WO2017088289A1 - Dérivé 4,7-diamino-pyrido[2,3-d]pyrimidine utilisé comme inhibiteur de jak - Google Patents

Dérivé 4,7-diamino-pyrido[2,3-d]pyrimidine utilisé comme inhibiteur de jak Download PDF

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WO2017088289A1
WO2017088289A1 PCT/CN2016/070339 CN2016070339W WO2017088289A1 WO 2017088289 A1 WO2017088289 A1 WO 2017088289A1 CN 2016070339 W CN2016070339 W CN 2016070339W WO 2017088289 A1 WO2017088289 A1 WO 2017088289A1
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methyl
pyrrole
ylamino
pyrimidin
pyrazol
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PCT/CN2016/070339
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Chinese (zh)
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陈亦林
彭红
陶琳
赵岩
张晓丽
赵银鹰
邹阳
李永华
王晓霞
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南昌弘益药业有限公司
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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
    • 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
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to novel compounds of a class of JAK kinase inhibitors, including pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, which are useful for modulating protein kinase activity to modulate cellular activity such as signal transduction Guidance, proliferation and secretion of cytokines. Further, 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
  • JAK kinase can both phosphorylate its binding cytokine receptor and phosphorylate multiple signal molecules containing a specific Src homology 2 domain (SH2).
  • 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 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.).
  • JAK When cytokines are specific to their target cells Binding of the receptor activates JAK, which in turn catalyzes the phosphorylation of tyrosine residues on the receptor and forms a corresponding "docking site" for binding of the STAT to the receptor complex. 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]. Arthritis Res Ther, 2004, 6(4): 159-168.) This pathway is the 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
  • 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 also showed SCID but did not show non-immune defects, suggesting that JAK3 inhibitors as immunosuppressive agents will have a relevant effect in vivo and thus become promising drugs 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
  • Tofactinib a JAK inhibitor developed by Pfizer, 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 rheumatoid with poor response to methotrexate. 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 hepatic steatosis and peripheral edema, most of Tofacitinib's other adverse reactions, monoclonal drugs are also present.
  • Tofacitinib acts as a JAK inhibitor, 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 inhibitors of JAK kinases, which are compounds of formula (I), and pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, and the like a pharmaceutical composition for preventing or treating a method of treating, controlling, delaying or preventing one or more disease states selected from diseases and conditions associated with Janus kinase (JAK) in a human patient or a mammalian patient; It can be used as a Janus kinase (JAK) inhibitor in medical, pharmaceutical, biological, physiological, biochemical and other experiments.
  • JAK Janus kinase
  • Y 1 , Y 2 is (CR 10 R 11 )n;
  • n 0 or 1
  • R 10 and R 11 are R 3 ;
  • Ring A and Ring B are 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 a -15 tricyclic group, wherein ring A and ring B are optionally substituted by one or more of the same or different R 1 , R 2 ;
  • R 1 , R 2 are H, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, wherein C 1-8 alkyl, C 2-8 alkenyl, C 2-8 The alkynyl group is optionally substituted by one or more of the same or different R 4 ; C 3-7 cycloalkyl, C 5-7 aromatic ring, C 5-7 aromatic heterocyclic, C 7-11 aromatic bicyclic, a C 7-11 aromatic heterobicyclic group, wherein these rings are optionally substituted by one or more of the same or different R 5 ;
  • R 3 is H, CN, NO 2 , CF 3 , COOH, COOR 5 , CONR 6 R 6' , SONR 7 R 7' , COR 8 , R 9 OH, halogen, 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 is optionally substituted by one or more of the same or different R 4 ; C 3-7 a cycloalkyl group, a C 5-7 aromatic ring group, a C 5-7 aromatic heterocyclic group, a C 7-11 aromatic bicyclic group, a C 7-11 aromatic heterobicyclic group, wherein these rings are optionally one or more of the same Or a different R 5 substitution;
  • R 4 is H, CN, NO 2 , CF 3 , COOH, COOR 5 , CONR 6 R 6' , SONR 7 R 7' , COR 8 , R 9 OH, halogen, 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 is optionally substituted by one or more of the same or different R 4 ; C 3-7 a cycloalkyl group, a C 5-7 aromatic ring group, a C 5-7 aromatic heterocyclic group, a C 7-11 aromatic bicyclic group, a C 7-11 aromatic heterobicyclic group, wherein these rings are optionally one or more of the same Or a different R 5 substitution;
  • R 5 is H, 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 are optionally One or more of the same or different R 4 substitutions; 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 groups wherein these rings are optionally substituted by one or more of the same or different R 5 ;
  • R 6 and R 6 ' are each H, CN, NO 2 , CF 3 , COOR 5 , CONR 6 R 6 ' , COR 8 , R 9 OH, halogen, 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 is optionally substituted by one or more of the same or different R 4 ; C 3-7 cycloalkyl a C 5-7 aromatic ring group, a C 5-7 aromatic heterocyclic group, a C 7-11 aromatic bicyclic group, a C 7-11 aromatic heterobicyclic group, wherein these rings are optionally selected by one or more of the same or different R 5 substitution;
  • R 7 and R 7 ' are H, CN, NO 2 , CF 3 , COOH, COOR 5 , CONR 6 R 6 ' , COR 8 , R 9 OH, halogen, C 1-8 alkyl, C 2-8 olefin, respectively.
  • C 2-8 alkynyl group wherein C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl is optionally substituted by one or more of the same or different R 4 ;
  • R 8 is H, CN, NO 2 , CF 3 , COOH, COOR 5 , CONR 6 R 6' , SONR 7 R 7' , COR 8 , R 9 OH, halogen, 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 is optionally substituted by one or more of the same or different R 4 ; C 3-7 a cycloalkyl group, a C 5-7 aromatic ring group, a C 5-7 aromatic heterocyclic group, a C 7-11 aromatic bicyclic group, a C 7-11 aromatic heterobicyclic group, wherein these rings are optionally one or more of the same Or a different R 5 substitution;
  • R 9 is H, 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 are optionally One or more of the same or different R 4 substitutions; 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 groups wherein these rings are optionally substituted by one or more of the same or different R 5 ;
  • the compound of the formula (I) described in the present invention is more preferably a compound of the formula (II), (III), (IV) or (V) shown below;
  • 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 Cl-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, CH 2 -CH 2 -C tri CH, CH 2 -CC-CH 3 .
  • Each hydrogen of the C 2-6 alkynyl carbon can be replaced by a further defined substituent.
  • the compound of formula (I) is selected from the group consisting of:
  • the compound of formula (II) is selected from the group consisting of:
  • the compound of formula (III) is selected from the group consisting of
  • the compound of formula (IV) is selected from the group consisting of:
  • the compound of formula (V) is selected from the group consisting of:
  • 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 invention also includes all tautomeric and stereoisomeric forms in all ratios together with mixtures thereof in any ratio, and pharmaceutically acceptable salts, prodrugs, metabolites thereof, Isotopic derivatives and solvates, and pharmaceutical compositions comprising the compounds.
  • the isomers can be separated by methods well known in the art, for example by liquid chromatography. Suitable for use by the use of, for example, the chiral stationary phase of the enantiomer.
  • the enantiomer can be converted to a diastereomer by conversion The separation is carried out by coupling with an enantiomerically pure auxiliary compound, followed by isolation of the resulting non-isomer and cleavage of the auxiliary residue.
  • any enantiomer of a compound of formula (I) can be obtained from stereoselective synthesis using optically pure starting materials.
  • 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, single crystal X-ray powder diffraction (XRPD) patterns, infrared (IR) spectroscopy, Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solids.
  • XRPD single crystal X-ray powder diffraction
  • IR infrared
  • Raman spectroscopy Raman spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • solidssNMR Nuclear magnetic resonance
  • 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.
  • “Pharmaceutical composition” when used as a medicament, a salt, an isotopic derivative, a metabolite, a prodrug, a solvate of the compound of the formula (I) and a compound of the formula (I) of the present invention and having biological activity and or no biological activity
  • a composition of a composition of matter as a JAK inhibitor for use 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.
  • 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, Surfactant, retarder, adsorbent, suspending agent, flocculating agent, deflocculating agent, emulsifier, common base Quality, solubilizer, cosolvent, latent solvent, preservative, flavoring agent, coloring agent, antioxidant, buffer, bacteriostatic agent, isotonicity adjusting agent, pH adjusting agent, metal ion complexing agent, hardening agent, Thickener, absorption enhancer, etc.
  • 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 mellitus (type I) affecting the pancreas, Hashimoto's thyroiditis and Graves' disease affecting the thyroid gland, pernicious anemia affecting the stomach, Cushing's disease affecting the adrenal gland, and Edison's disease Chronic active hepatitis affecting the liver; polycystic ovary syndrome (PCOS), celiac disease, psoriasis, inflammatory bowel disease (IBD) and ankylosing 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).
  • Rheumatoid arthritis is a chronic, systemic autoimmune disease characterized by symmetry and polyarthritis. 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. According to statistics, the prevalence rate in the world is about 1% on average, 3.0% in the US, 0.3% in Japan, and 0.29% in China's preliminary epidemiological survey.
  • Rheumatoid arthritis is currently the most comprehensive and effective class, including TNF antagonists (etanercept, infliximab, adalimumab), IL-1R antagonists, IL-6 mAb, CTL -4 fusion protein, anti-CD20 monoclonal antibody, etc.
  • TNF antagonists etanercept, infliximab, adalimumab
  • IL-1R antagonists IL-6 mAb
  • CTL -4 fusion protein anti-CD20 monoclonal antibody
  • TNF antagonists have significantly improved the quality of life of patients with RA; however, the researchers of the Spanish Society of Rheumatology have long-term use of different TNF antagonists in the Biologics Database of the Spanish Rheumatology Society (BIOBADASER database) officially launched in February 2000. The safety and tuberculosis were analyzed. The results showed that the prevalence of tuberculosis in patients with RA treated with TNF antagonists increased by 12-20 times.
  • TNF- ⁇ can increase the phagocytic ability of macrophages and kill Mycobacterium tuberculosis under physiological conditions, which can promote the formation of granuloma around M. tuberculosis infection and block its dissemination.
  • TNF- ⁇ When the action of TNF- ⁇ is blocked, these protective effects are weakened or disappeared, so treatment with TNF antagonists may increase the risk of tuberculosis.
  • 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 white Blood disease, acute myeloid leukemia (AML) or multiple myeloma
  • leukemia such as acute lymphoblastic white Blood disease, 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 Sezer
  • 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.
  • the compounds of the present invention and pharmaceutically acceptable salts, prodrugs, metabolites, isotopic derivatives and solvates thereof, and pharmaceutical compositions comprising the same, are useful for preventing or treating immunity, inflammation, autoimmunity
  • a method of 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 (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 irrigation in rats. No significant toxicity was observed in gastric administration.
  • Example 1 Preferred Formula (I), Formula (II), Formula (I), Formula (III), Formula (IV), and Formula (V) of the present invention
  • Compounds, Tofacitinib and Decernotinib were molecularly docked with JAK3, respectively, and their binding to JAK3 targets was observed.
  • a compound having a good binding property is preferred as the compound of Example 2-31.
  • the results are shown in Table 1.
  • Example 7 2- ⁇ 2-[methyl-(7- ⁇ methyl-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-amino ⁇ -7H-pyrrole [2 ,3-d]pyrimidin-4-yl)-amino]-imidazol-1-yl ⁇ -ethanol
  • Example 6 The synthesis method is referred to in Example 6.
  • Example 8 2-[2-(methyl- ⁇ 7-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-7H-pyrrole[2,3-d]pyrimidine -4-yl ⁇ -amino)-imidazol-1-yl]-ethanol
  • Example 6 The synthesis method is referred to in Example 6.
  • Example 6 The synthesis method is referred to in Example 6.
  • Example 6 The synthesis method is referred to in Example 6.
  • the synthesis method is referred to the embodiment 3.
  • the synthesis method is referred to the embodiment 3.
  • Example 17 2-(2- ⁇ 4-[3-(1-methyl-1H-pyrazol-4-yl)-benzylamino]-pyrrole[2,3-d]pyrimidin-7-ylamino ⁇ -imidazol-1-yl)-ethanol
  • Example 18 2-(2- ⁇ 4-[(3H-Benzimidazole-4-methyl)-amino]-pyrrole[2,3-d]pyrimidin-7-ylamino ⁇ -imidazol-1-yl )-ethanol
  • Example 19 2-(2- ⁇ 4-[(2,9-Dihydro-indol-3-methyl)-amino]-4a,7a-dihydro-pyrrole[2,3-d]pyrimidine-7 -ylamino ⁇ -imidazol-1-yl)-ethanol
  • 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 box 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 60 ° C was incubated 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.
  • Experimental method 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 ⁇ 106/ml, and 200 ⁇ l of cells were added to the above.
  • CII collagen-induced mouse rheumatoid arthritis
  • RA rheumatoid arthritis
  • 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 5.
  • Example 36 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 6.
  • 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 un nouveau composé qui est un inhibiteur de JAK. Le composé est un composé de formule (I), son sel pharmaceutiquement acceptable, un promédicament, un métabolite, un dérivé isotopique et un solvate, ou une composition pharmaceutique contenant le composé, et peut être utilisé pour prévenir ou traiter une maladie ou un symptôme associé à une Janus kinase (JAK) chez un patient humain ou un patient mammifère. La présente invention concerne également des applications du composé dans lesquelles le composé est utilisé en tant qu'inhibiteur de Janus kinase (JAK) dans des expériences médicales, des expériences pharmaceutiques, des expériences biologiques, des expériences physiologiques, des expériences biochimiques, et similaires.
PCT/CN2016/070339 2015-11-28 2016-01-07 Dérivé 4,7-diamino-pyrido[2,3-d]pyrimidine utilisé comme inhibiteur de jak WO2017088289A1 (fr)

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