WO2017020428A1 - Nouveaux composés destinés à être utilisés en tant qu'inhibiteurs de jak - Google Patents

Nouveaux composés destinés à être utilisés en tant qu'inhibiteurs de jak Download PDF

Info

Publication number
WO2017020428A1
WO2017020428A1 PCT/CN2015/091451 CN2015091451W WO2017020428A1 WO 2017020428 A1 WO2017020428 A1 WO 2017020428A1 CN 2015091451 W CN2015091451 W CN 2015091451W WO 2017020428 A1 WO2017020428 A1 WO 2017020428A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
ylamino
inventive example
fluoro
Prior art date
Application number
PCT/CN2015/091451
Other languages
English (en)
Chinese (zh)
Inventor
陈亦林
彭红
钱进
陶琳
赵岩
张晓丽
赵银鹰
邹阳
Original Assignee
南昌弘益科技有限公司
南昌弘益药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南昌弘益科技有限公司, 南昌弘益药业有限公司 filed Critical 南昌弘益科技有限公司
Publication of WO2017020428A1 publication Critical patent/WO2017020428A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems

Definitions

  • the present invention relates to a novel class of compounds which are JAK inhibitors, including pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, which are useful for modulating cellular activity such as signaling by modulating protein kinase activity. Transduction, proliferation and secretion of cytokines.
  • the present invention relates to a pharmaceutical composition comprising the compound, which is useful for preventing or treating a JAK inhibitor of a Janus kinase (JAK)-related disease, and can be used as a Janus kinase (JAK) inhibitor in medicine, pharmacy, biology, Physiology, biochemistry and other experiments.
  • the JAK-related diseases include inflammatory diseases, autoimmune diseases, proliferative diseases, proliferative diseases, and the like.
  • Protein kinases are a group of enzymes that regulate a variety of important biological processes, including, inter alia, cellular kinases that catalyze the phosphorylation of proteins, lipids, sugars, nucleosides, and other cellular metabolites in physiology of eukaryotic cells. All aspects play a key role. In particular, protein kinases and lipid kinases are involved in signaling events that control the activation, growth, differentiation and survival of cells that respond to extracellular regulators or stimuli such as growth factors, cytokines or chemokines.
  • JAK Janus kinase
  • SH2 Src homology 2 domain
  • JAK homology domains JH
  • JH1 domain is a kinase domain and functions to encode a kinase protein
  • JH2 domain is a "pseudo" kinase domain that regulates the activity of JH1.
  • Role; JH3-JH7 constitutes a four-in-one domain that regulates the binding of JAK to the receptor.
  • JAK3 points It is distributed in the bone marrow and lymphatic system, while JAK1, JAK2, and TYK2 are widely distributed in various tissue cells. JAK kinase is involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation.
  • STAT Signal transducers and activator of transcription
  • STATs The signal transduction and transcriptional activation (STATs) protein family includes seven members including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6.
  • the interaction between JAKs and STATs plays an important role in the cytokine receptor signaling pathway (O'SULLIVAN LA, LIONGUE C, LEWIS RS, et al. Cytokine receptor signaling through the Jak Stat pathway in disease [J]. MolImmunol , 2007, 44 ⁇ 10): 2497-2506.).
  • cytokine When a cytokine binds to a specific receptor on its target cell, it activates JAK, which in turn catalyzes the phosphorylation of the tyrosine residue on the receptor and forms a corresponding "parking site for STAT binding to the receptor complex. "(docking site).” Finally, JAK kinase catalyzes the phosphorylation of STAT protein. The activated STAT forms a homologous or heterodimer and then binds to a specific target gene in the human nucleus to regulate the expression of the target protein (LVASHKIV LB, HU XY. Signaling by STATs [J].
  • JAK/STAT signaling pathway Abnormal activation of JAK/STAT signal transduction pathway is closely related to the occurrence, development and prognosis of various diseases such as tumor and leukemia.
  • JAK/STAT signaling pathway is a newly discovered intracellular signal transduction pathway closely related to cytokines in recent years. It is involved in many important physiological processes such as cell proliferation, differentiation, apoptosis and immune regulation, and immune response and immunity to the body. Cell differentiation and inflammatory response have important effects, and play an important role in the occurrence and development of tumors, inflammation and various autoimmune diseases. Abnormal activation of the JAK/STAT signaling pathway is closely related to multiple tumorigenesis and development.
  • the JAK/STAT signaling pathway is a signal transduction pathway stimulated by a variety of cytokine receptors, including interleukins (eg IL-2-7, IL-9, IL-10, IL-15, IL-21, etc.). ), Interferons (including IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , etc.), erythropoietin (EPO), granulocyte and macrophage colony-stimulating factor (GM-CSF), somatotropin (GH), prolactin (PRL), thrombopoietin (TPO), platelet-derived factor (PDGF), and epidermal growth factor (EGF), which play a key role in biological processes such as immune regulation and immune cell proliferation (GHORESCHI K, LAURENCE A, O'SHEA JJ. Janus kinases in immune cell signaling [J]. Immunol Rev, 2009, 228(1): 273-287.). Different receptors activate JAK kinases of different subtypes to express
  • JAK1 knockout experiments on mouse models indicate that this enzyme plays a key role in regulating the biological effects of the various cytokine receptors described above (KISSELEVA T, BHATTACHARYA S, BRAUNSTEIN J, et al. Signaling through the JAK/ STAT pathway, recent advances and future challenges [J]. Gene, 2002, 285(1-2): 1-24.).
  • JAK2 in a mouse model can lead to animal death caused by anemia (SCHINDLER C, LEVY DE, DECKER T. JAK-STAT signaling: from interferons to cytokines [J]. J Biol Chem, 2007, 282(28): 20059 -20063.).
  • a base mutation in JAK2 gene in human body JAK2V617F which is associated with polycythemia (PV), idiopathic thrombocytosis (ET), idiopathic myelofibrosis (IMF), chronic in myeloproliferative diseases
  • PV polycythemia
  • ET idiopathic thrombocytosis
  • IMF idiopathic myelofibrosis
  • CML granulocyte leukemia
  • JAK2 inhibitors have been described for use in myeloproliferative disorders (Santos et al, Blood, 2010, 115: 1131; Barosi G. and Rosti V., Curr. Opin. Hematol., 2009, 16: 129; Atallah E. and Versotvsek S., 2009 Exp. Rev. Anticancer Ther. 9: 663).
  • JAK3 defects are first recognized in people with autosomal recessive severe combined immunodeficiency (SCID) (Macchi et al, 1995. Nature 377 (6544): 65-68). JAK3 knockout mice are also The SCID is shown but does not show non-immune defects, indicating that the JAK3 inhibitor as an immunosuppressive agent will have a relevant effect in vivo and thus become a promising drug for immunosuppression (Papageorgiou and Wikman 2004, Trends in Pharmacological Sciences 25(11): 558 -62). Inhibitors of the tyrosine kinase JAK3 have been described as useful as immunosuppressive agents (e.g., U.S. Patent No. 6,313,129; Borrie et al., Curr. Opin. Investigational Drugs, 2003, 4:1297).
  • TYK2 is the first member of the JAK family and is activated by a variety of receptors such as IF-Ns, IL-10, IL-6, IL-12, IL-23, IL-27.
  • IF-Ns IF-Ns
  • IL-10 IL-10
  • IL-6 IL-12
  • IL-23 IL-27
  • loss of TYK2 function causes defects in the signaling pathways of various cytokine receptors, leading to viral infection, decreased immune function, and increased likelihood of pulmonary infection (KISSELEVA T, BHATTACHARYA S, BRAUNSTEIN J , et al. Signaling through the JAK/STAT pathway, recent advances and future challenges [J]. Gene, 2002, 285(1-2): 1-24.).
  • JAK kinase Janus kinase
  • JAK Janus kinase
  • Tofacitinib developed by Pfizer in the United States can selectively inhibit JAK3 kinase. It was approved by the FDA on November 6, 2012 for the treatment of adult active and moderate to severe grades with poor response to methotrexate. Rheumatoid arthritis (RA).
  • the main side effects of Tofacitinib are severe infection rate and elevated LDL levels. The most common adverse reactions are upper respiratory tract infection, headache, diarrhea, nasal congestion, sore throat and nasopharyngitis. In addition to liver steatosis, surrounding water Exogenous, most of the other adverse reactions of Tofacitinib, monoclonal drugs are also present.
  • Tofacitinib acts as an immunosuppressant, and the warnings and precautions in the approved instructions are essentially the same as those of the anti-TNF monoclonal antibody. Due to partial inhibition of Jak2 activity and interference with cytokines such as erythropoietin and colony stimulating factor, clinical studies have also reported that Tofacitinib can cause side effects such as anemia and neutropenia. In addition, clinical trials have shown that Tofacitinib does not reduce the total number of T lymphocytes, but it leads to a decrease in CD8+ T cells and a slight decrease in natural killer cells (NK cells), so there are some uncertain risks when taking Tofacitinib. [JAK inhibitors for the treatment of rheumatoid arthritis, Xue Feng, Liu Fei, Wu Gang, You Qidong, Progress in Pharmacy 2014, 38(4): 264-273]
  • JAK kinase inhibitors Although a series of JAK kinase inhibitors have been published, these JAK kinase inhibitors that are on the market or in the research stage still have room for improvement in efficacy and safety, and there is still a need to develop better efficacy and safety. New compound.
  • the compounds of the present invention as inhibitors of Janus kinase (JAK), exhibit good activity and safety.
  • the present invention relates to a novel class of compounds which are JAK inhibitors, which are compounds of formula (I), and pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, and compositions comprising the same
  • JAK inhibitors which are compounds of formula (I)
  • pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof and compositions comprising the same
  • Ring A is C 3-7 cycloalkyl, C 5-7 aromatic ring group, C 5-7 aromatic heterocyclic group, C 7-11 aromatic bicyclic group, C 7-11 aromatic heterobicyclic group, C 11-15 three a cyclic group wherein ring A is optionally substituted by one or more of the same or different R, R 1 ;
  • R, R 1 is H, halogen, benzene, C 3-7 cycloalkyl, C 5-7 aromatic heterocyclic group, C 7-11 aromatic bicyclic group, C 7-11 aromatic heterobicyclic group, wherein these rings are Optionally substituted by one or more of the same or different R 5 ; C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, wherein C 1-8 alkyl, C 2-8 alkenyl, The C 2-8 alkynyl group is optionally substituted by one or more of the same or different R 6 ;
  • B 1 is H, CH 3 , CN, NO 2 , CF 3 , halogen
  • B 2 is H, CH 3 , CN, NO 2 , CF 3 , halogen
  • X is H, CH 3 , CN, NO 2 , CF 3 , C(O)NH 2 , halogen;
  • R 2 is H, CH 3 , CN, NO 2 , CF 3 , halogen
  • R 3 is H, CH 3 , CN, NO 2 , CF 3 , halogen
  • R 4 is H, CN, NO 2 , CF 3 , COOH, COOR 7 , CONR 8 R 8' , SONR 9 R 9' , COR 10 , R 11 OH, halogen; benzene, C 3-7 cycloalkyl, C a 5-7 aromatic heterocyclic group, a C 7-11 aromatic bicyclic group, a C 7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R 5 ; C 1-8 alkyl , C 2-8 alkenyl, C 2-8 alkynyl, wherein C 1-8 alkyl, C 2-8 alkenyl, C 2- 8 alkynyl group optionally substituted by one or more identical or different substituents R 6 ;
  • R 5 is H, CN, NO 2 , CF 3 , COOH, COOR 7 , CONR 8 R 8' , SONR 9 R 9' , COR 10 , R 11 OH, halogen; benzene, C 3-7 cycloalkyl, C a 5-7 aromatic heterocyclic group, a C 7-11 aromatic bicyclic group, a C 7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R 5 ; C 1-8 alkyl , C 2-8 alkenyl, C 2-8 alkynyl, wherein C 1-8 alkyl, C 2-8 alkenyl, C 2- 8 alkynyl group optionally substituted by one or more identical or different substituents R 6 ;
  • R 6 is H, CN, NO 2 , CF 3 , COOH, COOR 7 , CONR 8 R 8' , SONR 9 R 9' , COR 10 , R 11 OH, halogen; benzene, C 3-7 cycloalkyl, C a 5-7 aromatic heterocyclic group, a C 7-11 aromatic bicyclic group, a C 7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R 5 ; C 1-8 alkyl a C 2-8 alkenyl group, a C 2-8 alkynyl group, wherein the C 1-8 alkyl group, the C 2-8 alkenyl group, the C 2-8 alkynyl group are optionally substituted by one or more of the same or different R 6 ;
  • R 7 is benzene, C 3-7 cycloalkyl, C 5-7 aromatic heterocyclic, C 7-11 aromatic bicyclic, C 7-11 aromatic heterobicyclic, wherein these rings are optionally one or more Substituted or substituted by R 5 ; C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, wherein C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl Optionally substituted with one or more identical or different R 6 ;
  • R 8 and R 8 ' are H, CN, NO 2 , CF 3 , COOR 7 , CONR 8 R 8 ' , COR 10 , R 11 OH, halogen; benzene, C 3-7 cycloalkyl, C 5-7 An aromatic heterocyclic group, a C 7-11 aromatic bicyclic group, a C 7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R 5 ; C 1-8 alkyl, C 2 An alkenyl group, a C 2-8 alkynyl group, wherein the C 1-8 alkyl group, the C 2-8 alkenyl group, the C 2-8 alkynyl group is optionally substituted by one or more of the same or different R 6 ;
  • R 9 and R 9 ' are H, CN, NO 2 , CF 3 , COOH, COOR 7 , CONR 8 R 8 ' , COR 10 , R 11 OH, halogen; benzene, C 3-7 cycloalkyl, C 5 a -7 aromatic heterocyclic group, a C 7-11 aromatic bicyclic group, a C 7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R 5 ; C 1-8 alkyl, a C 2-8 alkenyl group, a C 2-8 alkynyl group, wherein the C 1-8 alkyl group, the C 2-8 alkenyl group, the C 2-8 alkynyl group are optionally substituted by one or more of the same or different R 6 ;
  • R 10 is H, CN, NO 2 , CF 3 , COOH, COOR 7 , CONR 8 R 8' , SONR 9 R 9' , COR 10 , R 11 OH, halogen; benzene, C 3-7 cycloalkyl, C a 5-7 aromatic heterocyclic group, a C 7-11 aromatic bicyclic group, a C 7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R 5 ; C 1-8 alkyl a C 2-8 alkenyl group, a C 2-8 alkynyl group, wherein the C 1-8 alkyl group, the C 2-8 alkenyl group, the C 2-8 alkynyl group are optionally substituted by one or more of the same or different R 6 ;
  • R 11 is H, benzene, C 3-7 cycloalkyl, C 5-7 aromatic heterocyclic group, C 7-11 aromatic bicyclic group, C 7-11 aromatic heterobicyclic group, wherein these rings are optionally one or Multiple identical or different R 5 substitutions; C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, wherein C 1-8 alkyl, C 2-8 alkenyl, C 2-8 An alkynyl group is optionally substituted by one or more of the same or different R 6 ;
  • Y is (CR 12 R 13 )n
  • n 0 or 1
  • R 12 and R 13 are R 5 ;
  • Z 1 , Z 2 may be respectively selected from C(R 14 ) or N(R 14 );
  • R 14 is H, CN, NO 2 , CF 3 , COOH, COOR 7 , CONR 8 R 8' , SONR 9 R 9' , COR 10 , R 11 OH, halogen; benzene, C 3-7 cycloalkyl, C a 5-7 aromatic heterocyclic group, a C 7-11 aromatic bicyclic group, a C 7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R 5 ; C 1-8 alkyl a C 2-8 alkenyl group, a C 2-8 alkynyl group, wherein the C 1-8 alkyl group, the C 2-8 alkenyl group, the C 2-8 alkynyl group are optionally substituted by one or more of the same or different R 6 .
  • Halogen means F, Cl, Br, I, At.
  • C 3-7 cycloalkyl refers to a cycloalkyl chain having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Each hydrogen of the cycloalkyl carbon can be replaced by a further defined substituent.
  • the "C 5-7 aromatic heterocyclic group” means an aromatic heterocyclic group having 5 to 7 carbon atoms, such as imidazole, thiazole, pyrazole, pyridine, pyrimidine or the like. Each hydrogen of the aromatic heterocyclic group may be replaced by a further defined substituent.
  • C 7-11 aromatic bicyclic group means an aromatic bicyclic group having 7 to 11 carbon atoms, such as naphthalene, anthracene or the like. Each hydrogen of the aromatic bicyclic group can be replaced by a further defined substituent.
  • C 7-11 aromatic heterobicyclic group means an aromatic heterobicyclic group having 7 to 11 carbon atoms, such as quinoline, isoquinoline, benzothiazole or the like. Each hydrogen of the aromatic heterobicyclic group can be replaced by a further defined substituent.
  • C l-8 alkyl means an alkyl chain having from 1 to 8 carbon atoms, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Tert-butyl.
  • Each hydrogen of the C 8-8 alkyl carbon can be replaced by a further defined substituent.
  • Each hydrogen of the C 2-8 alkenyl carbon may be replaced by a further defined substituent.
  • C 2-8 alkynyl means an alkynyl chain having 2-8 carbon atoms, for example: -C-CH, -CH., -C-CH, CH2-CH2-CTri-CH, CH2-CC- CH3.
  • Each hydrogen of the C 2-6 alkynyl carbon can be replaced by a further defined substituent.
  • the invention also includes all tautomeric and stereoisomeric forms and mixtures thereof, and pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvents thereof, in all ratios. And a pharmaceutical composition comprising the compound.
  • a pharmaceutically acceptable salt of a compound of formula (I), which comprises one or more basic or acidic groups also includes its corresponding pharmaceutically or toxicologically acceptable salts, in particular pharmaceutically acceptable salt.
  • compounds of the formula (I) which comprise an acidic group can be used according to the invention, for example as an alkali metal salt, an alkaline earth metal salt or as an ammonium salt. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids.
  • the compounds of the formula (I) which comprise one or more basic groups, ie groups which can be protonated, can be used in the form of their addition salts with inorganic or organic acids according to the invention.
  • suitable acids include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, lactic acid, malic acid, maleic acid, benzoic acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, and the like, as well as other acids known to those skilled in the art.
  • the compound of the formula (I) contains both acidic and basic groups in the molecule, the invention also includes internal salts or betaines (zwitterions) in addition to the salt forms mentioned.
  • the individual salts of formula (I) can be obtained by conventional methods known to those skilled in the art, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. obtain.
  • the invention also includes all salts of the compounds of formula (I) which are not directly suitable for use in medicine due to their low physiological compatibility, but which may, for example, be used as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • the term "pharmaceutically acceptable” means that the corresponding compound, carrier or molecule is suitable for administration to a human.
  • the term refers to a mammalian preferred person certified by a regulatory agency such as CFDA (China), EMEA (Europe), FDA (United States), and the like.
  • the "prodrug” means a derivative which is converted into a compound of the present invention by a reaction with an enzyme, a gastric acid or the like under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis or the like which is each carried out under an enzyme catalysis.
  • metabolite refers to all molecules derived from any compound of the invention in a cell or organism, preferably a human.
  • Isotopic derivative means a compound which contains an isotope in an unnatural ratio to one or more of the constituent compounds. For example, hydrazine (2H or D), carbon-13 (13C), nitrogen-15 (15N), and the like.
  • Solvate means a form of the compound which is usually physically associated with a solvent by a solvolysis reaction. This physical bond involves hydrogen bonding.
  • Conventional solvents include water, ethanol, methanol, acetic acid, and the like.
  • the compound of formula (I) can be prepared in crystalline form and can be in the form of a solvate (for example, in hydrated form).
  • Suitable solvates comprise pharmaceutically acceptable solvates (e.g., hydrates), and further comprise stoichiometric solvates and non-stoichiometric solvates. In certain instances, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be capable of dissociating.
  • “Solvate” encompasses both solution and dissociable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.
  • the compound of formula (I) may exist in crystalline or amorphous form. Furthermore, certain crystalline forms of the compounds of formula (I) may exist in polymorphic form and are included within the scope of the invention. Many conventional analytical techniques can be used including, but not limited to, X-ray powder diffraction (XRPD), infrared (IR), Raman, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid-state nuclear magnetic resonance. (ssNMR) characterization to distinguish polymorphs of the compounds of formula (I).
  • XRPD X-ray powder diffraction
  • IR infrared
  • Raman Raman
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • ssNMR solid-state nuclear magnetic resonance
  • a "pharmaceutical composition" when used as a medicament, a salt, an isotopic derivative, a metabolite, a prodrug, a solvate of a compound of the formula I according to the invention and a compound of the formula I in combination with a composition having biological activity and or no biologically active substance The use of a JAK inhibitor as a JAK inhibitor in the treatment or prevention of an immune, autoimmune or allergic condition, a proliferative or proliferative disease, inflammation, an allergic condition, transplant rejection, immune mediated.
  • the pharmaceutical compositions of the present invention may contain one or more pharmaceutically acceptable carriers for use as pharmaceutical formulations and pharmaceutical dosage forms for administration by injection and non-injection.
  • the carrier includes all pharmaceutical preparations which can be used in the pharmaceutical field for the preparation of injection and non-injection routes, such as diluents, wetting agents, fillers, binders, slip agents, disintegrating agents, absorption enhancers, Surfactants, retarders, adsorbents, suspending agents, flocculants, deflocculating agents, emulsifiers, common substrates, solubilizers, solubilizers, latent solvents, preservatives, flavoring agents, colorants, antioxidants A buffer, a bacteriostatic agent, an isotonicity adjusting agent, a pH adjusting agent, a metal ion complexing agent, a hardening agent, a thickening agent, an absorption enhancer, and the like.
  • the compounds of the formula (I) and pharmaceutical compositions of the invention may be formulated into pharmaceutical preparations and pharmaceutical dosage forms for administration by injection or non-injection. Suitable for subcutaneous injection, intramuscular injection, intravenous injection, oral administration, pulmonary (nasal or oral inhalation), rectal, topical, parenteral, intra-articular, ocular, nasal administration, etc., although most appropriate in any given case
  • the route will depend on the nature and severity of the disease state being treated and the nature of the active ingredient. They can conveniently be presented in a single dosage form and are prepared by any methods known in the art of pharmacy.
  • the diseases and conditions associated with Janus kinase (JAK) in the present invention are immune, inflammatory, autoimmune, proliferative diseases such as cancer, proliferative diseases, allergic conditions or diseases, transplant rejection or graft versus host disease, dry eye, and the like.
  • Autoimmune diseases are diseases that are caused, at least in part, by the body's immune response against its own components, such as proteins, lipids or DNA.
  • organ-specific autoimmune disorders are insulin-dependent diabetes (type I) affecting the pancreas, Hashimoto's thyroiditis affecting the thyroid gland, and Graves Disease, malignant anemia affecting the stomach, Cushing's disease and Edison's disease affecting the adrenal gland, chronic active hepatitis affecting the liver; polycystic ovary syndrome (PCOS), celiac disease, psoriasis, inflammatory bowel disease (IBD) and rigidity Spondylitis.
  • non-organ specific autoimmune disorders are rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus and myasthenia gravis.
  • IBD Inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn's disease
  • UC ulcerative colitis
  • Crohn's disease Crohn's disease
  • inflammation is continuous and is limited to the rectal and colonic mucosal layers.
  • a defined classification of Crohn's disease or ulcerative colitis cannot be made, and is referred to as "indeterminate colitis", limited to about 10% of the ileum and colon.
  • Both diseases include extraintestinal inflammation of the skin, eyes or joints. Neutrophil-induced damage can be prevented by the use of neutrophil migration inhibitors (Asakura et al, 2007, World J Gastroenterol. 13(15): 2145-9).
  • SLE Systemic lupus erythematosus
  • T-cell mediated B-cell activation causes glomerulonephritis and renal failure.
  • the early stage of human SLE is characterized by the expansion of persistent autoreactive CD4+ memory cells (D'Cruzetal., 2007, Lancet 369 (9561): 587-596).
  • RA Rheumatoid arthritis
  • RA Rheumatoid arthritis
  • the lesions mainly involve the synovial joints of the joints and the extra-articular manifestations are extensive and variable, eventually leading to joints. Structural damage, loss of function and high disability rate.
  • MS Multiple sclerosis
  • SOCS1 inhibits JAK2-induced phosphorylation of STAT3
  • JAK2 inhibitor AG490
  • SOCS1-JAK2-STAT3 signaling pathway in experimental autoimmune encephalomyelitis model of C57BL/6 mice, Dong Mei et al., Chinese Journal of Immunology, 2014, 30(4): 459-463.
  • Type I diabetes is secondary to the selective attack of insulin-producing islet beta cells by autoreactive T cells.
  • Targeting JAK3 in this disease is based on the observation that various cytokines known to transmit signals through the JAK pathway are involved in T cell-mediated autoimmune damage of beta cells.
  • the JAK3 inhibitor, JANEX-1 has been shown to prevent the development of spontaneous autoimmune diabetes in a NOD mouse model of type I diabetes.
  • Cancer contains a group of diseases characterized by uncontrolled growth and spread of abnormal cells. Generally, cancer is classified as a solid tumor (eg, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, colorectal cancer, breast cancer, cervical cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma).
  • a solid tumor eg, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, colorectal cancer, breast cancer, cervical cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma).
  • lymphoma e.g, lymphoma, leukemia, such as acute lymphoblastic leukemia, acute myeloid leukemia (AML) or multiple myeloma
  • leukemia such as acute lymphoblastic leukemia, acute myeloid leukemia (AML) or multiple myeloma
  • skin cancer such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma and exemplary skin T cells
  • lymphoma including Sezary syndrome and mycosis fungoides.
  • Transplant rejection includes, but is not limited to, acute and chronic allogeneic rejection following transplantation of, for example, kidney, heart, liver, lung, bone marrow, skin, and cornea.
  • T cells are known to play a key role in the specific immune response to allogeneic rejection.
  • Hyperacute, acute and chronic organ transplant rejection can be treated. Hyperacute rejection occurs within a few minutes of transplantation. Acute rejection usually occurs within six to twelve months of transplantation. Hyperacute and acute rejection are usually reversible, with immunosuppressive therapy.
  • Chronic rejection characterized by a gradual loss of organ function is of continuing concern to the transplant recipient as it can occur at any time after transplantation.
  • GVDH graft-versus-host disease
  • BMT heterologous bone marrow transplantation
  • JAK3 plays a key role in the induction of GVHD, and treatment with the JAK3 formulation JANEX-1 has been shown to attenuate the severity of GVHD (reviewed in Cetkovic-Cvrlje and Ucken, 2004).
  • Dry eye syndrome (DES, also known as dry keratoconjunctivitis) is one of the most common problems treated by ophthalmologists. Sometimes DES is called tear dysfunction syndrome (Jackson, 2009. Canadian Journal Ophthalmology 44 (4), 385-394). DES affects up to 10% of the population between the ages of 20 and 45, and the percentage increases with age. Although many types of artificial tear products are available, these products only provide temporary relief of symptoms. Therefore, there is a need for formulations, compositions, and methods of treatment for dry eye. Dry eye is sometimes referred to as dry keratoconjunctivitis, and treatment for dry eye includes improving specific symptoms of dry eye, such as eye discomfort, visual impairment, tear film instability, high tear pressure on the eye, and inflammation of the surface of the eye.
  • another aspect of the invention is a compound of the invention, and pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, and pharmaceutical compositions comprising the compounds, for use in prophylaxis or A method of treating immunity, inflammation, autoimmunity, proliferative diseases such as cancer, proliferative diseases, allergic conditions or diseases, transplant rejection or graft versus host disease, dry eye, and the like.
  • the results show that the compound (Formula I) of the present invention has good inhibition of JAK activity and pharmacokinetic properties, has biosimilarity with Tofacitinib, has no cytotoxicity, and is administered by a single oral administration in rats. No significant toxicity was observed in gastric administration.
  • Example 1 2-(2- ⁇ 5-Fluoro-4-[(pyrido[2,3-d]pyrimidin-6-methylene)-amine]-pyrimidin-2-ylamino ⁇ -imidazole-1 -base)-ethanol
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 8 2-(2- ⁇ 4-[3-(1-ethyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino ⁇ -imidazol-1-yl) -ethanol
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 12 2-[2-(5-Fluoro-4- ⁇ 1-[3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-ethylamino ⁇ -pyrimidine-2 -ylamino)-imidazol-1-yl]-ethanol
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 14 2-(2- ⁇ 5-Fluoro-4-[3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-anilino]-pyrimidin-2-ylamino ⁇ -imidazol-1-yl)-ethanol
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 1 The synthesis method is referred to in Example 1.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 22 2-[2-( ⁇ 5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-yl ⁇ -methyl -amine)-imidazol-1-yl]-ethanol
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 25 ⁇ 4-[3-( ⁇ 5-Fluoro-2-[1-(2-hydroxy-ethyl)-1H-imidazol-2-ylamino]-pyrimidin-4-ylamino ⁇ -methyl )-phenyl]-pyrazol-1-yl ⁇ -methylsulfonamide
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 26 ⁇ 4-[3-( ⁇ 5-Fluoro-2-[1-(2-hydroxy-ethyl)-1H-imidazol-2-ylamino]-pyrimidin-4-ylamino ⁇ -methyl )-phenyl]-pyrazol-1-yl ⁇ -acetic acid
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 27 ⁇ 4-[3-( ⁇ 5-Fluoro-2-[1-(2-hydroxy-ethyl)-1H-imidazol-2-ylamino]-pyrimidin-4-ylamino ⁇ -methyl )-phenyl]pyrazol-1-yl ⁇ -acetic acid methyl ester
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 28 2-(2- ⁇ 5-Fluoro-4-[3-(1-hydroxymethyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino ⁇ -imidazole -1-yl)-ethanol
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 36 (3- ⁇ 5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino ⁇ -[1,2 , 4] triazol-4-yl)-acetic acid methyl ester
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 40 (5- ⁇ 5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino ⁇ -[1,2 , 4] triazol-1-yl)-acetic acid
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 2 The synthesis method is referred to in Example 2.
  • Example 42 (5- ⁇ 5-Fluoro-4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrimidin-2-ylamino ⁇ -[1,2 , 4] triazol-1-yl)-methanol
  • Example 2 The synthesis method is referred to in Example 2.
  • the effect of the study compound on the activity of purified recombinant JAK was to study the inhibitory activity of the compound against JAK at the enzymatic level.
  • the experimental principle is to use a luminescent kinase assay to detect the ADP content produced by the reaction of JAK with the substrate Poly (4:1Glu, Tyr) peptide: ADP can be used as Ultra-Glo fluorescein after ADP is converted to ATP. The enzyme catalyzes the substrate of the reaction, producing an optical signal. The luminescent signal is positively correlated with the amount of ADP and kinase activity. Therefore, the inhibitory effect on the recombinant JAK was determined by observing the luminescence signal produced by the reaction of the compound with JAK and the substrate, and it was expressed by IC 50 .
  • the JAK-STAT signaling pathway occurs mainly in white blood cells and is therefore involved in immune regulation. Activation of the receptor on the cell membrane by IL-3 results in autophosphorylation and activation of JAK2.
  • the STAT protein binds to the phosphorylated receptor and is phosphorylated by JAK.
  • Phosphorylated STAT binds to another phosphorylated STAT protein to form a dimer and transfer to the nucleus. In the nucleus, STAT binds to DNA and promotes gene transcription, causing an immune response. Therefore, its inhibitory effect on JAK2 was determined by observing the phosphorylation of IL-3 mediated STAT5 (shown in the following table).
  • the incubator was stimulated for another 60 minutes; after 60 minutes of stimulation, 2% PFA was fixed at room temperature for 30 minutes; the fixed cells were added to a BD flow tube, centrifuged at 4 ° C for 1500 rpm for 5 minutes; 500 ⁇ l of methanol was added, and incubation was carried out at 4 ° C.
  • Induction of phosphorylation of STAT6 by IL-4 is a key assay to detect inhibitors at the cellular level of the JAK1-JAK3 pathway.
  • mice The compound was diluted with DMSO at 11 different concentrations, 200 ⁇ l of the diluted compound was added to a 24-well plate; THP1 cells (ATCC TIB-202) were adjusted to 2 ⁇ 10 6 /ml, and 200 ⁇ l of cells were added to the above.
  • Example 48 Effect on collagen-induced rheumatoid arthritis in mice
  • CII collagen-induced mouse rheumatoid arthritis
  • RA rheumatoid arthritis
  • Secondary immunization with 10 weeks old male DBA-1 mice primary immunization (on day 0): alcohol cotton ball disinfected the skin of the tail of the mouse, subcutaneously injected with emulsified collagen at 2-3 cm of the tail of the mouse 100 ⁇ l (CII to CFA volume ratio is 1:1) (containing CII 150 ⁇ g and heat inactivated Mycobacteria 50 ⁇ g); secondary immunization (on the 21st day): alcohol cotton ball disinfection of the skin of the tail of the mouse, subcutaneous injection of 50 ⁇ l of emulsified collagen at the root of the mouse at 2-3cm (the volume ratio of CII to IFA is 1:1) (containing CII 75 ⁇ g).
  • mice were randomly divided into control group (cosolvent group) and experimental group.
  • the test group suspended the compound in an aqueous suspension of 1% methylcellulose, and started the administration on the 23rd day until the end of the 41st day.
  • the drug dose was 30 mg/kg, 200 ⁇ l per administration twice a day;
  • the co-solvent is given by the same method.
  • the clinical inflammatory symptom score was measured daily.
  • the scoring criteria are as follows: 0 points: no erythema and edema; 1 point: erythema edema of the two small toe joints; 2 points: erythema edema of all toe joints or forefoot; 3 points: erythema edema extending to the toe joint below the ankle joint; 4 Points: ankle to full paw redness or joint deformity.
  • the total score of the limbs of each mouse was scored as the mouse arthritis index with a total score of 16 points.
  • the inflammatory symptoms of the control group and the experimental group were observed respectively, and the clinical inflammatory symptom scores were calculated.
  • the clinical inflammatory symptom scores of the test group and the control group were compared by double-sided and unpaired t-test, and the compounds were evaluated for collagen-induced small scores.
  • the effect of rheumatoid arthritis in rats is indicated by the P value. The results are shown in Table 6.
  • Example 49 Inhibition of proliferation of human tumor cells in vitro
  • 100 ⁇ l of the compound containing 2X and paclitaxel were added to the corresponding wells of a 96-well plate, and cultured in a carbon dioxide cell incubator for 72 hours.
  • the medium was removed, 150 ⁇ l of XTT working solution (0.3 mg/ml XTT; 0.00265 mg/ml PMS) was added to each well, and placed in a carbon dioxide incubator for 2 hours, the microplate oscillator was shaken for 5 minutes, and the absorbance was read by a microplate reader at 450 nm. The inhibition rate (%) of the compound against human tumor cells was calculated, and the IC 50 value ( ⁇ M) was determined. The results are shown in Table 7.
  • Wst-8 in CCK8 can be reduced by dehydrogenase in mitochondria to form a highly water-soluble orange-yellow formazan product (formazan) in the presence of an electron coupling reagent.
  • the depth of color is directly proportional to the proliferation of cells and inversely proportional to cytotoxicity.
  • the OD value was measured at a wavelength of 450 nm using a microplate reader, indirectly reflecting the number of viable cells, and was used to determine the cytotoxicity of the compound.

Abstract

La présente invention concerne de nouveaux composés destinés à être utilisés en tant qu'inhibiteurs de Janus kinase (JAK). Les composés sont des composés de formule I et des sels pharmaceutiquement acceptables, des promédicaments, des métabolites, des dérivés isotopiques et des solvates de ceux-ci, et des compositions pharmaceutiques comprenant les composés. Les compositions peuvent être utilisées pour la prévention ou le traitement de maladies et de symptômes associés à JAK chez l'homme ou chez le mammifère, et peuvent être appliquées en tant qu'inhibiteurs de JAK dans des expériences en médecine, pharmacie, biologie, physiologie, biochimie, etc.
PCT/CN2015/091451 2015-08-03 2015-10-08 Nouveaux composés destinés à être utilisés en tant qu'inhibiteurs de jak WO2017020428A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510481323.1A CN106397432B (zh) 2015-08-03 2015-08-03 作为jak抑制剂的一类化合物
CN201510481323.1 2015-08-03

Publications (1)

Publication Number Publication Date
WO2017020428A1 true WO2017020428A1 (fr) 2017-02-09

Family

ID=57942342

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/091451 WO2017020428A1 (fr) 2015-08-03 2015-10-08 Nouveaux composés destinés à être utilisés en tant qu'inhibiteurs de jak

Country Status (2)

Country Link
CN (1) CN106397432B (fr)
WO (1) WO2017020428A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113813228A (zh) * 2021-10-11 2021-12-21 北京鑫开元医药科技有限公司 一种具有jak激酶抑制活性的注射液及其制备方法和用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101903357A (zh) * 2007-07-17 2010-12-01 里格尔药品股份有限公司 作为pkc抑制剂的环状胺取代的嘧啶二胺

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006064375A2 (fr) * 2004-12-16 2006-06-22 Ab Science Composes heterocycliques a noyau a cinq elements a substitution aminoaryle pour le traitement de maladies
BRPI0608513A2 (pt) * 2005-03-15 2010-01-05 Irm Llc compostos e composições como inibidores da proteìna quinase
CN101707863A (zh) * 2007-06-15 2010-05-12 Irm责任有限公司 蛋白激酶抑制剂及其使用方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101903357A (zh) * 2007-07-17 2010-12-01 里格尔药品股份有限公司 作为pkc抑制剂的环状胺取代的嘧啶二胺

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113813228A (zh) * 2021-10-11 2021-12-21 北京鑫开元医药科技有限公司 一种具有jak激酶抑制活性的注射液及其制备方法和用途

Also Published As

Publication number Publication date
CN106397432A (zh) 2017-02-15
CN106397432B (zh) 2018-03-16

Similar Documents

Publication Publication Date Title
JP5997335B2 (ja) Ｎ含有複素環式化合物
JP7191799B2 (ja) ピリミジン化合物及びその医薬用途
EP2114900B1 (fr) Composés à base de thiopyrimidine et ses utilisations
KR101652229B1 (ko) 증식성 질환의 치료를 위한 키나제 저해제로서 유용한 다이하이드로나프타이리딘 및 관련 화합물
CN105283454B (zh) 作为ras/raf/mek/erk和pi3k/akt/pten/mtor通路双重抑制剂的喹唑啉和氮杂喹唑啉
US20120040955A1 (en) Fluoro substituted pyrimidine compounds as jak3 inhibitors
CN101678014A (zh) 杂环激酶调节剂
US20120172385A1 (en) Ortho substituted pyrimidine compounds as jak inhibitors
JP2014531449A (ja) キナーゼ阻害剤としてのピラゾロ［４，３―ｃ］ピリジン誘導体
WO2018019222A1 (fr) Composé hétérocyclique en tant qu'inhibiteur de jak, ses sels et leur utilisation thérapeutique
KR20120103553A (ko) 신규 １,２,３,４-테트라히드로-피리미도（１,２-ａ）피리미딘-６-온 유도체, 그의 제조법 및 그의 제약 용도
CA2982881C (fr) Methode de preparation d'un compose heterocyclique aromatique utilise comme inhibiteur selectif de la kinase jak3 et/ou jak1, et application dudit compose
US10792283B2 (en) Quinoline analogs as phosphatidylinositol 3-kinase inhibitors
WO2020077944A1 (fr) Dérivé de purine, son procédé de préparation et son utilisation
WO2017020428A1 (fr) Nouveaux composés destinés à être utilisés en tant qu'inhibiteurs de jak
WO2017088289A1 (fr) Dérivé 4,7-diamino-pyrido[2,3-d]pyrimidine utilisé comme inhibiteur de jak
JP2020534312A (ja) ２−置換ピラゾールアミノ−４−置換アミノ−５−ピリミジンホルムアミド系化合物、組成物およびその使用
CN102388041A (zh) 2-吗啉代-吡啶并[3,2-d]嘧啶
CN116063324A (zh) 具有大环结构的btk和/或ret抑制剂
JPWO2018097295A1 (ja) ピリド［３，４−ｄ］ピリミジン誘導体又はその溶媒和物の結晶

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15900198

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15900198

Country of ref document: EP

Kind code of ref document: A1