WO2017133630A1 - Inhibiteur de la tyrosine kinase de bruton - Google Patents

Inhibiteur de la tyrosine kinase de bruton 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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English (en)
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/zh
Publication of WO2017133630A1 publication Critical patent/WO2017133630A1/fr

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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

La présente invention concerne un inhibiteur de la tyrosine kinase de Bruton. Une structure de l'inhibiteur est représentée par la formule (I). L'inhibiteur a un bon effet inhibiteur sélectif.
PCT/CN2017/072716 2016-02-05 2017-01-26 Inhibiteur de la tyrosine kinase de bruton WO2017133630A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101610676A (zh) * 2006-09-22 2009-12-23 药品循环公司 布鲁顿酪氨酸激酶的抑制剂
CN103319488A (zh) * 2007-03-28 2013-09-25 环状药物公司 布鲁顿氏酪氨酸激酶抑制剂
CN103857396A (zh) * 2011-07-13 2014-06-11 药品循环公司 布鲁顿酪氨酸激酶抑制剂
WO2014188173A1 (fr) * 2013-05-20 2014-11-27 Redx Pharma Limited Dérivés pyrazolopyrimidine utiles comme inhibiteurs de la tyrosine kinase de bruton
WO2015048689A1 (fr) * 2013-09-30 2015-04-02 Pharmacyclics, Inc. Inhibiteurs de la tyrosine kinase de bruton

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101610676A (zh) * 2006-09-22 2009-12-23 药品循环公司 布鲁顿酪氨酸激酶的抑制剂
CN103319488A (zh) * 2007-03-28 2013-09-25 环状药物公司 布鲁顿氏酪氨酸激酶抑制剂
CN103857396A (zh) * 2011-07-13 2014-06-11 药品循环公司 布鲁顿酪氨酸激酶抑制剂
WO2014188173A1 (fr) * 2013-05-20 2014-11-27 Redx Pharma Limited Dérivés pyrazolopyrimidine utiles comme inhibiteurs de la tyrosine kinase de bruton
WO2015048689A1 (fr) * 2013-09-30 2015-04-02 Pharmacyclics, Inc. Inhibiteurs de la tyrosine kinase de bruton

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