂，商品名称2，4-二溴噻吩，CAS号3140-92-9，商品编号：1993)的甲苯溶液(50mL)中依次加入间甲苯硼酸(2.25g，16mmol)，(CAS号：17933-03-8，商品名称3-甲苯硼酸，购自百灵威科技，产品编号：256729)Na2CO3(3.5g，33mmol)，Pd(PPh3)4，(380mg，0.3mmol)以及H2O(50mL)，然后氩气置换保护，升温至100℃反应12小时，TLC跟踪反应结束。反应毕，降至室温用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩得到粗品用硅胶柱层析，洗脱溶剂为乙酸乙酯∶石油醚(1∶50-＞1∶20)得2g(产率50％)白色固体的2-溴-4-(间-甲苯基)噻吩。To a toluene solution (50 mL) of 2,4-dibromothiophene (4 g, 16 mmol) (available from West Asia Reagent, trade name 2,4-dibromothiophene, CAS No. 3140-92-9, commercial number: 1993) Addition of m-toluoboric acid (2.25 g, 16 mmol), (CAS No.: 17933-03-8, trade name 3-toluene boric acid, purchased from Belling Technology, product number: 256729) Na 2 CO 3 (3.5 g, 33 mmol), Pd (PPh 3 ) 4 , (380 mg, 0.3 mmol) and H 2 O (50 mL) were then subjected to argon gas exchange protection, and the mixture was warmed to 100 ° C for 12 hours, and the TLC was followed to complete the reaction. Completion of the reaction, cooled to room temperature and extracted with ethyl acetate, dried organic extracts were dried over anhydrous Na 2 SO 4, and concentrated under reduced pressure to give the crude product by silica gel column chromatography, eluent ethyl acetate: petroleum ether (1: 50->1:20) 2 g (yield 50%) of 2-bromo-4-(m-tolyl)thiophene as a white solid.
TLC：Rf 0.5(乙酸乙酯∶石油醚＝1∶30)TLC: R f 0.5 (ethyl acetate: petroleum ether = 1: 30)
MS(ESI)m/z 253(M+1)；1HNMR(400MHz，CDCl3)2.38(s，3H)，7.15-7.60(m，6H)。MS (ESI) m / z 253 (M + 1); 1 HNMR (400MHz, CDCl 3) 2.38 (s, 3H), 7.15-7.60 (m, 6H).
5.4中间体(4-(3-甲苯基)噻吩-2-基)硼酸的制备方法5.4 Preparation method of intermediate (4-(3-tolyl)thiophen-2-yl)boronic acid
2-溴-4-(3-甲苯基)噻吩(2g，8mmol)(如5.3方法制成)溶于四氢呋喃(10mL)在氮气环境下滴加到零下70℃的正丁基锂(6.4mL，2.5mol/L的正己烷溶液)的四氢呋喃(15mL)溶液中。在零下70℃下反应2小时，然后加入硼酸三甲酯(4g，40mmol)，(CAS号：121-43-7，购自贝斯特试剂，商品名称硼酸三甲酯，商品编号：B00269101)在零下70℃下继续反应30分钟，升至室温导入1mol/L的盐酸(30mL)中搅拌10分钟。用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩得到(4-(3-甲苯基)噻吩-2-基)硼酸粗品1.30g，由于产品易分解，不用精制直接用于下一步反应。2-Bromo-4-(3-methylphenyl)thiophene (2 g, 8 mmol) (prepared as 5.3) was dissolved in tetrahydrofuran (10 mL) and added dropwise to n-butyllithium (6.4 mL, 70 ° C, under nitrogen). A 2.5 mol/L solution of n-hexane in tetrahydrofuran (15 mL) was obtained. The reaction was carried out at minus 70 ° C for 2 hours, then trimethyl borate (4 g, 40 mmol) was added (CAS No.: 121-43-7, available from Best Reagent, trade name Trimethyl borate, commercial number: B00269101) The reaction was continued at minus 70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol/L hydrochloric acid (30 mL), and stirred for 10 minutes. After extracting with ethyl acetate, the organic layer was dried over anhydrous Na 2 SO 4 and then evaporated. The refining is used directly in the next reaction.
TLC：Rf0.5(乙酸乙酯∶石油醚＝1∶5)TLC: R f 0.5 (ethyl acetate: petroleum ether = 1:5)
MS(ESI)m/z 219(M+1)。 MS (ESI) m/z 195 (MH).
5.5中间体((5-(3-甲氧基苯基))噻吩-3-基)硼酸和((5-(4-甲氧基苯5.5 intermediate ((5-(3-methoxyphenyl))thiophen-3-yl)boronic acid and ((5-(4-methoxybenzene) 基))噻吩-3-基)硼酸的制备方法Method for preparing thiophen-3-yl)boronic acid
上述硼酸化合物的合成方法均同(4-(3-甲苯基)噻吩-2-基)硼酸的制备方法。The method for synthesizing the above boric acid compound is the same as the method for preparing (4-(3-tolyl)thiophen-2-yl)boronic acid.
5.6中间体(5-(间-甲苯基)噻吩-2-基)硼酸的制备方法5.6 Preparation method of intermediate (5-(m-tolyl)thiophen-2-yl)boronic acid
当R5、R6均为H，环1为3-甲苯基，L1为单键，3-甲苯基与噻吩的5位相连，1H-吡唑[3，4-d]嘧啶-1-基与噻吩的2位相连，化合物6’为(5-(间-甲苯基)噻吩-2-基)硼酸，制备方法为：向2，5-二溴噻吩(4g，16mmol)(购自青岛通缘医药有限公司，商品名称2，5-二溴噻吩，CAS号：3141-27-3)的甲苯溶液(50mL)中依次加入间甲苯硼酸(2.25g，16mmol)(CAS号：17933-03-8，购自上海海曲化工有限公司，商品名称间甲苯硼酸)，Na2CO3(3.5g，33mmol)，Pd(PPh3)4，(380mg，0.3mmol)以及H2O(50mL)，然后氩气置换保护，升温至100℃反应12小时，TLC跟踪反应结束。反应毕，降至室温用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩得到粗品用硅胶柱层析，洗脱溶剂为乙酸乙酯∶石油醚(1∶50-＞1∶20)得3.1g(产率75％)白色固体的2-溴-5-(间-甲苯基)噻吩。When R 5 and R 6 are both H, ring 1 is 3-tolyl, L 1 is a single bond, 3-tolyl is attached to the 5-position of thiophene, 1H-pyrazole [3,4-d]pyrimidin-1- The base is attached to the 2-position of the thiophene, and the compound 6' is (5-(m-tolyl)thiophen-2-yl)boronic acid by the preparation of 2,5-dibromothiophene (4 g, 16 mmol) (purchased from Qingdao). Tongyuan Pharmaceutical Co., Ltd., trade name 2,5-dibromothiophene, CAS No.: 3141-27-3) in toluene solution (50 mL) was added with m-tolueneboronic acid (2.25 g, 16 mmol) in sequence (CAS No.: 17933-03) -8, purchased from Shanghai Haiqu Chemical Co., Ltd., trade name toluene boronic acid), Na 2 CO 3 (3.5 g, 33 mmol), Pd (PPh 3 ) 4 , (380 mg, 0.3 mmol) and H 2 O (50 mL) Then, it was replaced with argon gas, heated to 100 ° C for 12 hours, and TLC followed the reaction. Completion of the reaction, cooled to room temperature and extracted with ethyl acetate, dried organic extracts were dried over anhydrous Na 2 SO 4, and concentrated under reduced pressure to give the crude product by silica gel column chromatography, eluent ethyl acetate: petroleum ether (1: 50->1:20) 3.1 g (yield 75%) of 2-bromo-5-(m-tolyl)thiophene as a white solid.
TLC：Rf0.5(乙酸乙酯∶石油醚＝1∶30)TLC: R f 0.5 (ethyl acetate: petroleum ether = 1: 30)
MS(ESI)m/z 253(M+1)；1HNMR(400MHz，CDCl3)2.33(s，3H)，7.10-7.70(m，6H)。MS (ESI) m / z 253 (M + 1); 1 HNMR (400MHz, CDCl 3) 2.33 (s, 3H), 7.10-7.70 (m, 6H).
2-溴-5-(间-甲苯基)噻吩(2g，8mmol)溶于四氢呋喃(10mL)在氮气环境下滴加到零下70℃的正丁基锂(6.4mL，2.5mol/L的正己烷溶液)的四氢呋喃(15mL)溶液中。在零下70℃下反应2小时，然后加入硼酸甲酯(4g，40mmol)，在零下70℃下继续反应30分钟，升至室温导入1mol/L的盐酸(30mL)中搅拌10分钟。用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩得到(5-(间-甲苯基)噻吩-2-基)硼酸粗品1.20g，由于产品易分解，不用精制直接用于下一步反应。2-Bromo-5-(m-tolyl)thiophene (2 g, 8 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to n-butyllithium (6.4 mL, 2.5 mol/L n-hexane) at 70 ° C under nitrogen. Solution) in tetrahydrofuran (15 mL). The reaction was carried out at -70 ° C for 2 hours, then methyl borate (4 g, 40 mmol) was added, and the reaction was continued at minus 70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol/L hydrochloric acid (30 mL) and stirred for 10 minutes. After extracting with ethyl acetate, the organic layer was dried over anhydrous Na 2 SO 4 and then evaporated. The refining is used directly in the next reaction.
TLC：Rf0.5(乙酸乙酯∶石油醚＝1∶5)TLC: R f 0.5 (ethyl acetate: petroleum ether = 1:5)
MS(ESI)m/z 219(M+1)。MS (ESI) m/z 195 (MH).
5.7.制备方法类似5.6的中间体5.7. Preparation method is similar to the intermediate of 5.6
以下中间体的制备方法类似于5.6的中间体： The following intermediates were prepared in a similar manner to the intermediates of 5.6:
(5-(3，4-二甲苯基)噻吩-2-基)硼酸(5-(3,4-dimethylphenyl)thiophen-2-yl)boronic acid
(5-(间-甲氧苯基)噻吩-2-基)硼酸(5-(m-methoxyphenyl)thiophen-2-yl)boronic acid
(5-(对-甲氧苯基)噻吩-2-基)硼酸(5-(p-methoxyphenyl)thiophen-2-yl)boronic acid
(5-(4-苯基)噻吩-2-基)硼酸(5-(4-phenyl)thiophen-2-yl)boronic acid
(5-(对-三氟甲苯基)噻吩-2-基)硼酸(5-(p-Trifluoromethylphenyl)thiophen-2-yl)boronic acid
(5-(间-三氟甲苯基)噻吩-2-基)硼酸(5-(m-Trifluoromethylphenyl)thiophen-2-yl)boronic acid
(5-(3，5-二甲苯基)噻吩-2-基)硼酸(5-(3,5-dimethylphenyl)thiophen-2-yl)boronic acid
(5-苯基)噻吩-2-基)硼酸(5-phenyl)thiophen-2-yl)boronic acid
(5-(邻-氟苯基)噻吩-2-基)硼酸(5-(o-fluorophenyl)thiophen-2-yl)boronic acid
(5-(间-氟苯基)噻吩-2-基)硼酸(5-(m-Fluorophenyl)thiophen-2-yl)boronic acid
(5-(对-氟苯基)噻吩-2-基)硼酸(5-(p-fluorophenyl)thiophen-2-yl)boronic acid
上述硼酸化合物的合成方法均同于(5-(间-甲苯基)噻吩-2-基)硼酸的制备方法。The method for synthesizing the above boric acid compound is the same as the method for preparing (5-(m-tolyl)thiophen-2-yl)boronic acid.
5.8中间体(2-(苯乙烯基)噻吩-4-基)硼酸的制备方法5.8 Preparation method of intermediate (2-(styryl)thiophen-4-yl)boronic acid
当R5、R6均为H，环1为苯乙烯基，L1为单键，苯乙烯基与噻吩的2位通过单键相连，1H-吡唑[3，4-d]嘧啶-1-基与噻吩的4位相连，m＝0，环2为哌啶，化合物6’为(2-(苯乙烯基)噻吩-4-基)硼酸，制备方法为：4-溴-2-噻吩-甲醛(4g，21mmol)(CAS18791-75-8，购自贝斯特试剂有限公司)和苄基三苯基氯化膦(10.9g，25mmol)溶于50mL异丙醇中，然后加入氢氧化锂一水化物(1.32g，32mmol)。升温至85℃反应4小时，TLC(薄层色谱检测，Rf0.5(乙酸乙酯∶石油醚＝1∶50))跟踪反应结束。反应毕，加入50mL乙酸乙酯，用50mL水洗2次，分离有机层干燥，减压旋干得到的粗品溶于30mL四氢呋喃，然后加入碘(0.78g，3mmol)室温搅拌10h。加入50mL乙酸乙酯，依次用饱和碳酸氢钠(50mL)和亚硫酸钠洗涤(50mL)，分离有机层干燥，减压旋干得到的粗品用硅胶柱的液相色谱分离，洗脱溶剂为乙酸乙酯∶石油醚(1∶100-＞1∶20)得到反2-(苯乙烯基)噻吩-4-溴4.7g，收率：85％)。When R 5 and R 6 are both H, ring 1 is a styryl group, L 1 is a single bond, and the styryl group is linked to the thiophene at the 2-position by a single bond, 1H-pyrazole [3,4-d]pyrimidine-1 - The group is bonded to the 4-position of the thiophene, m=0, the ring 2 is piperidine, and the compound 6' is (2-(styryl)thiophen-4-yl)boronic acid. The preparation method is: 4-bromo-2-thiophene - Formaldehyde (4g, 21mmol) (CAS18791-75-8, available from Best Reagent Co., Ltd.) and benzyltriphenylphosphonium chloride (10.9g, 25mmol) dissolved in 50mL of isopropanol, then lithium hydroxide Monohydrate (1.32 g, 32 mmol). The temperature was raised to 85 ° C for 4 hours, and TLC (TLC detection, R f 0.5 (ethyl acetate: petroleum ether = 1:50)) was followed to complete the reaction. After completion of the reaction, 50 mL of ethyl acetate was added, and the mixture was washed twice with 50 mL of water. The organic layer was dried and evaporated to dryness. After adding 50 ml of ethyl acetate, the mixture was washed with EtOAc (EtOAc) Petroleum ether (1:100->1:20) gave 4.7 g of trans-2-(styryl)thiophene-4-bromide, yield: 85%).
薄层色谱检测：TLC：Rf0.5(乙酸乙酯∶石油醚＝1∶15)Thin layer chromatography: TLC: R f 0.5 (ethyl acetate: petroleum ether = 1:15)
质谱检测：MS(ESI)m/z 265(M+1)；Mass spectrometry: MS (ESI) m/z 265 (M + 1);
核磁共振检测：1HNMR(400MHz，CDCl3)6.80-7.00(m，2H)，7.08(s，1 H)，7.20(s，1H)，7.25-7.65(m，5H)。Nuclear magnetic resonance detection: 1H NMR (400 MHz, CDCl 3 ) 6.80-7.00 (m, 2H), 7.08 (s, 1 H), 7.20 (s, 1H), 7.25-7.65 (m, 5H).
反2-(苯乙烯基)噻吩-4-溴(2g，7.5mmol)溶于四氢呋喃(10mL)在氮气环境下滴加到零下70℃的正丁基锂(6mL，2.5mol/L的正己烷溶液)的四氢呋喃(15mL)溶液中。在零下70℃下反应2小时，然后加入硼酸甲酯(3.85g，38mmol)，在零下70℃下继续反应30分钟，升至室温导入1mol/L的盐酸(30mL)中搅拌10分钟。用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩得到反(2-(苯乙烯基)噻吩-4-基)硼酸粗品1.60g，由于产品易分解，不用精制直接用于下一步反应。Trans-2-(styryl)thiophene-4-bromo (2 g, 7.5 mmol) in tetrahydrofuran (10 mL) was added dropwise to n-butyllithium (6 mL, 2.5 mol/L n-hexane) at 70 ° C under nitrogen. Solution) in tetrahydrofuran (15 mL). The reaction was carried out at -70 ° C for 2 hours, then methyl borate (3.85 g, 38 mmol) was added, and the reaction was continued at minus 70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol/L hydrochloric acid (30 mL) and stirred for 10 minutes. After extracting with ethyl acetate, the organic layer was dried over anhydrous Na 2 SO 4 and then evaporated to dryness to give 1.60 g of crude (2-(styryl)thiophen-4-yl)boronic acid. The refining is used directly in the next reaction.
TLC：Rf0.5(乙酸乙酯∶石油醚＝1∶5)TLC: R f 0.5 (ethyl acetate: petroleum ether = 1:5)
MS(ESI)m/z 231(M+1)。MS (ESI) m/z 231 (MH).
5.9(2-(苯乙基)噻吩-4-基)硼酸的制备方法Preparation method of 5.9(2-(phenethyl)thiophen-4-yl)boronic acid
当R5、R6均为H，环1为苯乙基，L1为单键，苯乙基与噻吩的2位相连，1H-吡唑[3，4-d]嘧啶-1-基与噻吩的4位相连，m＝0，环2为哌啶，化合物6’为(2-(苯乙基)噻吩-4-基)硼酸。When R 5 and R 6 are both H, ring 1 is phenethyl, L 1 is a single bond, phenethyl is attached to the 2-position of thiophene, 1H-pyrazole [3,4-d]pyrimidin-1-yl and The thiophene is attached at the 4-position, m=0, ring 2 is piperidine, and compound 6' is (2-(phenethyl)thiophen-4-yl)boronic acid.
反2-(苯乙烯基)噻吩-4-溴(2.5g，9.5mmol)溶于乙酸乙酯(30mL)，加入10％鈀炭(1g)在室温氢气环境下反应2h，TLC(薄层色谱检测，Rf0.5(乙酸乙酯∶石油醚＝1∶50))跟踪反应结束。过滤掉鈀炭得到的有机相通过减压浓缩得到的粗品用硅胶柱的液相色谱分离，洗脱溶剂为乙酸乙酯∶石油醚(1∶100-＞1∶20)得到2-(苯乙基)噻吩-4-溴2g，收率：80％。Anti-2-(styryl)thiophene-4-bromo (2.5 g, 9.5 mmol) was dissolved in ethyl acetate (30 mL), and 10% palladium charcoal (1 g) was added to react at room temperature under hydrogen for 2 h, TLC (thin layer chromatography Detection, R f 0.5 (ethyl acetate: petroleum ether = 1:50) was followed to complete the reaction. The crude phase obtained by filtering off the palladium on carbon was concentrated by vacuum chromatography on a silica gel column. The eluting solvent was ethyl acetate: petroleum ether (1:100->1:20) to give 2-(phenylethyl) Base) thiophene-4-bromide 2g, yield: 80%.
薄层色谱检测：TLC：Rf0.5(乙酸乙酯∶石油醚＝1∶15)Thin layer chromatography: TLC: R f 0.5 (ethyl acetate: petroleum ether = 1:15)
质谱检测：MS(ESI)m/z 267(M+1)；Mass spectrometric detection: MS (ESI) m/z 267 (M+1);
核磁共振检测：1HNMR(400MHz，CDCl3)2.65-2.90(m，4H)，6.54(s，1H)，6.66(s，1H)，7.20-7.45(m，5H)。Nuclear magnetic resonance detection: 1H NMR (400 MHz, CDCl 3 ) 2.65-2.90 (m, 4H), 6.54 (s, 1H), 6.66 (s, 1H), 7.20-7.45 (m, 5H).
粗品1.20g，由于产品易分解，不用精制直接用于下一步反应。The crude product is 1.20g. Since the product is easily decomposed, it can be directly used in the next reaction without purification.
薄层色谱TLC：Rf0.5(乙酸乙酯∶石油醚＝1∶5)Thin layer chromatography TLC: R f 0.5 (ethyl acetate: petroleum ether = 1:5)
MS(ESI)m/z 267(M+1)。MS (ESI) m/z 266 (MH).
2-(苯乙基)噻吩-4-溴(2g，7.5mmol)溶于四氢呋喃(10mL)在氮气环境下滴加到零下70℃的正丁基锂(6mL，2.5mol/L的正己烷溶液)的四氢呋喃(15mL)溶液中。在零下70℃下反应2小时，然后加入硼酸甲酯(3.85g，38mmol)，在零下70℃下继续反应30分钟，升至室温导入1mol/L 的盐酸(30mL)中搅拌10分钟。用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩得到(2-(苯乙基)噻吩-4-基)硼酸粗品1.40g，由于产品易分解，不用精制直接用于下一步反应。2-(Phenylethyl)thiophene-4-bromo (2 g, 7.5 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to n-butyllithium (6 mL, 2.5 mol/L n-hexane) at 70 ° C under nitrogen. In a solution of tetrahydrofuran (15 mL). The reaction was carried out at -70 ° C for 2 hours, then methyl borate (3.85 g, 38 mmol) was added, and the reaction was continued at minus 70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol/L hydrochloric acid (30 mL) and stirred for 10 minutes. After extracting with ethyl acetate, the organic layer was dried over anhydrous Na 2 SO 4 and then evaporated. Used directly in the next step.
TLC：Rf0.5(乙酸乙酯∶石油醚＝1∶5)MS(ESI)m/z 233(M+1)。TLC: R f 0.5 (ethyl acetate: petroleum ether = 1:5) MS (ESI) m / z 233 (M + 1).
本发明的化合物也通过以下路线3进行制备：The compounds of the invention are also prepared by Scheme 3 below:
Figure PCTCN2017072716-appb-000053
Figure PCTCN2017072716-appb-000053
反应路线3中步骤1的反应是公知的，在以上的合成路线中，作为起始原料的化合物5’是由与路线1中的相同的方法制备的。化合物5’与化合物10’，在有机溶剂(二甲基甲酰胺、乙二醇二甲醚、四氢呋喃和1，4-二氧六环(1，4-doxane))中，在金属钯，例如：包括四(三苯基膦)钯Pd(PPh3)4、双苯基磷二氯钯Pd(PPh3)2Cl2和[1，1′-双(二苯基磷)二茂铁]二氯化钯Pd(dppf)Cl2中任意一种或几种的催化下，在60-80℃下反应，由此进行发生偶联反应得到化合物11’。The reaction of the step 1 in the reaction scheme 3 is well known, and in the above synthetic route, the compound 5' as a starting material is prepared by the same method as in the route 1. Compound 5' and compound 10' in an organic solvent (dimethylformamide, ethylene glycol dimethyl ether, tetrahydrofuran and 1,4-dioxane (1,4-doxane)), in metal palladium, for example : including tetrakis(triphenylphosphine)palladium Pd(PPh 3 ) 4 , bisphenylphosphine dichloropalladium Pd(PPh 3 ) 2 Cl 2 and [1,1'-bis(diphenylphosphino)ferrocene] The compound 11' is obtained by a coupling reaction at 60-80 ° C under the catalysis of any one or more of palladium dichloride Pd(dppf)Cl 2 .
反应路线3中步骤2的反应是公知的，化合物11’在四氢呋喃中，在四丁基氟化铵的存在下，在0℃到室温下反应，由此进行，进行脱叔丁基二甲基硅烷保护基的反应得到化合物12’。 The reaction of the step 2 in the reaction scheme 3 is known, and the compound 11' is reacted in tetrahydrofuran in the presence of tetrabutylammonium fluoride at 0 ° C to room temperature, thereby proceeding to carry out de-tert-butyldimethyl group. Reaction of the silane protecting group gives compound 12'.
反应路线3中步骤3的反应是公知的，化合物12’在乙腈中，依次加入磷酸盐缓冲液(pH＝6.7)、2，2，6，6-四甲基哌啶-氮氧化物(TEMPO)、NaClO2(亚氯酸钠)和NaClO(次氯酸钠)，在35℃下反应，由此进行，进行羟基氧化反应得到羧酸化合物13’。The reaction of the step 3 in the reaction scheme 3 is well known, and the compound 12' is sequentially added to the phosphate buffer (pH=6.7), 2,2,6,6-tetramethylpiperidine-nitrogen oxide (TEMPO) in acetonitrile. ), NaClO 2 (sodium chlorite) and NaClO (sodium hypochlorite) are reacted at 35 ° C to carry out a hydroxy oxidation reaction to obtain a carboxylic acid compound 13'.
反应路线2中的步骤4的反应是公知的，化合物13’，在有机溶剂(二氯甲烷或二甲基甲酰胺)中，在缩合剂1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCL)(CAS号25952-53-8，购自济南泛诺化工有限公司)、2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(HATU)(CAS号148893-10-1，购自上海紫一试剂厂)或O-苯并三氮唑-N，N，N′，N′-四甲基脲四氟硼酸酯(TBTU)(CAS号125700-67-6，购自南京肽业生物科技有限公司)的存在下与化合物14’在室温下反应，由此进行，发生缩合反应得到化合物15’。其中化合物14’可选自2-氨基吡啶、3-氨基吡啶、4-氨基吡啶或苯胺。The reaction of step 4 in Scheme 2 is well known, compound 13', in an organic solvent (dichloromethane or dimethylformamide), in the condensing agent 1-ethyl-(3-dimethylaminopropyl) Carbodiimide hydrochloride (EDCL) (CAS No. 25952-53-8, purchased from Jinan Panuo Chemical Co., Ltd.), 2-(7-azobenzotriazole)-N, N, N' , N'-tetramethylurea hexafluorophosphate (HATU) (CAS No. 148893-10-1, purchased from Shanghai Ziyi Reagent Factory) or O-benzotriazole-N, N, N', N' - Tetramethylurea tetrafluoroborate (TBTU) (CAS No. 125700-67-6, purchased from Nanjing Peptide Biotechnology Co., Ltd.) reacts with compound 14' at room temperature, thereby performing condensation The reaction gives compound 15'. Wherein compound 14' can be selected from the group consisting of 2-aminopyridine, 3-aminopyridine, 4-aminopyridine or aniline.
反应路线3中的步骤5的反应是公知的与反应路线1中的步骤5的操作相同。反应路线3中的步骤6的反应是公知的与反应路线1中的步骤6的操作相同，其中涉及的原料氨基吡啶均购自北京维达化工有限公司，其中3-氨基吡啶商品号为462-08-8，2-氨基吡啶商品号为504-29-0，4-氨基吡啶商品号为504-24-5。The reaction of the step 5 in the reaction scheme 3 is known to be the same as the operation of the step 5 in the reaction scheme 1. The reaction of the step 6 in the reaction scheme 3 is known to be the same as the operation of the step 6 in the reaction scheme 1, wherein the starting aminopyridine is purchased from Beijing Vinda Chemical Co., Ltd., wherein the 3-aminopyridine product number is 462- 08-8, 2-aminopyridine commercial number is 504-29-0, 4-aminopyridine commercial number is 504-24-5.
实施例6Example 6
在反应路线3的步骤1中当化合物10’为((5-叔丁基二甲基硅氧亚甲基)噻吩-2-基)硼酸，化合物11’中叔丁基二甲基硅氧亚甲基与噻吩的5位相连，1H-吡唑[3，4-d]嘧啶-1-基与噻吩的2位相连，m＝0，环2为哌啶，化合物11’为叔丁基-3-(4-氨基-3-(5-(叔丁基二甲基硅氧亚甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯。其制备方法为：在室温下向(R)叔丁基-3-(-4-氨基-3-碘-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯(300mg，0.68mmol)的乙二醇二甲醚(5mL)、水(2mL)的溶液中依次加入(5-(叔丁基二甲基硅氧亚甲基))噻吩-2-基)硼酸(345mg，1.35mmol)，四三苯基磷鈀(39mg，0.03mmol)，Na2CO3(215mg，2.1mmol)。然后在80℃下反应16小时，冷却至室温，倒入50mL水中，用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩溶剂得到的粗品用硅胶柱的液相色谱 分离，洗脱溶剂为石油醚∶乙酸乙酯(8∶1→2∶1)得到目标产物(R)叔丁基-3-(4-氨基-3-(5-(叔丁基二甲基硅氧亚甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯(275mg，收率78％)。In step 1 of Scheme 3, when compound 10' is ((5-tert-butyldimethylsiloxymethylene)thiophen-2-yl)boronic acid, tert-butyldimethylsilyloxide in compound 11' The methyl group is attached to the 5-position of the thiophene, the 1H-pyrazole [3,4-d]pyrimidin-1-yl group is attached to the 2-position of the thiophene, m=0, the ring 2 is piperidine, and the compound 11' is a tert-butyl group- 3-(4-Amino-3-(5-(tert-butyldimethylsilyloxy)methylthiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)piperidin Pyridine-1-carboxylate. The preparation method is as follows: (R) tert-butyl-3-(-4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- (5-(tert-Butyldimethylsiloxymethylene))thiophene-2- was added to a solution of formic acid ester (300 mg, 0.68 mmol) in ethylene glycol dimethyl ether (5 mL) and water (2 mL). Boric acid (345 mg, 1.35 mmol), tetratriphenylphosphine palladium (39 mg, 0.03 mmol), Na 2 CO 3 (215 mg, 2.1 mmol). Then, the reaction was carried out at 80 ° C for 16 hours, cooled to room temperature, poured into 50 mL of water, and extracted with ethyl acetate. The organic layer was extracted with anhydrous Na 2 SO 4 and then evaporated. Chromatography and elution solvent: petroleum ether: ethyl acetate (8:1→2:1) to give the desired product (R) tert-butyl-3-(4-amino-3-(5-(tert-butyl) Methylsiloxymethylidene)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (275 mg, yield 78%).
薄层色谱：(TLC)检测：Rf0.5(石油醚∶乙酸乙酯＝3∶1展开相)Thin layer chromatography: (TLC) detection: R f 0.5 (petroleum ether: ethyl acetate = 3:1 unfolded phase)
质谱检测：MS(ESI)m/z 545(M+1)；Mass spectrometry: MS (ESI) m/z 545 (M+1);
核磁共振：1HNMR(400MHz，CDCl3)：0.20(s，3H)，0.21(s，3H)，1.59(s，9H)、1.69(s，9H)、1.60-2.45(m，4H)、2.90-4.90(m，5H)、5.31(s，2H)、6.30-6.40(m，1H)、6.60-6.70(m，1H)、7.00-7.15(m，2H)、8.40(s，1H)。NMR: 1 H NMR (400 MHz, CDCl 3 ): 0.20 (s, 3H), 0.21 (s, 3H), 1.59 (s, 9H), 1.69 (s, 9H), 1.60-2.45 (m, 4H), 2.90 - 4.90 (m, 5H), 5.31 (s, 2H), 6.30-6.40 (m, 1H), 6.60-6.70 (m, 1H), 7.00-7.15 (m, 2H), 8.40 (s, 1H).
在反应路线3的步骤2中的化合物11’的叔-丁基二甲基硅氧亚甲基与噻吩的5位相连，1H-吡唑[3，4-d]嘧啶-1-基与噻吩的2位相连，m＝0，环2为哌啶，化合物11’为(R)叔-丁基-3-(4-氨基-3-(5-(叔-丁基二甲基硅氧亚甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯，化合物12’为(R)叔-丁基-3-(4-氨基-3-(5-(羟基亚甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯，其制备方法为：The tert-butyldimethylsiloxymethylene group of compound 11' in step 2 of Reaction Scheme 3 is linked to the 5-position of thiophene, 1H-pyrazole [3,4-d]pyrimidin-1-yl and thiophene The 2 positions are linked, m=0, ring 2 is piperidine, and compound 11' is (R) tert-butyl-3-(4-amino-3-(5-(tert-butyldimethylsiloxane) Methyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate, compound 12' is (R) tert-butyl-3- (4-Amino-3-(5-(hydroxymethylene)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate, The preparation method is:
在室温下向化合物11’，(R)叔-丁基-3-(4-氨基-3-(5-(叔丁基二甲基硅氧亚甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯(250mg，0.46mmol)，的四氢呋喃(20mL)溶液中加入四丁基氟化铵(180mg，0.61mmol)。然后在室温下反应3小时，加入饱和氯化铵溶液(50mL)，用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩溶剂得到的粗品用硅胶柱的液相色谱分离，洗脱溶剂为石油醚∶乙酸乙酯(4∶1→1∶1)得到目标产物(R)叔-丁基-3-(4-氨基-3-(5-(羟基亚甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯(158mg，收率80％)。To the compound 11', (R) tert-butyl-3-(4-amino-3-(5-(tert-butyldimethylsilyloxy)methylthiophen-2-yl)-1H- at room temperature Add a solution of pyrazole [3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (250 mg, 0.46 mmol) in tetrahydrofuran (20 mL), tetrabutylammonium fluoride (180 mg, 0.61 mmol) . Then, it was reacted for 3 hours at room temperature, and a saturated ammonium chloride solution (50 mL) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 and then evaporated. Chromatographic separation, elution solvent petroleum ether: ethyl acetate (4:1 → 1:1) to give the desired product (R) tert-butyl-3-(4-amino-3-(5-(hydroxy- Thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (158 mg, yield 80%).
薄层色谱：(TLC)检测：Rf0.5(石油醚∶乙酸乙酯＝1∶1展开相)Thin layer chromatography: (TLC) detection: R f 0.5 (petroleum ether: ethyl acetate = 1 : 1 unfolded phase)
质谱检测：MS(ESI)m/z 431(M+1)；Mass spectrometry: MS (ESI) m/z 431 (M+1);
核磁共振：1HNMR(400MHz，CDCl3)：1.68(s，9H)、1.60-2.45(m，4H)、2.90-4.90(m，5H)、5.34(s，2H)、6.30-6.45(m，1H)、6.62-6.70(m，1H)、7.00-7.15(m，2H)、8.41(s，1H)。Nuclear Magnetic Resonance: 1 H NMR (400 MHz, CDCl 3 ): 1.68 (s, 9H), 1.60-2.45 (m, 4H), 2.90-4.90 (m, 5H), 5.34 (s, 2H), 6.30-6.45 (m, 1H), 6.62-6.70 (m, 1H), 7.00-7.15 (m, 2H), 8.41 (s, 1H).
在反应路线3的步骤3中的化合物12’的羟基亚甲基与噻吩的5位相连，1H-吡唑[3，4-d]嘧啶-1-基与噻吩的2位相连，m＝0，环2为哌啶，化合物12’为(R)叔-丁基-3-(4-氨基-3-(5-(羟基亚甲基)噻吩-2-基)-1H-吡唑[3，4-d] 嘧啶-1-基)哌啶-1-甲酸酯，化合物13’为(R)叔-丁基-3-(3-(5-甲酸噻吩-2-基)-4-氨基-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯，其制备方法为：在室温下向化合物12’，(R)叔-丁基-3-(4-氨基-3-(5-(羟基亚甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯(150mg，0.34mmol)的乙腈溶液(5mL)中加入磷酸缓冲液(1.5mL，pH＝6.7)，2，2，6，6-四甲基哌啶氮氧化物(5mg，0.03mmol)，NaClO2(80mg，纯度80％，溶于0.5mL水中)和NaClO(0.015mL，5％的水溶液)。然后在35℃下反应5小时，加入磷酸缓冲液(10mL，pH＝3.6)，用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩溶剂得到的粗品目标产物(R)叔-丁基-3-(3-(5-甲酸噻吩-2-基)-4-氨基-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯(120mg)，(化合物13’)不用进一步纯化直接用于下一步反应。The hydroxymethylene group of compound 12' in step 3 of Scheme 3 is attached to the 5-position of thiophene, and the 1H-pyrazole [3,4-d]pyrimidin-1-yl group is attached to the 2-position of thiophene, m=0 Ring 2 is piperidine and compound 12' is (R) tert-butyl-3-(4-amino-3-(5-(hydroxymethylene)thiophen-2-yl)-1H-pyrazole [3 , 4-d]pyrimidin-1-yl)piperidine-1-carboxylate, compound 13' is (R) tert-butyl-3-(3-(5-carboxylic acid thiophen-2-yl)-4- Amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate prepared by the method of 12', (R) tert-butyl-3 at room temperature -(4-Amino-3-(5-(hydroxymethylene)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate ( 150 mg, 0.34 mmol) in acetonitrile solution (5 mL) was added phosphate buffer (1.5 mL, pH=6.7), 2,2,6,6-tetramethylpiperidine oxynitride (5 mg, 0.03 mmol), NaClO 2 (80 mg, purity 80%, dissolved in 0.5 mL water) and NaClO (0.015 mL, 5% aqueous solution). Then, the reaction was carried out at 35 ° C for 5 hours, and a phosphate buffer solution (10 mL, pH = 3.6) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 and then evaporated. (R) tert-Butyl-3-(3-(5-carboxylic acid thiophen-2-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- Formate (120 mg), (Compound 13') was used in the next step without further purification.
薄层色谱：(TLC)检测：Rf0.5(二氯甲烷∶乙酸乙酯＝1∶2展开相)Thin layer chromatography: (TLC) detection: R f 0.5 (dichloromethane: ethyl acetate = 1:2 unfolded phase)
质谱检测：MS(ESI)m/z 445(M+1)。Mass spectrometry: MS (ESI) m/z 445 (M + 1).
在反应路线3的步骤4中的化合物化合物13’为(R)叔-丁基-3-(3-(5-甲酸噻吩-2-基)-4-氨基-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯，化合物14’为(R)-2-氨基吡啶，化合物15’为(R)-3-(4-氨基-3-(5-(2-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯，其制备方法为：The compound of the compound 13' in the step 4 of the reaction scheme 3 is (R) tert-butyl-3-(3-(5-carboxylic acid thiophen-2-yl)-4-amino-1H-pyrazole [3, 4 -d]pyrimidin-1-yl)piperidine-1-carboxylate, compound 14' is (R)-2-aminopyridine, and compound 15' is (R)-3-(4-amino-3-(5) -(2-Pyridinylcarbonyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester, which is prepared by:
在室温下向化合物13’，叔-丁基-3-(3-(5-甲酸噻吩-2-基)-4-氨基-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯(120mg，0.27mmol)的N，N-二甲基甲酰胺(5mL)溶液中加入化合物14’，2-氨基吡啶(76mg，0.81mmol)(CAS号504-29-0，购自阿法埃莎(中国)化学有限公司)，HATU(2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯)(154mg，0.41mmol)(CAS号：148893-10-1，购自上海芃硕生物科技有限公司)和N，N-二异丙基乙胺(172mg，1.1mmol)。然后在室温下反应10小时，加入饱和氯化铵溶液(20mL)，用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩溶剂得到的粗品用硅胶柱的液相色谱分离，洗脱溶剂为石油醚∶乙酸乙酯(4∶1→1∶1)得到目标产物化合物15’(R)-叔-丁基-3-(4-氨基-3-(5-(2-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯(98mg，收率70％)。To the compound 13' at room temperature, tert-butyl-3-(3-(5-carboxylic acid thiophen-2-yl)-4-amino-1H-pyrazole [3,4-d]pyrimidin-1-yl) Add a solution of the compound 14', 2-aminopyridine (76 mg, 0.81 mmol) (CAS No. 504-29) to a solution of piperidine-1-carboxylate (120 mg, 0.27 mmol) in N,N-dimethylformamide (5 mL). -0, purchased from Alfa Aesar (China) Chemical Co., Ltd.), HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Ester) (154 mg, 0.41 mmol) (CAS No.: 148893-10-1, purchased from Shanghai Shuo Biotech Co., Ltd.) and N,N-diisopropylethylamine (172 mg, 1.1 mmol). Then, it was reacted for 10 hours at room temperature, and a saturated ammonium chloride solution (20 mL) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 and then evaporated. Chromatographic separation, elution solvent petroleum ether: ethyl acetate (4:1 → 1:1) to give the title compound 15'(R)-tert-butyl-3-(4-amino-3-(5- (2-Pyridinylcarbonyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (98 mg, yield 70%).
薄层色谱：(TLC)检测：Rf0.5(石油醚∶乙酸乙酯＝1∶1展开相) Thin layer chromatography: (TLC) detection: R f 0.5 (petroleum ether: ethyl acetate = 1 : 1 unfolded phase)
质谱检测：MS(ESI)m/z 521(M+1)；Mass spectrometry: MS (ESI) m/z 521 (M+1);
核磁共振：1HNMR(400MHz，CDCl3)：1.66(s，9H)，1.60-2.45(m，4H)，2.85-4.95(m，5H)，6.45-6.65(m，2H)，6.70-6.90(m，2H)，7.40-8.15(m，4H)，8.42(s，1H)，9.18(s，1H)。在反应路线3的步骤5中的化合物16’为(R)-3-(4-氨基-3-(5-(2-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)-1-哌啶，其制备方法为：在室温下向化合物15’，(R)叔-丁基-3-(4-氨基-3-(5-(2-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-甲酸酯(90mg，0.17mmol)的二氯甲烷(5mL)溶液中加入三氟乙酸2mL。然后在室温反应4小时，(得到(R)-3-(4-氨基-3-(5-(2-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)-1-哌啶的三氟乙酸盐，也可以在溶液中加入盐酸、硫酸或者乙酸，得到相应的盐酸盐、硫酸盐或者乙酸盐。通过减压浓缩溶剂得到的粗品溶于乙酸乙酯(20mL)，用Na2CO3饱和溶液洗涤然后用无水Na2SO4干燥后，通过减压浓缩溶剂得到化合物(R)-3-(4-氨基-3-(5-(2-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)-1-哌啶(化合物16’)的粗品70mg，直接用于下一步的反应。Nuclear Magnetic Resonance: 1 H NMR (400 MHz, CDCl 3 ): 1.66 (s, 9H), 1.60-2.45 (m, 4H), 2.85-4.95 (m, 5H), 6.45-6.65 (m, 2H), 6.70-6.90 ( m, 2H), 7.40-8.15 (m, 4H), 8.42 (s, 1H), 9.18 (s, 1H). Compound 16' in step 5 of Scheme 3 is (R)-3-(4-amino-3-(5-(2-pyridylaminocarbonyl)thiophen-2-yl)-1H-pyrazole [3 , 4-d]pyrimidin-1-yl)-1-piperidine, which is prepared by the method of 15', (R) tert-butyl-3-(4-amino-3-(5-) at room temperature. (2-Pyridinylcarbonyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (90 mg, 0.17 mmol) in dichloromethane (5 mL) of the solution was added 2 mL of trifluoroacetic acid. Then, it was reacted at room temperature for 4 hours to obtain (R)-3-(4-amino-3-(5-(2-pyridylcarbamoyl)thiophen-2-yl)-1H-pyrazole [3,4-d Pyrimidin-1-yl)-1-piperidine trifluoroacetate, hydrochloric acid, sulfuric acid or acetic acid may also be added to the solution to obtain the corresponding hydrochloride, sulfate or acetate. The solvent is concentrated under reduced pressure. the resulting crude product was dissolved in ethyl acetate (20mL), washed with a saturated solution of Na 2 CO 3 and then dried with anhydrous Na 2 SO 4, to give the compound (R) by concentrating the solvent under reduced pressure using 3- (4-amino-3 -(5-(2-Pyridinylcarbonyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidine (Compound 16'), 70 mg, Used directly in the next step of the reaction.
薄层色谱检测：TLC：Rf0.5(二氯甲烷∶甲醇＝5∶1)Thin layer chromatography: TLC: R f 0.5 (dichloromethane:methanol = 5:1)
质谱检测：MS(ESI)m/z 421(M+1)。Mass spectrometry: MS (ESI) m/z 421 (M + 1).
在反应路线3的步骤6中的化合物17’为(R)-1-(3-(4-氨基-3-(5-(2-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮，其制备方法为：The compound 17' in the step 6 of the scheme 3 is (R)-1-(3-(4-amino-3-(5-(2-pyridylcarbamoyl)thiophen-2-yl)-1H-pyridyl Azole [3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, which is prepared by:
在0℃下向(R)-3-(4-氨基-3-(5-(2-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)-1-哌啶(化合物16’)(70mg，0.17mmol)的二氯甲烷(5mL)溶液中依次加入丙烯酸(23mg，0.30mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(64mg，0.30mmol)，4-二甲基胺吡啶(13mg，0.10mmol)，然后在室温反应2小时，用水洗涤然后用无水Na2SO4干燥后，通过减压浓缩溶剂得到的粗品，通过薄层色谱(乙酸乙酯∶甲醇＝40∶1)纯化，得到化合物17’(R)-1-(3-(4-氨基-3-(5-(2-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮(51mg，收率63％)。(R)-3-(4-Amino-3-(5-(2-pyridylcarbamoyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidine-1 at 0 °C Acrylic acid (23 mg, 0.30 mmol), 1-(3-dimethylaminopropyl)-, was added sequentially to a solution of 1-phenylpiperidine (Compound 16') (70 mg, 0.17 mmol) in dichloromethane (5 mL) 3-ethylcarbodiimide hydrochloride (64 mg, 0.30 mmol), 4-dimethylaminopyridine (13 mg, 0.10 mmol), then reacted at room temperature for 2 hours, washed with water and dried over anhydrous Na 2 SO 4 The crude product obtained by concentrating the solvent under reduced pressure was purified by chromatography (ethyl acetate:methanol=40:1) to afford compound 17'(R)-1-(3-(4-amino-3-(5) -(2-pyridylcarbamoyl)thiophen-2-yl)-1H-pyrazo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one ( 51 mg, yield 63%).
TLC：Rf0.5(乙酸乙酯∶甲醇＝30∶1)TLC: R f 0.5 (ethyl acetate:methanol = 30:1)
MS(ESI)m/z 475(M+1)；1HNMR(400MHz，CDCl3)MS (ESI) m / z 475 (M + 1); 1 H NMR (400 MHz, CDCl 3 )
1.60-2.45(m，4H)，2.89-4.95(m，5H)，5.25-5.65(m，3H)，6.55-6.95(m，4H)， 7.30-7.32(m，2H)，7.30-8.15(m，4H)，8.42(s，1H)，9.14(s，1H)。1.60-2.45 (m, 4H), 2.89-4.95 (m, 5H), 5.25-5.65 (m, 3H), 6.55-6.95 (m, 4H), 7.30-7.32 (m, 2H), 7.30-8.15 (m, 4H), 8.42 (s, 1H), 9.14 (s, 1H).
按照与实施例6类似的方法将化合物10’进行改变，可以得到如下表1所示的化合物51-62，其中化合物10’可以选自如下化合物：The compound 10' was changed in a similar manner to Example 6 to give the compound 51-62 shown in the following Table 1, wherein the compound 10' may be selected from the following compounds:
(5-(叔丁基二甲基硅氧亚甲基)噻吩-2-基)硼酸；(5-(tert-butyldimethylsilyloxymethylene)thiophen-2-yl)boronic acid;
(4-(叔丁基二甲基硅氧亚甲基)噻吩-2-基)硼酸；(4-(tert-butyldimethylsilyloxymethylene)thiophen-2-yl)boronic acid;
(2-(叔丁基二甲基硅氧亚甲基)噻吩-4-基)硼酸(2-(tert-butyldimethylsilyloxymethylene)thiophen-4-yl)boronic acid
当叔丁基二甲基硅氧亚甲基与噻吩5位相连，噻吩2位与1H-吡唑[3，4-d]嘧啶基3位相连，化合物10’为(5-(叔丁基二甲基硅氧亚甲基)噻吩-2-基)硼酸。When tert-butyldimethylsiloxymethylene is attached to the 5-position of thiophene, the 2-position of thiophene is attached to the 3-position of the 1H-pyrazole [3,4-d]pyrimidinyl group, and the compound 10' is (5-(tert-butyl) Dimethylsiloxymethylene)thiophen-2-yl)boronic acid.
化合物10’(5-(叔丁基二甲基硅氧亚甲基)噻吩-2-基)硼酸及其合成方法Compound 10'(5-(tert-butyldimethylsilyloxymethylene)thiophen-2-yl)boronic acid and synthesis method thereof 为：for:
在室温下向2-溴噻吩-5-甲醇(4g，20mmol)(CAS为79387-71-6购于上海泰坦科技股份有限公司)的N，N-二甲基甲酰胺(50mL)溶液中依次加咪唑(2g，30mmol)和叔丁基二甲基氯化硅(3.9g，25mmol)(CAS号18162-48-6，购自海门贝斯特精细化工有限公司)。然后在室温下反应2小时，加入200mL水，然后用乙酸乙酯萃取，分离有机层用水(100mL)洗2次，然后将有机相用无水硫酸钠干燥，通过减压浓缩溶剂得到的粗品用硅胶柱的液相色谱分离，洗脱溶剂为乙酸乙酯∶石油醚(1∶30-＞1∶15)得到2-溴-(5-叔丁基二甲基硅氧亚甲基)噻吩)(5.5g，收率：90％)。To a solution of 2-bromothiophene-5-methanol (4 g, 20 mmol) (CAS 79387-71-6 purchased from Shanghai Titan Technology Co., Ltd.) in N,N-dimethylformamide (50 mL) at room temperature Imidazole (2 g, 30 mmol) and tert-butyldimethylsilyl chloride (3.9 g, 25 mmol) (CAS No. 18162-48-6, purchased from Haimen Best Fine Chemical Co., Ltd.). Then, it was reacted for 2 hours at room temperature, 200 mL of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water (100 mL), and then the organic phase was dried over anhydrous sodium sulfate. The liquid chromatography was carried out on a silica gel column. The eluting solvent was ethyl acetate: petroleum ether (1:30->1:15) to give 2-bromo-(5-tert-butyldimethylsiloxymethylene)thiophene) (5.5 g, yield: 90%).
薄层色谱检测：TLC：Rf0.5(乙酸乙酯∶石油醚＝1∶10)质谱检测：MS(ESI)m/z 307(M+1)；TLC: R f 0.5 (ethyl acetate: petroleum ether = 1 : 10) mass spectroscopy: MS (ESI) m/z 307 (M+1);
核磁共振检测：1HNMR(400MHz，CDCl3)：0.20(s，3H)，0.21(s，3H)，1.60(s，9H)，5.21(s，2H)，6.55-6.75(m，2H)。NMR detection: 1 H NMR (400 MHz, CDCl 3 ): 0.20 (s, 3H), 0.21 (s, 3H), 1.60 (s, 9H), 5.21. (s, 2H), 6.55-6.75 (m, 2H).
2-溴-(5-叔丁基二甲基硅氧亚甲基)噻吩(1.8g，5.9mmol)溶于四氢呋喃(15mL)在氮气环境下滴加到零下70℃的正丁基锂(4.8mL，2.5mol/L的正己烷溶液)的四氢呋喃(10mL)溶液中。在零下70℃下反应2小时，然后加入硼酸甲酯(3.15g，30mmol)，在零下70℃下继续反应30分钟，升至室温导入1mol/L的盐酸(30mL)中搅拌10分钟。用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩得到化合物10’(5-(叔丁基二甲基硅氧亚甲基)噻吩-2-基)硼酸粗品1.20g，由于产品易分解，不用 精制直接用于下一步反应。2-Bromo-(5-tert-butyldimethylsilyloxymethylene)thiophene (1.8 g, 5.9 mmol) was dissolved in tetrahydrofuran (15 mL) and added dropwise to n-butyllithium at a temperature of 70 ° C under nitrogen. A solution of mL, 2.5 mol/L in n-hexane) in tetrahydrofuran (10 mL). The reaction was carried out at -70 ° C for 2 hours, then methyl borate (3.15 g, 30 mmol) was added, and the reaction was continued at minus 70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol/L hydrochloric acid (30 mL) and stirred for 10 minutes. After extraction with ethyl acetate, the organic layer was dried over anhydrous Na 2 SO 4 and then concentrated to give compound 10' (5-(t-butyldimethylsiloxymethylene)thiophen-2-yl)boronic acid The crude product is 1.20g. Since the product is easily decomposed, it can be directly used in the next reaction without purification.
薄层色谱检测：TLC：Rf0.5(乙酸乙酯∶石油醚＝1∶5)TLC: TLC: R f 0.5 (ethyl acetate: petroleum ether = 1:5)
质谱检测：MS(ESI)m/z 273(M+1)；Mass spectrometry: MS (ESI) m/z 273 (M + 1);
(4-(叔丁基二甲基硅氧亚甲基)噻吩-2-基)硼酸(4-(tert-butyldimethylsilyloxymethylene)thiophen-2-yl)boronic acid
(2-(叔丁基二甲基硅氧亚甲基)噻吩-4-基)硼酸(2-(tert-butyldimethylsilyloxymethylene)thiophen-4-yl)boronic acid
上述硼酸化合物的合成方法均同于化合物10’(5-(叔丁基二甲基硅氧亚甲基)噻吩-2-基)硼酸的制备方法。The above-described method for synthesizing a boric acid compound is the same as the method for producing the compound 10' (5-(tert-butyldimethylsiloxymethylene)thiophen-2-yl)boronic acid.
实施例7Example 7
当R5、R6均为H，环1为2-吡啶基，L1为单键，2-吡啶基与噻吩的5位相连，1H-吡唑[3，4-d]-嘧啶-1-基与噻吩的2位相连，m＝0，环2为哌啶，化合物6’为(5-(2-吡啶基)噻吩-2-基)硼酸，制备方法为：在室温下向2-溴吡啶(3g，19.1mmol)(CAS号：109-04-6，购自贝斯特试剂，商品号B012654)的乙二醇二甲醚(60mL)溶液中依次加入水(30mL)、(噻吩-2-基)硼酸(3.4g，26.7mmol)、四三苯基磷鈀(454mg，3.8mmol)和Na2CO3(6.1g，57.3mmol)。然后氩气置换3次后在80℃下反应6小时，冷却至室温，倒入50mL水中，用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩溶剂得到的粗品用硅胶柱的液相色谱分离，洗脱溶剂为石油醚∶乙酸乙酯(100∶1→60∶1)得到目标产物2-(2-吡啶基)噻吩(2.5g，收率83％)。When R 5 and R 6 are both H, ring 1 is 2-pyridyl, L 1 is a single bond, 2-pyridyl is attached to the 5-position of thiophene, and 1H-pyrazole [3,4-d]-pyrimidine-1 - The group is bonded to the 2-position of the thiophene, m=0, the ring 2 is piperidine, and the compound 6' is (5-(2-pyridyl)thiophen-2-yl)boronic acid. The preparation method is as follows: 2- at room temperature Water (30 mL), (thiophene-) was added to a solution of bromopyridine (3 g, 19.1 mmol) (CAS No.: 109-04-6, available from Best Reagent, commercial number B012654) in ethylene glycol dimethyl ether (60 mL). 2-yl)boronic acid (3.4 g, 26.7 mmol), tetratriphenylphosphine palladium (454 mg, 3.8 mmol) and Na 2 CO 3 (6.1 g, 57.3 mmol). After argon gas replacement for 3 times, the reaction was carried out at 80 ° C for 6 hours, cooled to room temperature, poured into 50 mL of water, extracted with ethyl acetate, and the organic layer was extracted with anhydrous Na 2 SO 4 and then evaporated. The crude product was separated by chromatography on silica gel column eluting eluting elution elution elution elution .
薄层色谱：(TLC)检测：Rf0.5(石油醚∶乙酸乙酯＝8∶1展开相)；质谱检测：MS(ESI)m/z 162(M+1)；核磁共振：1HNMR(400MHz，CDCl3)：7.10-7.45(m，2H)、7.60-7.95(m，4H)、8.50-8.60(m，1H)。Thin layer chromatography: (TLC) detection: R f 0.5 (petroleum ether: ethyl acetate = 8:1 unfolded phase); mass spectrometric detection: MS (ESI) m/z 162 (M+1); NMR: 1 H NMR ( 400 MHz, CDCl 3 ): 7.10-7.45 (m, 2H), 7.60-7.95 (m, 4H), 8.50-8.60 (m, 1H).
7.1 2-溴-5-(2-吡啶基)噻吩的制备方法：7.1 Preparation method of 2-bromo-5-(2-pyridyl)thiophene :
在0℃下向2-(2-吡啶基)噻吩(2.5g，15.5mmol)的二氯甲烷(100mL)，中滴加溴(2.50g，15.6mmol)的二氯甲烷(50mL)溶液。1小时滴加完毕后升至室温搅拌2小时，倒入饱和Na2CO3(200mL)中，分离有机相，用无水Na2SO4干燥后，通过减压浓缩溶剂得到的粗品用硅胶柱的液相色谱分离，洗脱溶剂为石油醚∶乙酸乙酯(100∶1→80∶1)得到目标产物2-溴-5-(2-吡啶基)噻吩(3g，收率81％)。To a solution of 2-(2-pyridyl)thiophene (2.5 g, 15.5 mmol) in dichloromethane (100 mL), EtOAc (EtOAc) After 1 hour of dropwise addition, the mixture was stirred at room temperature for 2 hours, poured into saturated Na 2 CO 3 (200 mL), and the organic phase was separated, dried over anhydrous Na 2 SO 4 The liquid chromatography was separated, and the solvent was eluted with petroleum ether: ethyl acetate (100:1 → 80:1) to give the desired product 2-bromo-5-(2-pyridyl)thiophene (3 g, yield 81%).
薄层色谱：(TLC)检测：Rf0.5(石油醚∶乙酸乙酯＝8∶1展开相)； 质谱检测：MS(ESI)m/z 240(M+1)；核磁共振：1HNMR(400MHz，CDCl3)：7.15-7.50(m，3H)、7.65-7.95(m，2H)、8.55-8.60(m，1H)。Thin layer chromatography: (TLC) detection: R f 0.5 (petroleum ether: ethyl acetate = 8:1 unfolded phase); mass spectrometric detection: MS (ESI) m/z 240 (M+1); NMR: 1H NMR (400 MHz) , CDCl3): 7.15-7.50 (m, 3H), 7.65-7.95 (m, 2H), 8.55-8.60 (m, 1H).
(5-(2-吡啶基)噻吩-2-基)硼酸的制备方法：2-溴-5-(2-吡啶基)噻吩(2g，8.3mmol)溶于四氢呋喃(15mL)在氮气环境下滴加到零下70℃的正丁基锂(6.6mL，2.5mol/L的正己烷溶液)的四氢呋喃(15mL)溶液中。30分钟滴加完毕后，在零下70℃下继续反应2小时，然后加入硼酸三甲酯(5.2g，50mmol)，在零下70℃下继续反应30分钟，升至室温导入1mol/L的盐酸(20mL)中搅拌10分钟。用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩得到(5-(2-吡啶基)噻吩-2-基)硼酸粗品1.50g，由于产品易分解，不用精制直接用于下一步反应。接下来重复路线1步骤4-6。Preparation of (5-(2-pyridyl)thiophen-2-yl)boronic acid: 2-bromo-5-(2-pyridyl)thiophene (2 g, 8.3 mmol) dissolved in tetrahydrofuran (15 mL) Add to a solution of n-butyllithium (6.6 mL, 2.5 mol/L in n-hexane) in tetrahydrofuran (15 mL) at 70 °C. After completion of the dropwise addition for 30 minutes, the reaction was continued at minus 70 ° C for 2 hours, then trimethyl borate (5.2 g, 50 mmol) was added, and the reaction was continued at minus 70 ° C for 30 minutes, and the temperature was raised to room temperature to introduce 1 mol/L hydrochloric acid ( Stir in 20 mL) for 10 minutes. After extracting with ethyl acetate, the organic layer was dried over anhydrous Na 2 SO 4 and then evaporated. The refining is used directly in the next reaction. Next, repeat route 1 steps 4-6.
TLC：Rf 0.5(乙酸乙酯∶石油醚＝1∶5)TLC: Rf 0.5 (ethyl acetate: petroleum ether = 1:5)
MS(ESI)m/z 206(M+1)。MS (ESI) m/z 206 (M+1).
制备上述中间体的路线4如下：Route 4 for the preparation of the above intermediates is as follows:
Figure PCTCN2017072716-appb-000054
Figure PCTCN2017072716-appb-000054
在以上路线中，R7选自甲基、氰基、甲酰氨基或乙酰氨基，R7可以位于吡啶基的5位或6位。通过选择不同位置取代的噻吩硼酸，选择不同位置取代溴吡啶基，可以得到想要连接位置的吡啶基和噻吩基。In the above route, R 7 is selected from methyl, cyano, formylamino or acetylamino, and R 7 may be at the 5- or 6-position of the pyridyl group. The pyridyl group and the thienyl group to which the position is desired can be obtained by selecting a thiophene boric acid substituted at a different position and selecting a bromopyridyl group at a different position.
7.2.制备方法类似7.1的中间体7.2. Preparation method is similar to the intermediate of 7.1
(5-(3-吡啶基)噻吩-2-基)硼酸(5-(3-pyridyl)thiophen-2-yl)boronic acid
5-(2-(6-甲基吡啶基))噻吩-2-基)硼酸5-(2-(6-methylpyridyl))thiophen-2-yl)boronic acid
5-(2-(5-甲基吡啶基))噻吩-2-基)硼酸5-(2-(5-methylpyridyl))thiophen-2-yl)boronic acid
(4-(2-吡啶基)噻吩-2-基)硼酸(4-(2-pyridyl)thiophen-2-yl)boronic acid
(4-(3-吡啶基)噻吩-2-基)硼酸(4-(3-pyridyl)thiophen-2-yl)boronic acid
上述硼酸化合物的合成方法均类似于化合物6’(5-(2-吡啶基)噻吩-2-基)硼酸的制备方法。The above synthesis methods of the boronic acid compound are similar to the preparation method of the compound 6'(5-(2-pyridyl)thiophen-2-yl)boronic acid.
7.3当R5、R6均为H，环1为2-(6-氰基吡啶基)，L1为单键，2-(6-氰基) 吡啶基与噻吩的5位相连，1H-吡唑[3，4-d]嘧啶-1-基与噻吩的2位相连，m＝0，环2为哌啶，化合物6’为(5-(6-氰基吡啶-2-基)噻吩-2-基)硼酸，制备方法为：5-溴-((6-氰基吡啶-2-基)噻吩-2基)的制备方法类似于2-溴-5-(2-吡啶基)噻吩的制备方法。在室温下向5-溴-((6-氰基吡啶-2-基)噻吩-2-基)(3g，11.3mmol)的乙二醇二甲醚(60mL)溶液中依次加入水(30mL)、双(频哪醇合)二硼(2.88g，11.3mmol)、1，1-双(二苯基膦)二茂铁二氯化钯二氯甲烷络合物(920mg，1.1mmol)和NaOAc(3.1g，22.6mmol)。然后氩气置换3次后在80℃下反应12小时，冷却至室温，倒入50mL水中，用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩溶剂得到的粗品溶于30mL乙酸乙酯加入0.1M的盐酸10mL室温搅拌5h，用饱和Na2CO3调制pH＝6左右，用乙酸乙酯萃取，萃取有机液用无水Na2SO4干燥后，通过减压浓缩溶剂得到的粗品目标产物(5-(6-氰基吡啶-2-基)噻吩-2-基)硼酸，由于产物不稳定，不用纯化直接用于下一步反应。7.3 When R 5 and R 6 are both H, ring 1 is 2-(6-cyanopyridyl), L 1 is a single bond, and 2-(6-cyano)pyridinyl is attached to the 5-position of thiophene, 1H- Pyrazole [3,4-d]pyrimidin-1-yl is attached to the 2-position of thiophene, m=0, ring 2 is piperidine, and compound 6' is (5-(6-cyanopyridin-2-yl)thiophene 2-yl)boronic acid, prepared by the method of 5-bromo-((6-cyanopyridin-2-yl)thiophen-2-yl) similar to 2-bromo-5-(2-pyridyl)thiophene Preparation method. To a solution of 5-bromo-((6-cyanopyridin-2-yl)thiophen-2-yl) (3 g, 11.3 mmol) in ethylene glycol dimethyl ether (60 mL), water (30 mL) Bis (pinacol) diboron (2.88 g, 11.3 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium chloride dichloromethane complex (920 mg, 1.1 mmol) and NaOAc (3.1 g, 22.6 mmol). After argon gas replacement for 3 times, the reaction was carried out at 80 ° C for 12 hours, cooled to room temperature, poured into 50 mL of water, extracted with ethyl acetate, and the organic layer was extracted with anhydrous Na 2 SO 4 and then evaporated. The crude product was dissolved in 30 mL of ethyl acetate and added with 10 mL of 0.1 M hydrochloric acid. The mixture was stirred at room temperature for 5 h, and the mixture was adjusted to pH=6 with saturated Na 2 CO 3 , and extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 The crude target product (5-(6-cyanopyridin-2-yl)thiophen-2-yl)boronic acid obtained by pressure concentration of the solvent was used in the next reaction without purification.
薄层色谱：(TLC)检测：Rf 0.5(石油醚∶乙酸乙酯＝6∶1展开相)；质谱检测：MS(ESI)m/z 231(M+1)。TLC: (TLC): Rf 0.5 ( petroleum ether: ethyl acetate = 6:1).
7.4制备方法类似7.3的中间体7.4 Preparation method Intermediates similar to 7.3
5-(2-(5-氰基吡啶基)噻吩-2-基)硼酸5-(2-(5-cyanopyridinyl)thiophen-2-yl)boronic acid
5-(2-(5-甲酰氨基吡啶基)噻吩-2-基)硼酸5-(2-(5-formylaminopyridyl)thiophen-2-yl)boronic acid
5-(2-(6-甲酰氨基吡啶基)噻吩-2-基)硼酸5-(2-(6-formylaminopyridyl)thiophen-2-yl)boronic acid
5-(2-(5-(氨基乙酰基)吡啶基)噻吩-2-基)硼酸5-(2-(5-(aminoacetyl)pyridyl)thiophen-2-yl)boronic acid
5-(2-(6-(氨基乙酰基)吡啶基)噻吩-2-基)硼酸5-(2-(6-(aminoacetyl)pyridyl)thiophen-2-yl)boronic acid
按照实施例5公开的中间体的制备方法结合本发明的合成路线，得到了如下表1所示化合物1-50，按照实施例6公开的中间体的制备方法结合本发明的合成路线，得到了如下表1所示化合物51-62：According to the preparation method of the intermediate disclosed in Example 5, in combination with the synthetic route of the present invention, the compound 1-50 shown in the following Table 1 was obtained, and the preparation method of the intermediate disclosed in Example 6 was combined with the synthetic route of the present invention. Compounds 51-62 as shown in Table 1 below:
表1Table 1
Figure PCTCN2017072716-appb-000055
Figure PCTCN2017072716-appb-000055
Figure PCTCN2017072716-appb-000056
Figure PCTCN2017072716-appb-000056
Figure PCTCN2017072716-appb-000057
Figure PCTCN2017072716-appb-000057
Figure PCTCN2017072716-appb-000058
Figure PCTCN2017072716-appb-000058
Figure PCTCN2017072716-appb-000059
Figure PCTCN2017072716-appb-000059
Figure PCTCN2017072716-appb-000060
Figure PCTCN2017072716-appb-000060
Figure PCTCN2017072716-appb-000061
Figure PCTCN2017072716-appb-000061
Figure PCTCN2017072716-appb-000062
Figure PCTCN2017072716-appb-000062
Figure PCTCN2017072716-appb-000063
Figure PCTCN2017072716-appb-000063
Figure PCTCN2017072716-appb-000064
Figure PCTCN2017072716-appb-000064
Figure PCTCN2017072716-appb-000065
Figure PCTCN2017072716-appb-000065
Figure PCTCN2017072716-appb-000066
Figure PCTCN2017072716-appb-000066
Figure PCTCN2017072716-appb-000067
Figure PCTCN2017072716-appb-000067
Figure PCTCN2017072716-appb-000068
Figure PCTCN2017072716-appb-000068
Figure PCTCN2017072716-appb-000069
Figure PCTCN2017072716-appb-000069
Figure PCTCN2017072716-appb-000070
Figure PCTCN2017072716-appb-000070
Figure PCTCN2017072716-appb-000071
Figure PCTCN2017072716-appb-000071
Figure PCTCN2017072716-appb-000072
Figure PCTCN2017072716-appb-000072
Figure PCTCN2017072716-appb-000073
Figure PCTCN2017072716-appb-000073
实施例8Example 8
BTK抑制活性和对Btk选择性的测定BTK inhibitory activity and determination of Btk selectivity
实验材料： Experimental materials :
1.布鲁顿激酶抑制剂(BTK)1. Bruton kinase inhibitor (BTK)
英杰公司，商品号：PR5442A(Invitrogen-PR5442A)Yingjie Company, product number: PR5442A (Invitrogen-PR5442A)
2.检测试剂盒 2. Test kit
赛斯生物公司(Cisbio)，商品号62TK0PEJCisbio, product number 62TK0PEJ
3.检测板3. Test board
铂金埃尔默公司，商品号：6007299Platinum Elmer, product number: 6007299
(PerkinElmer-6007299)(PerkinElmer-6007299)
4.荧光板读数器/容和通用酶标仪4. Fluorescent plate reader / volume and universal microplate reader
铂金埃尔默公司，商品号：2104(PerkinElmer-2104)Elmer, Platinum, trade number: 2104 (PerkinElmer-2104)
实验步骤：Experimental steps:
1.化合物稀释：待测化合物与阳性化合物依鲁替尼(Ibrutinib)用二甲亚砜(DMSO)3倍进行稀释，共11个浓度，最终体系浓度从10μM至0.17nM。1. Compound dilution: The test compound and the positive compound Ibrutinib were diluted 3 times with dimethyl sulfoxide (DMSO) for a total of 11 concentrations, and the final system concentration was from 10 μM to 0.17 nM.
2.在缓冲液为50mM4-羟乙基哌嗪乙磺酸(Hepes)(pH7.5)，5mM MgCl2，0.01mM Na3VO4，1％牛血清蛋白(BSA)的10L反应体系中，包括1nM布鲁顿酪氨酸激酶(Btk)，1M生物素多肽(biotin-TK peptide)，20M ATP，在缓冲液为50mM 4-羟乙基哌嗪乙磺酸(Hepes)(pH7.5)，将受测化合物的二甲亚砜(DMSO)稀释溶液添加到96孔测试板中在23℃孵育90分钟。然后加入10μl含有20mM乙二胺四乙酸(EDTA)，6.7nM胸腺嘧啶核苷Btk缺陷型抗体(TK)抗体，62.5nM终止溶液(SA-XL665，购自上海拜力生物科技有限公司(cisbio))，在23℃孵育60分钟。2. In a 10 L reaction system of 50 mM 4 -hydroxyethylpiperazineethanesulfonic acid (Hepes) (pH 7.5), 5 mM MgCl 2 , 0.01 mM Na 3 VO 4 , 1% bovine serum albumin (BSA), Including 1nM Bruton's tyrosine kinase (Btk), 1M biotin peptide (biotin-TK peptide), 20M ATP, 50mM 4-hydroxyethylpiperazineethanesulfonic acid (Hepes) in buffer (pH 7.5) The diluted dimethyl sulfoxide (DMSO) solution of the test compound was added to a 96-well test plate and incubated at 23 ° C for 90 minutes. Then add 10 μl of 20 mM ethylenediaminetetraacetic acid (EDTA), 6.7 nM thymidine Btk-deficient antibody (TK) antibody, 62.5 nM stop solution (SA-XL665, purchased from Shanghai Baili Biotechnology Co., Ltd. (cisbio) ), incubate at 23 ° C for 60 minutes.
3.使用荧光板读数器/容和通用酶标仪测定各孔在445nm和520nm处的荧光强度。磷酸化的比例根据试剂盒所附的的说明书，通过445nm(香豆素显色)处相对于520nm(荧光素显色)处的显色比例来确定。3. The fluorescence intensity of each well at 445 nm and 520 nm was measured using a fluorescent plate reader/capacitor and a universal microplate reader. The ratio of phosphorylation was determined by the coloration ratio at 445 nm (coumarin color development) relative to 520 nm (fluorescein color development) according to the instructions attached to the kit.
4.将仪器读取的数据计算出化合物的抑制率，然后计算出IC50值。(运用IDBS的XLFIT5中模式205)4. Calculate the inhibition rate of the compound from the data read by the instrument, and then calculate the IC 50 value. (Using IDBS's XLFIT5 Mode 205)
受测试化合物的抑制率(％)使用以下公式计算：The inhibition rate (%) of the test compound was calculated using the following formula:
磷酸化抑制率(％)＝1-{(AC-AX)/(AC-AB)}X 100Phosphorylation inhibition rate (%) = 1 - {(A C - A X ) / (A C - A B )} X 100
AC：只添加二甲亚砜(对照)时的磷酸化率A C : Phosphorylation rate when only dimethyl sulfoxide (control) was added
AX：添加受测试化合物时的磷酸化率A X : Phosphorylation rate when adding test compound
AB：添加ATP(空白)时的磷酸化率A B : Phosphorylation rate when ATP (blank) is added
由基于受测试化合物的各浓度下的抑制率的抑制曲线，计算受测试化合 物的50％抑制率的值(IC50值)。The value (IC 50 value) of the 50% inhibition rate of the test compound was calculated from the inhibition curve based on the inhibition rate at each concentration of the test compound.
其他酪氨酸激酶组如Lck的抑制活性的测定使用各种激酶代替Btk，与上述方法同样操作。The measurement of the inhibitory activity of other tyrosine kinase groups such as Lck uses various kinases instead of Btk, and operates in the same manner as the above method.
表2本发明代表性化合物对酪氨酸激酶的抑制作用Table 2 Inhibition of tyrosine kinase by representative compounds of the invention
序号Serial number 化合物Compound Btk IC50(nM)Btk IC 50 (nM) Lck IC50(nM)Lck IC 50 (nM)
11 依鲁替尼Ibrutinib 22  
22 化合物1Compound 1 2828 25952595
33 化合物2Compound 2 2020 1000010000
44 化合物3Compound 3 1717 33333333
55 化合物4Compound 4 100100 1000010000
66 化合物5 Compound 5 1111 977977
77 化合物6Compound 6 5454 1000010000
88 化合物7Compound 7 1919 29242924
99 化合物8Compound 8 21twenty one 33333333
1010 化合物9Compound 9 1414 33333333
1111 化合物10 Compound 10 21twenty one 33333333
1212 化合物11Compound 11 5555 1000010000
1313 化合物12Compound 12 3535 1000010000
1414 化合物13Compound 13 150150 1000010000
1515 化合物14Compound 14 5555 33333333
1616 化合物15 Compound 15 1414 32003200
1717 化合物16Compound 16 21twenty one 1000010000
1818 化合物17Compound 17 1010 1000010000
1919 化合物18Compound 18 44 1000010000
2020 化合物19Compound 19 6262 50955095
21twenty one 化合物20Compound 20 210210 54775477
22twenty two 化合物21Compound 21 8686 65106510
23twenty three 化合物22Compound 22 157157 1000010000
24twenty four 化合物23Compound 23 7878 1000010000
2525 化合物24Compound 24 180180 73417341
2626 化合物25Compound 25 6060 31043104
2727 化合物26Compound 26 6868 50695069
2828 化合物27Compound 27 21twenty one 33333333
2929 化合物28Compound 28 8888 42094209
3030 化合物29Compound 29 7070 29242924
3131 化合物30Compound 30 6464 1000010000
3232 化合物31Compound 31 6262 40954095
3333 化合物32Compound 32 1313 54775477
3434 化合物33Compound 33 1414 65106510
3535 化合物34Compound 34 9292 1000010000
3636 化合物35Compound 35 110110 1000010000
3737 化合物36Compound 36 5858 33423342
3838 化合物37Compound 37 157157 1000010000
3939 化合物38Compound 38 7373 60906090
4040 化合物39Compound 39 4545 80908090
4141 化合物40Compound 40 3333 1000010000
4242 化合物41Compound 41 2929 1000010000
4343 化合物42Compound 42 3030 1000010000
4444 化合物43Compound 43 3535 1000010000
4545 化合物44Compound 44 1010 1000010000
4646 化合物45Compound 45 23twenty three 13411341
4747 化合物46Compound 46 88 31043104
4848 化合物47Compound 47 5151 50695069
4949 化合物48Compound 48 1010 70987098
5050 化合物49Compound 49 3737 55455545
5151 化合物50Compound 50 1313 1000010000
5252 化合物51Compound 51 1313 1000010000
5353 化合物52Compound 52 3030 50905090
5454 化合物53Compound 53 6565 64906490
5555 化合物54Compound 54 8080 75107510
5656 化合物55Compound 55 1515 1000010000
5757 化合物56Compound 56 3535 1000010000
5858 化合物57Compound 57 9090 33423342
5959 化合物58Compound 58 112112 43044304
6060 化合物59Compound 59 2020 60906090
6161 化合物60Compound 60 2020 80908090
6262 化合物61Compound 61 103103 1000010000
6363 化合物62Compound 62 44 32303230
6464 化合物63Compound 63 2020 1000010000
6565 化合物64Compound 64 3535 ＞10,000>10,000
6666 化合物65Compound 65 22 2,3122,312
6767 化合物66Compound 66 1010 1,6131,613
6868 化合物67Compound 67 23twenty three 1,3411,341
6969 化合物68Compound 68 1414 6,5106,510
7070 化合物69Compound 69 8888 4,2094,209
7171 化合物70Compound 70 88 3,1043,104
7272 化合物71Compound 71 5151 5,0695,069
7373 化合物72Compound 72 7575 4,2894,289
7474 化合物73Compound 73 1010 7,0987,098
7575 化合物74Compound 74 3737 5,5455,545
以上的结果表明本发明的化合物对Btk具有良好的选择性抑制作用。The above results indicate that the compound of the present invention has a good selective inhibitory effect on Btk.
实施例9Example 9
人淋巴瘤拉莫斯细胞(Ramos细胞)Btk特异性信号传导通路活性的测定 Determination of Btk-specific signaling pathway activity in human lymphoma Ramos cells
1.试验材料Test material
Ramos细胞Ramos cell
Figure PCTCN2017072716-appb-000074
Figure PCTCN2017072716-appb-000074
2.试验步骤2. Test procedure
IgM EC80检测：收集细胞，用含0.1％FBS(胎牛血清)的1640培养基重悬细胞并调整浓度至5x106/mL。在细胞板中加入20L/孔细胞悬液，加入40L Fluo-4负载染料(loading dye)，37℃孵育50分钟。3倍梯度稀释IgM，终浓度为10g/mL到0.0046g/mL，使用高通量细胞水平筛选***(FLIPR)转移10L的IgM至细胞板中，并读取荧光值。计算IgM的药物浓度(EC80)。Detecting IgM EC 80: The cells were collected, containing 0.1% FBS (fetal bovine serum) 1640 medium and resuspended cells were adjusted to a concentration of 5x10 6 / mL. A 20 L/well cell suspension was added to the cell plate, and 40 L of Fluo-4 loading dye was added and incubated at 37 ° C for 50 minutes. IgM was serially diluted 3 fold to a final concentration of 10 g/mL to 0.0046 g/mL, and 10 L of IgM was transferred to the cell plate using a high throughput cell level screening system (FLIPR) and the fluorescence values were read. The drug concentration of IgM (EC 80 ) was calculated.
化合物IC50检测：收集细胞，用含0.1％FBS的1640培养基重悬细胞并调整浓度至5x106/mL。在细胞板中加入20L/孔细胞悬液。3倍梯度稀释待测化合物及阳性化合物依鲁替尼(Ibrutinib)，终浓度为10M到0.0046M，转移10L化合物至细胞板中，37℃孵育60分钟。加入40L荧光负载染料(Fluo-4loading dye)，37℃孵育50min。使用高通量细胞转移筛选***(FLIPR)转移10L 8×EC80IgM至细胞板中，并读取荧光值。使用绘图软件(Prism)GraphPad Software)制作抑制率的曲线图，计算化合物IC50。Compound IC 50 detection: Cells were harvested with 0.1% FBS containing medium cells were resuspended in 1640 and adjusted to a concentration of 5x10 6 / mL. A 20 L/well cell suspension was added to the cell plate. The test compound and the positive compound Ibrutinib were diluted 3 fold to a final concentration of 10 M to 0.0046 M, and 10 L of the compound was transferred to a cell plate and incubated at 37 ° C for 60 minutes. Add 40 L of Fluo-4 loading dye and incubate for 50 min at 37 °C. 10 L of 8 x EC 80 IgM was transferred to the cell plates using a high-throughput cell transfer screening system (FLIPR) and the fluorescence values were read. Using graphics software (Prism) GraphPad Software) Production inhibition rate graph, the compound is calculated IC 50.
表3本发明代表性化合物对Ramos细胞Btk特异性信号传导通路的抑制作用Table 3 Inhibition of representative compounds of the present invention on Btk-specific signaling pathways in Ramos cells
Figure PCTCN2017072716-appb-000075
Figure PCTCN2017072716-appb-000075
Figure PCTCN2017072716-appb-000076
Figure PCTCN2017072716-appb-000076
以上的结果表明本发明化合物对Ramos细胞Btk特异性信号传导通路的具有优于依鲁替尼的抑制作用。The above results indicate that the compounds of the present invention have an inhibitory effect on the Btk-specific signaling pathway of Ramos cells over ibrutinib.
实施例10Example 10
非霍奇金(Non-Hodgkin)淋巴瘤细胞系增殖活性的测定Determination of proliferative activity of non-Hodgkin lymphoma cell lines
1.试验材料Test material
Ramos(人伯基特(Burkitts)淋巴瘤细胞)Ramos (Burkitts lymphoma cells)
HBL-1(人弥漫性大B淋巴瘤细胞)HBL-1 (human diffuse large B lymphoma cells)
Daudi(人伯基特(Burkitts)淋巴瘤细胞)Daudi (Burkitts lymphoma cells)
DOHH-2(人滤泡性淋巴瘤细胞)DOHH-2 (human follicular lymphoma cells)
JeKo-1(人套细胞淋巴瘤细胞)JeKo-1 (human mantle cell lymphoma cells)
OCI-LY-19(伯基特(Burkitts)淋巴瘤细胞)OCI-LY-19 (Burkitts lymphoma cells)
Z-138(人套细胞淋巴瘤细胞)Z-138 (human mantle cell lymphoma cells)
SU-DHL-4(人弥漫性大B淋巴瘤细胞)SU-DHL-4 (human diffuse large B lymphoma cells)
SU-DHL-10(人弥漫性大B淋巴瘤细胞)SU-DHL-10 (human diffuse large B lymphoma cells)
WSU-DLCL2(人滤泡性淋巴瘤细胞)WSU-DLCL2 (human follicular lymphoma cells)
酶标仪Molecular Devices Spectra MAX I3Microplate reader Molecular Devices Spectra MAX I3
细胞培养基(RPMI1640)    赛默飞公司(Gibco)#C11875500BTCell Culture Medium (RPMI1640) Thermo Scientific (Gibco) #C11875500BT
胎牛血清FBS                 英杰公司(Invitrogen)#10099-141Fetal bovine serum FBS Yingjie Company (Invitrogen) #10099-141
细胞增殖与活性检测试剂盒(CCK-8)    同仁化工(Dojindo)#CK04BCell Proliferation and Activity Detection Kit (CCK-8) Tongjin Chemical (Dojindo) #CK04B
384-孔平板(384-孔板)              康宁公司(Corning)#3701384-well plate (384-well plate) Corning (Corning) #3701
2.试验步骤2. Test procedure
收集细胞，用含10％FBS(胎牛血清)的1640培养基重悬细胞并调整浓度至3x104/mL。在细胞板中加入50μL/孔细胞悬液。3倍梯度稀释待测化合物及阳性化合物依鲁替尼(Ibrutinib)，转移5μL化合物溶液至细胞板中， 使终浓度从50μM或1μM到0.128nM或0.0026nM，37℃孵育72小时。加入2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2，4-二磺酸苯)-2H-四唑单钠盐溶液，即CCK-8溶液(购自上海前生生物科技有限公司，商品名称CCK-8试剂盒，商品号40203ES60)5μL，37℃孵育3小时。使用酶标仪读取荧光值。使用绘图软件Prism5.0(GraphPad Software)制作细胞增殖曲线图，计算化合物IC50。The cells were collected, and the cells were resuspended in 1640 medium containing 10% FBS (fetal calf serum) and the concentration was adjusted to 3 x 10 4 /mL. 50 μL/well of cell suspension was added to the cell plate. The test compound and the positive compound Ibrutinib were diluted 3-fold, and 5 μL of the compound solution was transferred to a cell plate to a final concentration of 50 μM or 1 μM to 0.128 nM or 0.0026 nM, and incubated at 37 ° C for 72 hours. Add 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonic acid benzene)-2H-tetrazole monosodium salt solution , that is, CCK-8 solution (purchased from Shanghai Qiansheng Biotechnology Co., Ltd., trade name CCK-8 kit, commercial number 40203ES60) 5 μL, and incubated at 37 ° C for 3 hours. The fluorescence value was read using a microplate reader. Using drawing software Prism5.0 (GraphPad Software) graph prepared cell proliferation, the compound is calculated IC 50.
细胞生长抑制率(％)＝1-{(AC-AX)/(AC-AB)}X 100Cell growth inhibition rate (%) = 1 - {(AC-AX) / (AC-AB)} X 100
AC：只添加二甲亚砜(对照)时的阴性对照吸光度值AC: negative control absorbance value when only dimethyl sulfoxide (control) was added
AX：添加受测试化合物孔的吸光度值AX: Add the absorbance value of the test compound well
AB：空白对照(blank)的吸光度值AB: Absorbance value of blank control (blank)
表4本发明代表性化合物对非霍奇金淋巴瘤细胞增殖的抑制作用Table 4 Inhibition of Proliferation of Non-Hodgkin's Lymphoma Cells by Representative Compounds of the Invention
序号Serial number 化合物Compound Romas IC50(M)Romas IC 50 (M) HBL-1IC50(M)HBL-1IC 50 (M) Daudi IC50(M)Daudi IC 50 (M)
11 依鲁替尼Ibrutinib 1.621.62 15.415.4 44
22 化合物1Compound 1 11.311.3 10.510.5 2020
33 化合物3Compound 3 2020 32.732.7 3232
44 化合物17Compound 17 0.690.69 1.451.45 0.510.51
55 化合物18Compound 18 4.904.90 1111 2020
66 化合物30Compound 30 6.346.34 0.220.22 3.803.80
77 化合物32Compound 32 88 5.575.57 1111
88 化合物33Compound 33 3.573.57 0.430.43 3.283.28
99 化合物44Compound 44 4.454.45 8.258.25 6262
1010 化合物45Compound 45 4.704.70 0.700.70 1.861.86
1111 化合物38Compound 38 0.470.47 0.600.60 2.102.10
1212 化合物39Compound 39 5.455.45 0.070.07 1.501.50
1313 化合物40Compound 40 6.806.80 0.140.14 3.803.80
1414 化合物51Compound 51 3030 7.67.6 12.1512.15
1515 化合物54Compound 54 0.650.65 0.790.79 0.800.80
1616 化合物63Compound 63 0.210.21 0.0050.005 0.250.25
1717 化合物64Compound 64 0.300.30 0.020.02 0.150.15
1818 化合物65Compound 65 1.031.03 1.251.25 10.1510.15
1919 化合物66Compound 66 0.650.65 0.790.79 0.800.80
2020 化合物67Compound 67 0.210.21 0.0050.005 0.250.25
21twenty one 化合物68Compound 68 0.300.30 0.020.02 0.150.15
22twenty two 化合物69Compound 69 1.031.03 1.251.25 10.1510.15
23twenty three 化合物70Compound 70 1.031.03 1.251.25 10.1510.15
24twenty four 化合物71Compound 71 1.031.03 1.251.25 10.1510.15
2525 化合物73Compound 73 0.650.65 0.790.79 0.800.80
表5table 5
Figure PCTCN2017072716-appb-000077
Figure PCTCN2017072716-appb-000077
以上的结果表明本发明的化合物对非霍奇金(Non-Hodgkin)淋巴瘤细胞增殖有明显的抑制作用，并且部分化合物活性明显优于依鲁替尼。The above results indicate that the compounds of the present invention have a significant inhibitory effect on the proliferation of non-Hodgkin lymphoma cells, and some of the compounds are significantly more active than ibrutinib.
实施例11Example 11
本发明化合物在II型胶原诱发小鼠关节炎模型中的药效学研究Pharmacodynamic study of compounds of the invention in type II collagen induced mouse arthritis model
胶原诱导性关节炎是具有种属特异性胶原II型免疫后所诱发的实验动物模型。因其遗传背景和免疫病理学改变与临床类风湿性关节炎极为相似而成为目前研究类风湿性关节炎较为理想的动物模型。Collagen-induced arthritis is an experimental animal model induced by species-specific collagen type II immunization. Because its genetic background and immunopathological changes are very similar to clinical rheumatoid arthritis, it is an ideal animal model for studying rheumatoid arthritis.
模型制作方法：DBA/1J小鼠，7周龄，体重18-22g，雄性，(购自济南奥诺生物工程有限公司，商品名称DBA/1J小鼠，型号：DBA/1J)。取适量牛II型胶原，溶于0.01mol/L乙酸中(4mg胶原/ml)，与等量完全弗氏佐剂在冰浴环境下充分乳化，每只小鼠以0.1ml(含胶原200μg)乳剂，于尾根部作皮内注射，第21天再用等量胶原经不完全弗氏佐剂乳化，加强免疫1次。Model making method: DBA/1J mice, 7 weeks old, weighing 18-22 g, male, (purchased from Jinan Ono Bioengineering Co., Ltd., trade name DBA/1J mice, model: DBA/1J). Take appropriate amount of bovine type II collagen, dissolved in 0.01mol/L acetic acid (4mg collagen/ml), fully emulsified with an equal amount of complete Freund's adjuvant in an ice bath environment, 0.1ml per mouse (including collagen 200μg) The emulsion was intradermally injected at the base of the tail. On the 21st day, the same amount of collagen was emulsified by incomplete Freund's adjuvant, and the immunization was boosted once.
材料和方法：受试化合物17、化合物63、化合物64以浓度200mg/ml溶于聚乙二醇400∶蓖麻油的乙氧基化物(KolliphorRH40)＝8∶2。(蓖麻油的乙氧基化物CAS号61788-85-0，购自德国巴斯夫公司)按25mg/kg的用药量每日一次经口服灌喂II型胶原诱发关节炎的DBA/1J小鼠。小鼠分为受试化合物17、化合物63、化合物64和溶媒四个组，其中溶媒组通过乙二醇400∶蓖麻油的乙氧基化物＝8∶2的比例，以100mg/kg的用药量每天一次向小鼠用 药，连续用药14天。Materials and Methods: Test compound 17, compound 63, and compound 64 were dissolved in polyethylene glycol 400: castor oil ethoxylate (Kolliphor RH40) = 8:2 at a concentration of 200 mg/ml. (The ethoxylate of castor oil CAS No. 61788-85-0, purchased from BASF, Germany) DBA/1J mice were induced by oral administration of type II collagen-induced arthritis once daily at a dose of 25 mg/kg. The mice were divided into four groups: test compound 17, compound 63, compound 64 and vehicle, wherein the solvent group was administered by the ratio of ethoxylate of ethylene glycol 400: castor oil = 8:2 to 100 mg/kg. Once a day to mice Drug, continuous medication for 14 days.
观测指标与分析：关节炎指数评分。按Wood氏的关节炎评分标准作关节炎指数评分。0分，正常；1分，红肿涉及1指个关节；2分，红肿涉及2个以上指关节或整个足爪轻度红肿；3分，足爪红肿较重；4分，足爪重度红肿，关节僵硬，缺乏弹性。4只足爪中每只爪的损害都分为0-4计算四肢的总积分，每组鼠发生关节炎的肢体数以百分率表示，并比较不同时间的积分(关节炎指数)，也同时记录关节炎的发病率和关节炎的起病时间。见图1，通过图1可见，随着用药时间增长，小鼠的关节炎情况均有所改善。Observation indicators and analysis: Arthritis index score. The arthritis index score was scored according to Wood's arthritis scoring criteria. 0 points, normal; 1 point, redness involves 1 finger joint; 2 points, redness involves more than 2 knuckles or the entire foot is slightly red and swollen; 3 points, the feet are red and swollen; 4 points, the feet are severely red and swollen, The joints are stiff and inelastic. The damage of each of the 4 paws was divided into 0-4 to calculate the total score of the limbs. The number of limbs in each group of rats with arthritis was expressed as a percentage, and the scores at different times (arthritis index) were also recorded. The incidence of arthritis and the onset of arthritis. As shown in Fig. 1, it can be seen from Fig. 1 that the arthritis condition of the mice is improved as the time of administration increases.
实施例12化合物对慢性白血病K562细胞的体外生长抑制作用Inhibitory effect of the compound of Example 12 on the growth of chronic leukemia K562 cells in vitro
慢性白血病K562细胞的体外CellTiter-
Figure PCTCN2017072716-appb-000078
ATP发光细胞活力检测In vitro CellTiter- of chronic leukemia K562 cells
Figure PCTCN2017072716-appb-000078
ATP luminescence cell viability assay
白血病K562细胞来自于ATCC，并维持在37℃，5％CO2气氛以及在杜尔贝科培养基(IMDM)和10％胎牛血清中。细胞以6*103个/孔的密度接种在96孔板上，将测试化合物溶于DMSO中，并以浓度为0μM、0.3μM、0.5μM、1μM、2μM、3μM、5μM、10μM、20μM、30μM、50μM和100μM作用于K562细胞72小时，然后用CellTiter-Glo发光法细胞活力检测试剂盒来检测被化合物作用后的细胞，并记录发光值。Leukemia K562 cells were derived from ATCC and maintained at 37 ° C in a 5% CO 2 atmosphere as well as in Dulbecco's medium (IMDM) and 10% fetal bovine serum. The cells were seeded at a density of 6*10 3 cells/well in 96-well plates, and the test compound was dissolved in DMSO at concentrations of 0 μM, 0.3 μM, 0.5 μM, 1 μM, 2 μM, 3 μM, 5 μM, 10 μM, 20 μM, K562 cells were treated with 30 μM, 50 μM and 100 μM for 72 hours, and then the cells treated with the compound were detected using the CellTiter-Glo luminescence cell viability assay kit, and luminescence values were recorded.
本发明部分化合物体外对白血病K562细胞活力影响结果列举在下表6中。The results of in vitro effects of some of the compounds of the present invention on leukemia K562 cell viability are listed in Table 6 below.
表6Table 6
Figure PCTCN2017072716-appb-000079
Figure PCTCN2017072716-appb-000079

Claims (38)

  1. 一种具有通式(I)所示的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物：A compound of the formula (I), a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or N- Oxide:
    Figure PCTCN2017072716-appb-100001
    Figure PCTCN2017072716-appb-100001
    其中：W为4-6元的含氮饱和杂环基、苯亚甲(C3-C6)环烷基或[3.3-5]含氮饱和杂螺环基；Wherein: W is a 4-6 membered nitrogen-containing saturated heterocyclic group, a benzylidene (C 3 -C 6 )cycloalkyl group or a [3.3-5] nitrogen-containing saturated heterospirocyclic group;
    R1或R2各自独立地选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基、(C1-C4)卤代烷氧基、苯基、取代苯基、苯(C2-C4)炔基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、取代苯(C1-C4)烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
    Figure PCTCN2017072716-appb-100002
    中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；取代苯基或取代含氮杂苯基上的取代基可各自独立地选自卤素、(C1-C4)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基、胺甲酰基、乙酰胺基和(C1-C4)卤代烷氧基中的一种或多种；    R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 ) Haloalkoxy, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, phenyl (C 1 -C 4 )alkyl, benzylidene (C 3 -C 6 )cycloalkyl, substituted benzene C 1 -C 4 )alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 - C 4 ) alkenyl, substituted benzene (C 2 -C 4 ) alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, nitrogen-containing Heterophenyl substituted (C 1 -C 4 ) alkoxy group and
    Figure PCTCN2017072716-appb-100002
    One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; a substituted phenyl group or a substituted nitrogen-containing heterophenyl group The substituents above may each independently be selected from the group consisting of halogen, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, carbamoyl, One or more of an acetamide group and a (C 1 -C 4 )haloalkoxy group;
    n＝0-4之间的任一个整数；Any integer between n=0-4;
    R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
  2. 根据权利要求1所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(II)所 示：A compound according to claim 1, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (II) Show:
    Figure PCTCN2017072716-appb-100003
    Figure PCTCN2017072716-appb-100003
    其中，W为4-6元的含氮饱和杂环基、苯亚甲(C3-C6)环烷基或[3.3-5]含氮饱和杂螺环基；Wherein W is a 4-6 membered nitrogen-containing saturated heterocyclic group, a benzylidene (C 3 -C 6 )cycloalkyl group or a [3.3-5] nitrogen-containing saturated heterospirocyclic group;
    R1或R2各自独立地选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基、(C1-C4)卤代烷氧基、苯基、取代苯基、苯(C2-C4)炔基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
    Figure PCTCN2017072716-appb-100004
    中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；    R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 ) Haloalkoxy, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, phenyl (C 1 -C 4 )alkyl, benzylidene (C 3 -C 6 )cycloalkyl, phenoxy a substituted phenoxyalkyl group, a benzene (C 1 -C 4 ) alkoxy group, a substituted benzene (C 1 -C 4 ) alkoxy group, a benzene (C 2 -C 4 ) alkenyl group, a substituted benzene group (C 2 - C 4 ) alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, nitrogen-containing heterophenyl substituted (C 1 -C 4 ) Alkoxy and
    Figure PCTCN2017072716-appb-100004
    One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group;
    n＝0-4之间的任一个整数；Any integer between n=0-4;
    R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
  3. 根据权利要求2所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(III)所示： A compound according to claim 2, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (III):
    Figure PCTCN2017072716-appb-100005
    Figure PCTCN2017072716-appb-100005
    其中，R1或R2各自独立地选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基、(C1-C4)卤代烷氧基、苯基、取代苯基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
    Figure PCTCN2017072716-appb-100006
    中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；    Wherein R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C) 4 ) haloalkoxy, phenyl, substituted phenyl, benzene (C 1 -C 4 )alkyl, benzylidene (C 3 -C 6 )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy group, benzene (C 2 -C 4 ) alkenyl group, substituted benzene (C 2 -C 4 ) alkenyl group, nitrogen-containing heterophenyl group, substituted nitrogen-containing heterophenyl group, nitrogen-containing hetero a phenyl-substituted (C 1 -C 4 )alkyl group, a nitrogen-containing heterophenyl-substituted (C 1 -C 4 ) alkoxy group, and
    Figure PCTCN2017072716-appb-100006
    One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group;
    n＝0-4之间的任一个整数；Any integer between n=0-4;
    R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
  4. 根据权利要求1或3所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(IV)所示：The compound according to claim 1 or 3, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide , as shown in formula (IV):
    Figure PCTCN2017072716-appb-100007
    Figure PCTCN2017072716-appb-100007
    其中，所述的R2选自苯基、取代苯基、苯(C1-C4)烷基、取代苯(C1-C4)烷基、取代苯(C1-C4)烷氧基、苯亚甲(C3-C6)环烷基、苯氧烷基、取代苯氧烷 基、苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
    Figure PCTCN2017072716-appb-100008
    中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；    Wherein R 2 is selected from the group consisting of phenyl, substituted phenyl, phenyl (C 1 -C 4 ) alkyl, substituted benzene (C 1 -C 4 ) alkyl, substituted benzene (C 1 -C 4 ) alkoxy a benzylidene (C 3 -C 6 )cycloalkyl group, a phenoxyalkyl group, a substituted phenoxyalkylene group, a benzene (C 1 -C 4 ) alkoxy group, a benzene (C 2 -C 4 )alkenyl group, Substituted benzene (C 2 -C 4 ) alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, nitrogen-containing heterophenyl substituted ( C 1 -C 4 ) alkoxy and
    Figure PCTCN2017072716-appb-100008
    One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group;
    n＝0-4之间的任一个整数；Any integer between n=0-4;
    R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
  5. 根据权利要求4所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(V)所示：A compound according to claim 4, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (V):
    Figure PCTCN2017072716-appb-100009
    Figure PCTCN2017072716-appb-100009
    其中，X、Y各自独立地选自CH或N，R4选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基、胺甲酰基、乙酰胺基和(C1-C4)卤代烷氧基中的一种。Wherein X and Y are each independently selected from CH or N, and R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 - C 4 ) one of a haloalkyl group, a carbamoyl group, an acetamide group, and a (C 1 -C 4 )haloalkoxy group.
  6. 根据权利要求5所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(VI)所示： A compound according to claim 5, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (VI):
    Figure PCTCN2017072716-appb-100010
    Figure PCTCN2017072716-appb-100010
    其中，R4选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基、胺甲酰基、乙酰胺基和(C1-C4)卤代烷氧基中的一种。Wherein R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, carbamoyl, acetamide One of a (C 1 -C 4 )haloalkoxy group.
  7. 根据权利要求5所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(VII)所示：A compound according to claim 5, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (VII):
    Figure PCTCN2017072716-appb-100011
    Figure PCTCN2017072716-appb-100011
    其中，R4选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基、胺甲酰基、乙酰胺基和(C1-C4)卤代烷氧基中的一种。Wherein R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, carbamoyl, acetamide One of a (C 1 -C 4 )haloalkoxy group.
  8. 根据权利要求5所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(VIII)所示： A compound according to claim 5, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (VIII):
    Figure PCTCN2017072716-appb-100012
    Figure PCTCN2017072716-appb-100012
    其中，R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
  9. 根据权利要求4所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(IX)所示：A compound according to claim 4, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (IX):
    Figure PCTCN2017072716-appb-100013
    Figure PCTCN2017072716-appb-100013
    其中，R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
  10. 根据权利要求4所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X) 所示：A compound according to claim 4, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (X) Shown as follows:
    Figure PCTCN2017072716-appb-100014
    Figure PCTCN2017072716-appb-100014
    其中，X、Y和Z各自独立地选自CH或N；R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或几种。Wherein X, Y and Z are each independently selected from CH or N; and R 5 and R 6 are each independently selected from H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl One or more of a cyano group, a (C 1 -C 4 )haloalkyl group, and a (C 1 -C 4 )haloalkoxy group.
  11. 根据权利要求1或3所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XI)所示：The compound according to claim 1 or 3, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide , as shown in formula (XI):
    Figure PCTCN2017072716-appb-100015
    Figure PCTCN2017072716-appb-100015
    其中，R1选自苯基、取代苯基、苯(C2-C4)炔基、苯(C1-C4)烷基、取代苯(C1-C4)烷基、取代苯(C1-C4)烷氧基、苯亚甲(C3-C6)环烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯 基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
    Figure PCTCN2017072716-appb-100016
    中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；    Wherein R 1 is selected from the group consisting of phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, phenyl (C 1 -C 4 )alkyl, substituted benzene (C 1 -C 4 )alkyl, substituted benzene ( C 1 -C 4 ) alkoxy, benzylidene (C 3 -C 6 )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 )alkenyl, substituted benzene (C 2 -C 4 )alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, a nitrogen-containing heterophenyl-substituted (C 1 -C 4 ) alkoxy group and
    Figure PCTCN2017072716-appb-100016
    One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group;
    R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
  12. 根据权利要求11所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XII)所示：The compound according to claim 11, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (XII):
    Figure PCTCN2017072716-appb-100017
    Figure PCTCN2017072716-appb-100017
    其中，X、Y各自独立地选自CH或N，R4选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基、胺甲酰基、乙酰胺基和(C1-C4)卤代烷氧基中的一种。Wherein X and Y are each independently selected from CH or N, and R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 - C 4 ) one of a haloalkyl group, a carbamoyl group, an acetamide group, and a (C 1 -C 4 )haloalkoxy group.
  13. 根据权利要求11所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XIII)所示： The compound according to claim 11, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (XIII):
    Figure PCTCN2017072716-appb-100018
    Figure PCTCN2017072716-appb-100018
    其中，R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
  14. 根据权利要求11所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XIV)所示：The compound according to claim 11, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as As shown in formula (XIV):
    Figure PCTCN2017072716-appb-100019
    Figure PCTCN2017072716-appb-100019
    其中，R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
  15. 根据权利要求11所述的化合物、其顺反异构体、顺反异构体的混合 物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XV)所示：The compound according to claim 11, a cis-trans isomer, a cis-trans isomer thereof a substance, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, as shown in formula (XV):
    Figure PCTCN2017072716-appb-100020
    Figure PCTCN2017072716-appb-100020
    其中，X、Y和Z各自独立地选自CH或N；R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein X, Y and Z are each independently selected from CH or N; and R 5 and R 6 are each independently selected from H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl One or more of a cyano group, a (C 1 -C 4 )haloalkyl group, and a (C 1 -C 4 )haloalkoxy group.
  16. 根据权利要求12所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XVI)所示：A compound according to claim 12, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (XVI):
    Figure PCTCN2017072716-appb-100021
    Figure PCTCN2017072716-appb-100021
    其中，R4选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基、胺甲酰基、乙酰胺基和(C1-C4)卤代烷氧基中的一种。Wherein R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, carbamoyl, acetamide One of a (C 1 -C 4 )haloalkoxy group.
  17. 根据权利要求12所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XVII)所示：A compound according to claim 12, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (XVII):
    Figure PCTCN2017072716-appb-100022
    Figure PCTCN2017072716-appb-100022
    其中，R4选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基、胺甲酰基、乙酰胺基和(C1-C4)卤代烷氧基中的一种。Wherein R 4 is selected from the group consisting of H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl, carbamoyl, acetamide One of a (C 1 -C 4 )haloalkoxy group.
  18. 根据权利要求1所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XVIII)所示：A compound according to claim 1, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (XVIII):
    Figure PCTCN2017072716-appb-100023
    Figure PCTCN2017072716-appb-100023
    其中，R1或R2各自独立地选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基、(C1-C4)卤代烷氧基、苯基、取代苯基、苯(C2-C4)炔基、苯(C1-C4)烷基、取代苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
    Figure PCTCN2017072716-appb-100024
    中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；    Wherein R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C) 4 ) haloalkoxy, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, benzene (C 1 -C 4 )alkyl, substituted benzene (C 1 -C 4 )alkyl, benzene methylene (C 3 -C 6 )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 )alkenyl, substituted benzene (C 2 -C 4 )alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, a nitrogen-containing heterophenyl-substituted (C 1 -C 4 ) alkoxy group and
    Figure PCTCN2017072716-appb-100024
    One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group;
    n＝0-4之间的任一个整数；Any integer between n=0-4;
    R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
  19. 根据权利要求18所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XIX)所示：The compound according to claim 18, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (XIX):
    Figure PCTCN2017072716-appb-100025
    Figure PCTCN2017072716-appb-100025
    其中，R2选自苯基、取代苯基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、取代苯(C1-C4)烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯氧烷基、取代苯氧烷基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
    Figure PCTCN2017072716-appb-100026
    中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取 代含氮杂苯基中的一种或几种；    Wherein R 2 is selected from the group consisting of phenyl, substituted phenyl, phenyl(C 1 -C 4 )alkyl, benzylidene(C 3 -C 6 )cycloalkyl, substituted benzene(C 1 -C 4 )alkyl, Benzene (C 1 -C 4 )alkoxy, substituted benzene (C 1 -C 4 )alkoxy, phenoxyalkyl, substituted phenoxyalkyl, phenyl(C 2 -C 4 )alkenyl, substituted benzene C 2 -C 4 )alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, nitrogen-containing heterophenyl substituted (C 1 - C 4 ) alkoxy and
    Figure PCTCN2017072716-appb-100026
    One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group;
    R1选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基或(C1-C4)卤代烷氧基；R 1 is selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl or (C 1 -C 4 )haloalkoxy;
    R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
  20. 据权利要求19所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XX)所示：A compound according to claim 19, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as As shown in formula (XX):
    Figure PCTCN2017072716-appb-100027
    Figure PCTCN2017072716-appb-100027
    其中，R2选自苯基、取代苯基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、取代苯(C1-C4)烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯氧烷基、取代苯氧烷基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
    Figure PCTCN2017072716-appb-100028
    中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；    Wherein R 2 is selected from the group consisting of phenyl, substituted phenyl, phenyl(C 1 -C 4 )alkyl, benzylidene(C 3 -C 6 )cycloalkyl, substituted benzene(C 1 -C 4 )alkyl, Benzene (C 1 -C 4 )alkoxy, substituted benzene (C 1 -C 4 )alkoxy, phenoxyalkyl, substituted phenoxyalkyl, phenyl(C 2 -C 4 )alkenyl, substituted benzene C 2 -C 4 )alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, nitrogen-containing heterophenyl substituted (C 1 - C 4 ) alkoxy and
    Figure PCTCN2017072716-appb-100028
    One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group;
    R3选自(C2-C4)烯基、(C2-C4)炔基、胺丙烯基、N，N-二取代胺丙烯基和(C4-C7)含氮饱和杂环取代的丙烯基中的一种或几种，其中所述的取代胺上的取代基包括(C1-C4)烷基和羟基中的一种或几种。R 3 is selected from (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C 4 -C 7 ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C 1 -C 4 )alkyl group and a hydroxyl group.
  21. 根据权利要求20所述的化合物、其顺反异构体、顺反异构体的混合 物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XXI)所示：A compound according to claim 20, a cis-trans isomer thereof, a cis-trans isomer mixture thereof a substance, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, as shown in formula (XXI):
    Figure PCTCN2017072716-appb-100029
    Figure PCTCN2017072716-appb-100029
    其中，R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
  22. 根据权利要求14所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(X XII)所示The compound according to claim 14, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as Formula (X XII)
    Figure PCTCN2017072716-appb-100030
    Figure PCTCN2017072716-appb-100030
    其中，R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。 Wherein R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
  23. 根据权利要求18所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XXIII)所示：The compound according to claim 18, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as As shown in formula (XXIII):
    Figure PCTCN2017072716-appb-100031
    Figure PCTCN2017072716-appb-100031
    其中，R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或多种。Wherein R 5 and R 6 are each independently selected from the group consisting of H, halogen, (C 1 -C 3 ) alkoxy, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )haloalkyl and One or more of (C 1 -C 4 )haloalkoxy groups.
  24. 根据权利要求18所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，如式(XXIV)所示： The compound according to claim 18, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as As shown in formula (XXIV):
    Figure PCTCN2017072716-appb-100032
    Figure PCTCN2017072716-appb-100032
    其中，X、Y和Z各自独立地选自CH或N；R5、R6各自独立地选自H、卤素、(C1-C3)烷氧基、(C1-C4)烷基、氰基、(C1-C4)卤代烷基和(C1-C4)卤代烷氧基中的一种或几种。Wherein X, Y and Z are each independently selected from CH or N; and R 5 and R 6 are each independently selected from H, halogen, (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkyl One or more of a cyano group, a (C 1 -C 4 )haloalkyl group, and a (C 1 -C 4 )haloalkoxy group.
  25. 根据权利要求1-24中任一项所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物，其中所述的化合物选自如下化合物中的一种或几种：A compound according to any one of claims 1 to 24, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or An N-oxide wherein the compound is selected from one or more of the following compounds:
    1-(3-(4-氨基-3-(5-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)piperidin-1- Propyl-2-en-1-one;
    1-(3-(4-氨基-3-(5-苯基噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(5-phenylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)propane- 2-en-1-one;
    1-(3-(4-氨基-3-(4-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(4-(phenoxymethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- Propyl-2-en-1-one;
    1-(3-(4-氨基-3-(5-甲基-4-(苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(5-methyl-4-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
    1-(3-(4-氨基-3-(5-(苯氧甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(5-(phenoxymethyl)thiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- Propyl-2-en-1-one;
    1-(3-(4-氨基-3-(4-((2-甲基)苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1- 基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(4-((2-methyl)phenoxymethyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
    1-(3-(4-氨基-3-(4-((间-甲基)苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(4-((m-methyl)phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
    1-(3-(4-氨基-3-(4-((对-甲基)苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(4-((p-methyl)phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
    1-(3-(4-氨基-3-(4-((2-甲氧基)苯氧基甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(4-((2-methoxy)phenoxymethyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidine-1 -yl)piperidin-1-yl)prop-2-en-1-one;
    1-(3-(4-氨基-3-(4-((3-甲氧基)苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(4-((3-methoxy)phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
    1-(3-(4-氨基-3-(4-((4-甲氧基)苯氧甲基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(4-(4-methoxy)phenoxymethyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
    1-(3-(4-氨基-3-(2-((2-氰基)苯氧甲基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(2-((2-cyano)phenoxymethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
    1-(3-(4-氨基-3-(2-((4-氰基)苯氧甲基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(2-(4-cyano)phenoxymethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
    1-(3-(4-氨基-3-(2-((3-氰基)苯氧甲基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(2-((3-cyano)phenoxymethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
    1-(3-(4-氨基-3-(2-(2-甲氧基苯)氧甲基噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(2-(2-methoxyphenyl)oxymethylthiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
    1-(3-(4-氨基-3-(2-(3-甲氧基苯)氧甲基噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(2-(3-methoxyphenyl)oxymethylthiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-苯噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-phenylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl )prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(苯氧甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(phenoxymethyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)piperidin Pyridin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-((嘧啶-4-基氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((pyrimidin-4-yloxy)methyl)thiophen-3-yl)-1H-pyrazole [3,4-d] Pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;
    1-(3-(4-氨基-3-(5-((2-甲氧基-4-甲基苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(5-((2-methoxy-4-methylphenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3,4- d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;
    1-(3-(4-氨基-3-(5-((2-甲氧基-4-氯苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d] 嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；1-(3-(4-Amino-3-(5-((2-methoxy-4-chlorophenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3,4-d ] Pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-((2-甲氧基-4-氰基苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((2-methoxy-4-cyanophenoxy)methyl)thiophen-3-yl)-1H-pyrazole [ 3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-((2-氯-5-甲氧基苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((2-chloro-5-methoxyphenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3 , 4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-((3-氯-5-甲氧基苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((3-chloro-5-methoxyphenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3 , 4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-((3-甲氧基-4-氰基苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((3-methoxy-4-cyanophenoxy)methyl)thiophen-3-yl)-1H-pyrazole [ 3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(2-甲基苯氧甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(2-methylphenoxymethyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidine-1 -yl)piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(4-甲苯氧基甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(4-methyloxymethyl)thiophen-3-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(3-甲基苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3-methylphenyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(3，4-二甲基苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3,4-dimethylphenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidine- 1-yl)piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(3-甲氧基苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3-methoxyphenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(4-甲氧基苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(4-methoxyphenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(4-苯基噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(4-phenylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- Propyl-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-苯基噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-phenylthiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- Propyl-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(4-三氟甲基苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(4-trifluoromethylphenyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidine-1 -yl)piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(3-三氟甲苯)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3-trifluorotoluene)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(3，5-二甲苯)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌 啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3,5-dimethylphenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl Piper Pyridin-1-yl)prop-2-en-1-one;
    (S)-1-(3-(4-氨基-3-(5-苯基噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(S)-1-(3-(4-Amino-3-(5-phenylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1- Propyl-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(2-氟苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(2-fluorophenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(3-氟苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3-fluorophenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(4-氟苯基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(4-fluorophenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(2-(3-甲基苯基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(2-(3-methylphenyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(2-(4-甲氧基苯基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(2-(4-methoxyphenyl)thiophen-4-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(3-甲氧基苯基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3-methoxyphenyl)thiophen-3-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-((2-氟苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((2-fluorophenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3,4-d]pyrimidine -1-yl)piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-((3-氟苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((3-fluorophenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3,4-d]pyrimidine -1-yl)piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-((4-氟苯氧基)甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-((4-fluorophenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3,4-d]pyrimidine -1-yl)piperidin-1-yl)prop-2-en-1-one;
    (S)-1-(3-(4-氨基-3-(5-(苯氧基甲基)噻吩-3-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(S)-1-(3-(4-Amino-3-(5-(phenoxymethyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(2-(苯乙基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(2-(phenylethyl)thiophen-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine -1-yl)prop-2-en-1-one;
    (R)反-1-(3-(4-氨基-3-(2-苯乙烯噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R) trans-1-(3-(4-amino-3-(2-styrenethiophen-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -yl)prop-2-en-1-one;
    1-(3-(1-(4-氨基-3-(2-(3-甲基苯)氧甲基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮1-(3-(1-(4-Amino-3-(2-(3-methylphenyl)oxymethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidine-1 -yl)piperidin-1-yl)prop-2-en-1-one
    (R)-1-(3-(4-氨基-3-(5-(2-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶 -1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(2-pyridylcarbamoyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidine -1-yl)piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(3-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(3-pyridylcarbamoyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(4-吡啶胺甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(4-pyridylcarbamoyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(苯胺基甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(anilinoyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)piperidin Pyridin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(2-(2-吡啶胺基甲酰基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(2-(2-pyridylaminocarbonyl)thiophen-4-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(2-(3-吡啶胺基甲酰基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(2-(3-pyridylaminocarbonyl)thiophen-4-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(2-(4-吡啶胺基甲酰基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(2-(4-pyridylaminocarbonyl)thiophen-4-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(2-(苯胺基甲酰基)噻吩-4-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(2-(anilinoyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)piperidin Pyridin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(4-(2-吡啶胺基甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(4-(2-pyridylaminocarbonyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(4-(3-吡啶胺基甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(4-(3-pyridylaminocarbonyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(4-(4-吡啶胺基甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(4-(4-pyridylaminocarbonyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1- Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(4-(苯胺基甲酰基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(4-(anilinoyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)piperidin Pyridin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(吡啶-2-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(pyridin-2-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(吡啶-3-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(pyridin-3-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(4-(吡啶-2-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(4-(pyridin-2-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(4-(吡啶-3-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌 啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(4-(pyridin-3-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piper Pyridin-1-yl)prop-2-en-1-one;
    (S)-1-(3-(4-氨基-3-(5-(吡啶-2-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(S)-1-(3-(4-Amino-3-(5-(pyridin-2-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(6-氰基吡啶-2-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(6-cyanopyridin-2-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidine- 1-yl)piperidin-1-yl)prop-2-en-1-one;
    (R)-6-(5-(1-(1-丙烯酰哌啶-3-基)-4-氨基-1H-吡唑[3，4-d]嘧啶-3-基)噻吩-2-基)-吡啶酰胺；(R)-6-(5-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene-2- Base)-pyridine amide
    (R)-6-(5-(1-(1-丙烯酰哌啶-3-基)-4-氨基-1H-吡唑[3，4-d]嘧啶-3-基)噻吩-2-基)-3-吡啶甲酰胺；(R)-6-(5-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene-2- Base)-3-pyridinecarboxamide;
    (R)-N-(6-(5-(1-(1-丙烯酰哌啶-3-基)-4-氨基-1H-吡唑[3，4-d]嘧啶-3-基)噻吩-2-基)吡啶-2-基)乙酰胺；(R)-N-(6-(5-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene -2-yl)pyridin-2-yl)acetamide;
    (R)-N-(6-(5-(1-(1-丙烯酰哌啶-3-基)-4-氨基-1H-吡唑[3，4-d]嘧啶-3-基)噻吩-2-基)吡啶-3-基)乙酰胺；(R)-N-(6-(5-(1-(1-acryloylpiperidin-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene -2-yl)pyridin-3-yl)acetamide;
    (R)-1-(3-(4-氨基-3-(5-(6-甲基吡啶-2-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮；(R)-1-(3-(4-Amino-3-(5-(6-methylpyridin-2-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidine- 1-yl)piperidin-1-yl)prop-2-en-1-one;
    (R)-1-(3-(4-氨基-3-(5-(5-甲基吡啶-2-基)噻吩-2-基)-1H-吡唑[3，4-d]嘧啶-1-基)哌啶-1-基)丙-2-烯-1-酮。(R)-1-(3-(4-Amino-3-(5-(5-methylpyridin-2-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidine- 1-yl)piperidin-1-yl)prop-2-en-1-one.
  26. 一种如下式(XXV)所示的化合物或该化合物的盐，a compound represented by the following formula (XXV) or a salt of the compound,
    Figure PCTCN2017072716-appb-100033
    Figure PCTCN2017072716-appb-100033
    其中，R1或R2各自独立地选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基、(C1-C4)卤代烷氧基、苯基、取代苯基、苯(C2-C4)炔基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、取代苯(C1-C4)烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯 基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
    Figure PCTCN2017072716-appb-100034
    中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；R7选自H或者
    Figure PCTCN2017072716-appb-100035
    其中R3选自三氟甲基、叔丁氧基和苄氧基中的一种；当R7为H时，式(XXV)化合物的盐可以为盐酸盐、硫酸盐、乙酸盐和三氟乙酸盐中的一种。    Wherein R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C) 4 ) haloalkoxy, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, benzene (C 1 -C 4 )alkyl, benzyl (C 3 -C 6 )cycloalkyl, substituted Benzene (C 1 -C 4 )alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 )alkenyl, substituted benzene (C 2 -C 4 ) alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, a nitrogen-containing heterophenyl-substituted (C 1 -C 4 ) alkoxy group and
    Figure PCTCN2017072716-appb-100034
    One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R 7 is selected from H or
    Figure PCTCN2017072716-appb-100035
    Wherein R 3 is selected from the group consisting of trifluoromethyl, tert-butoxy and benzyloxy; when R 7 is H, the salt of the compound of formula (XXV) may be hydrochloride, sulfate, acetate and One of the trifluoroacetate salts.
  27. 根据权利要求26所示的化合物，其中所述化合物如下所示：A compound according to claim 26, wherein said compound is as follows:
    Figure PCTCN2017072716-appb-100036
    Figure PCTCN2017072716-appb-100036
    其中，R1或R2各自独立地选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基、(C1-C4)卤代烷氧基、苯基、取代苯基、苯(C2-C4)炔基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、取代苯(C1-C4)烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
    Figure PCTCN2017072716-appb-100037
    中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；R7选自H或者
    Figure PCTCN2017072716-appb-100038
    其中R3选自三氟甲基，叔丁氧基和苄氧基中的一种；当R7为H时，式(XXVI)化合物的盐可以为盐酸盐、硫酸盐、乙酸盐和三氟乙酸盐中的一种。     Wherein R 1 or R 2 are each independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C) 4 ) haloalkoxy, phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, benzene (C 1 -C 4 )alkyl, benzyl (C 3 -C 6 )cycloalkyl, substituted Benzene (C 1 -C 4 )alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 )alkenyl, substituted benzene (C 2 -C 4 )alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl, a nitrogen-containing heterophenyl-substituted (C 1 -C 4 ) alkoxy group and
    Figure PCTCN2017072716-appb-100037
    One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R 7 is selected from H or
    Figure PCTCN2017072716-appb-100038
    Wherein R 3 is selected from the group consisting of trifluoromethyl, tert-butoxy and benzyloxy; when R 7 is H, the salt of the compound of formula (XXVI) may be hydrochloride, sulfate, acetate and One of the trifluoroacetate salts.
  28. 根据权利要求26所示的化合物，其中所述化合物如下所示：A compound according to claim 26, wherein said compound is as follows:
    Figure PCTCN2017072716-appb-100039
    Figure PCTCN2017072716-appb-100039
    其中，R1选自H、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)卤代烷基、(C1-C4)卤代烷氧基、苯基、取代苯基、苯(C2-C4)炔基、苯(C1-C4)烷基、苯亚甲(C3-C6)环烷基、取代苯(C1-C4)烷基、苯氧烷基、取代苯氧烷基、苯(C1-C4)烷氧基、取代苯(C1-C4)烷氧基、苯(C2-C4)烯基、取代苯(C2-C4)烯基、含氮杂苯基、取代含氮杂苯基、含氮杂苯基取代的(C1-C4)烷基、含氮杂苯基取代的(C1-C4)烷氧基和
    Figure PCTCN2017072716-appb-100040
    中的一种或几种；其中R”选自苯基、取代苯基、含氮杂苯基和取代含氮杂苯基中的一种或几种；R7选自H或者
    Figure PCTCN2017072716-appb-100041
    其中R3选自三氟甲基、叔丁氧基和苄氧基中的一种；当R7为H时，式(XXVII)化合物的盐可以为其盐酸盐、硫酸盐、乙酸盐和三氟乙酸盐中的一种。    Wherein R 1 is selected from the group consisting of H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy, Phenyl, substituted phenyl, benzene (C 2 -C 4 ) alkynyl, benzene (C 1 -C 4 )alkyl, benzylidene (C 3 -C 6 )cycloalkyl, substituted benzene (C 1 -C 4 ) alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C 1 -C 4 ) alkoxy, substituted benzene (C 1 -C 4 ) alkoxy, benzene (C 2 -C 4 ) olefin a substituted benzene (C 2 -C 4 )alkenyl group, a nitrogen-containing heterophenyl group, a substituted nitrogen-containing heterophenyl group, a nitrogen-containing heterophenyl-substituted (C 1 -C 4 )alkyl group, a nitrogen-containing heterophenyl group substituted (C 1 -C 4 ) alkoxy group and
    Figure PCTCN2017072716-appb-100040
    One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R 7 is selected from H or
    Figure PCTCN2017072716-appb-100041
    Wherein R 3 is selected from the group consisting of trifluoromethyl, tert-butoxy and benzyloxy; when R 7 is H, the salt of the compound of formula (XXVII) may be the hydrochloride, sulfate or acetate thereof. And one of the trifluoroacetate salts.
  29. 一种如下式(XXVIII)所示的化合物，其中所述的化合物如下所示：A compound of the formula (XXVIII) wherein the compound is as follows:
    Figure PCTCN2017072716-appb-100042
    Figure PCTCN2017072716-appb-100042
    其中，R8选自H、Br或者硼酸基，R9选自H、甲基、氰基、胺甲酰基或者乙酰胺基。Wherein R 8 is selected from H, Br or a boronic acid group, and R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido.
  30. 根据权利要求29所述的化合物，其中所述的化合物如下式(XXIX)所示： The compound according to claim 29, wherein said compound is represented by the following formula (XXIX):
    Figure PCTCN2017072716-appb-100043
    Figure PCTCN2017072716-appb-100043
    其中，R8选自H、Br或者硼酸基，R9选自H、甲基、氰基、胺甲酰基或者乙酰胺基。Wherein R 8 is selected from H, Br or a boronic acid group, and R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido.
  31. 根据权利要求29所述的化合物，其中所述的化合物如下式(XXX)所示：The compound according to claim 29, wherein said compound is represented by the following formula (XXX):
    Figure PCTCN2017072716-appb-100044
    Figure PCTCN2017072716-appb-100044
    其中，R8选自H、Br或者硼酸基，R9选自H、甲基、氰基、胺甲酰基或者乙酰胺基。Wherein R 8 is selected from H, Br or a boronic acid group, and R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido.
  32. 根据权利要求29所述的化合物，其中所述的化合物如下式(XXXI)所示：The compound according to claim 29, wherein said compound is represented by the following formula (XXXI):
    Figure PCTCN2017072716-appb-100045
    Figure PCTCN2017072716-appb-100045
    其中，R8选自H、Br或者硼酸基，R9选自H、甲基、氰基、胺甲酰基或者乙酰胺基。Wherein R 8 is selected from H, Br or a boronic acid group, and R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido.
  33. 根据权利要求29所述的化合物，其中所述的化合物如下式(XXXII)所示： The compound according to claim 29, wherein said compound is represented by the following formula (XXXII):
    Figure PCTCN2017072716-appb-100046
    Figure PCTCN2017072716-appb-100046
    其中，R8选自H、Br或者硼酸基，R9选自H、甲基、氰基、胺甲酰基或者乙酰胺基。Wherein R 8 is selected from H, Br or a boronic acid group, and R 9 is selected from the group consisting of H, methyl, cyano, carbamoyl or acetamido.
  34. 权利要求1-25中任一项所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物在制备用于治疗与包括恶性肿瘤、自身免疫性疾病和过敏性疾病相关药物中的用途。A compound according to any one of claims 1 to 25, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or a N - Use of an oxide for the preparation of a medicament for the treatment of diseases involving malignant tumors, autoimmune diseases and allergic diseases.
  35. 根据权利要求34所述的用途，其中所述的恶性肿瘤包括淋巴瘤、浆细胞瘤和白血病中的一种或几种。The use according to claim 34, wherein said malignant tumor comprises one or more of lymphoma, plasmacytoma and leukemia.
  36. 根据权利要求36所述的用途，其中所述的淋巴瘤包括非霍奇金淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、小淋巴细胞淋巴瘤、外套细胞淋巴瘤、血管内大细胞型B细胞淋巴瘤、伯基特淋巴瘤、艾滋病相关性淋巴瘤和边缘区B细胞淋巴瘤中的一种或几种；优选地，所述的非霍奇金淋巴瘤包括B细胞性非霍奇金淋巴瘤；更优选地，所述的B细胞性非霍奇金淋巴瘤包括弥漫性大B细胞淋巴瘤和人体B淋巴细胞瘤中的一种或几种。The use according to claim 36, wherein said lymphoma comprises non-Hodgkin's lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, intravascular large cell type One or more of B cell lymphoma, Burkitt's lymphoma, AIDS-associated lymphoma, and marginal zone B-cell lymphoma; preferably, the non-Hodgkin's lymphoma includes B-cell non-Hodge More preferably, the B-cell non-Hodgkin's lymphoma comprises one or more of diffuse large B-cell lymphoma and human B-lymphoma.
  37. 根据权利要求34所述的用途，其中所述的自身免疫性疾病包括关节炎、风湿、炎性肠炎和红斑狼疮中的一种或几种。The use according to claim 34, wherein the autoimmune disease comprises one or more of arthritis, rheumatism, inflammatory bowel disease and lupus erythematosus.
  38. 一种布鲁顿酪氨酸激酶抑制剂组合物，其中包括本发明权利要求1-25中任一项所述的化合物、其顺反异构体、顺反异构体的混合物、光学对映异构体、对映异构体的混合物、外消旋体或N-氧化物。 A Bruton tyrosine kinase inhibitor composition comprising a compound according to any one of claims 1 to 25 of the present invention, a cis-trans isomer thereof, a mixture of cis-trans isomers, and an optical alignment Isomer, mixture of enantiomers, racemate or N-oxide.
PCT/CN2017/072716 2016-02-05 2017-01-26 Inhibitor of bruton's tyrosine kinase WO2017133630A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101610676A (en) * 2006-09-22 2009-12-23 药品循环公司 The inhibitor of bruton's tyrosine kinase
CN103319488A (en) * 2007-03-28 2013-09-25 环状药物公司 Inhibitors of bruton's tyrosine kinase
CN103857396A (en) * 2011-07-13 2014-06-11 药品循环公司 Inhibitors of bruton's tyrosine kinase
WO2014188173A1 (en) * 2013-05-20 2014-11-27 Redx Pharma Limited Pyrazolopyrimidine derivatives useful as inhibitors of bruton's tyrosine kinase
WO2015048689A1 (en) * 2013-09-30 2015-04-02 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101610676A (en) * 2006-09-22 2009-12-23 药品循环公司 The inhibitor of bruton's tyrosine kinase
CN103319488A (en) * 2007-03-28 2013-09-25 环状药物公司 Inhibitors of bruton's tyrosine kinase
CN103857396A (en) * 2011-07-13 2014-06-11 药品循环公司 Inhibitors of bruton's tyrosine kinase
WO2014188173A1 (en) * 2013-05-20 2014-11-27 Redx Pharma Limited Pyrazolopyrimidine derivatives useful as inhibitors of bruton's tyrosine kinase
WO2015048689A1 (en) * 2013-09-30 2015-04-02 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase

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