WO2014187262A1 - Inhibiteurs de la tyrosine kinase de bruton - Google Patents

Inhibiteurs de la tyrosine kinase de bruton Download PDF

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WO2014187262A1
WO2014187262A1 PCT/CN2014/077570 CN2014077570W WO2014187262A1 WO 2014187262 A1 WO2014187262 A1 WO 2014187262A1 CN 2014077570 W CN2014077570 W CN 2014077570W WO 2014187262 A1 WO2014187262 A1 WO 2014187262A1
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group
fluorenyl
heterocycloalkyl
cyclodecyl
hydrogen
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PCT/CN2014/077570
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Chinese (zh)
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金秋
黄伟
王亚洲
赵兴俄
蔡建锋
杨洁
唐锋
赵勇
祝建平
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江苏先声药物研究有限公司
江苏先声药业有限公司
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Publication of WO2014187262A1 publication Critical patent/WO2014187262A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to novel derivatives for inhibiting Bruton's kinase (Btk) and for treating autoimmune diseases and inflammatory diseases caused by abnormal B cell activation.
  • Btk Bruton's kinase
  • the novel derivative 2-phenyl-isoquinolin-1-one derivatives described herein can be used to treat arthritis.
  • Protein kinases constitute one of the largest families of human enzymes and regulate many different signaling processes by the addition of phosphate groups to proteins (T. Hunter, Cell 1987 50:823-829).
  • tyrosine kinase phosphorylates proteins in the phenolic portion of tyrosine residues.
  • the tyrosine kinase family includes members that control cell growth, migration, and differentiation.
  • Abnormal kinase activity has been implicated in many human diseases, including cancer, autoimmune diseases and inflammatory diseases. Because protein kinases are key regulators of cell signaling, they provide the goal of regulating cell function with small molecule kinase inhibitors and are therefore good drug design targets.
  • selective and potent inhibitors of kinase activity can be used to study cellular signaling processes and to identify other therapeutically significant cellular targets.
  • B cells play a key role in the pathogenesis of autoimmune and/or inflammatory diseases.
  • Protein-based therapeutics that deplete B cells, such as Rituxan are effective against autoantibody-induced inflammatory diseases such as rheumatoid arthritis (Rastetter et al, Annu Rev Med 2004 55:477). Therefore, an inhibitor of protein kinase that plays a role in B cell activation should be a therapeutic agent for B cell-mediated disease pathology such as autoantibody production.
  • BCR B cell receptor
  • Btk is a member of the Tec family of tyrosine kinases and shows early B cell formation as well as mature B cell activity. Key regulators of chemistry and survival (Khan et al, Immuni ty 1995 3: 283; Ellmeier et al, J. Exp. Med. 2000 192: 1611). Human Btk mutations lead to disease X-linked agammaglobulin deficiency (XLA) (reviewed in Rosen et al., New Eng J. Med. 1995 333: 431, P Li ndvall et al., Immunol. Rev. 2005 203:200). These patients are immunocompromised and show impaired B cell maturation, reduced immunoglobulin and topical B cell levels, reduced T cell-independent immune responses, and reduced calcium motility after BCR stimulation.
  • XLA X-linked agammaglobulin deficiency
  • Btk-deficient mice showed a significant improvement in disease progression in a preclinical mouse model of systemic lupus erythematosus (SLE). Furthermore, Btk-deficient mice are resistant to collagen-induced arthritis (Jansson Wo P Holmda Clin. Exp. Immunol. 1993 94:459). The dose-dependent efficacy of selective Btk inhibitors in the mouse arthritis model has been demonstrated (z. Pan et al, Chem. Med Chem. 2007 2: 58-61).
  • Btk is also expressed by cells that may be involved in disease processes in addition to B cells.
  • Btk is expressed by mast cells and Btk-deficient bone marrow-derived mast cells show impaired antigen-induced degranulation (Iwaki et al. J. Biol. Chem. 2005 280: 40261). This shows that Btk can be used to treat pathological mast cell responses such as allergies and asthma.
  • monocytes from XLA patients lacking Btk activity show reduced TNFa production following stimuli (Horwood et al J Exp Med 197: 1603, 2003).
  • TNFa-mediated inflammation can be modulated by small molecule Btk inhibitors.
  • Btk has been reported to play a role in apoptosis in Oslam and Smith Immunol. Rev. 2000178:49), and thus Btk inhibitors will be effective in the treatment of certain B cell lymphomas and leukemias (Feldha n et al J) Exp. Med. 2005 201: 183 7).
  • a class of 2-phenyl-isoquinoline 1-one derivatives as Bruton kinase inhibitors is disclosed by Roche in WO2010100070.
  • the representative compound is RN486 and has entered the clinical research stage.
  • the methyl group on the piperazine ring at the end of the molecule may be easily metabolized, which will result in faster clearance of the compound in the body, and the exposure is not high.
  • the reports in the literature have also verified our speculation (Xu et al. Pharmacol. Exp. Ther. 2012 341: 1 90). Therefore, in order to obtain compounds with excellent pharmacokinetic properties and in vivo efficacy and excellent effects, we conducted a more systematic study on the terminal piperazine ring and obtained the expected compounds.
  • R 1 is -R 6 - R 7 - R 8 ;
  • R 2 is selected from hydrogen or -C 6 fluorenyl
  • R 3 is selected from the group consisting of hydrogen, dC 6 fluorenyl or hydroxy CC 6 fluorenyl;
  • R 4 is selected from the group consisting of hydrogen, C r C 6 fluorenyl or 3 ⁇ 4 8 cyclodecyl;
  • R 5 is selected from hydrogen or halogen
  • X, Y, ⁇ are independently selected from CH or ⁇ ;
  • Q is selected from CH or ⁇ , provided that when ⁇ is ⁇ , Q is CH;
  • D, G are independently selected from CH or N, but D and G are not N at the same time;
  • R 6 is selected from C 6 -C 1Q aryl, C 5 -C 1Q heteroaryl, C 3 -C 8 cyclodecyl or C 4 -C 8 heterocycloalkyl, each of which is optionally one or more R 1Q substitution;
  • R 7 is selected from C 3 -C 8 cyclodecyl or C 4 -C 8 heterocycloalkyl, each of which is optionally substituted by one or more R 11 ;
  • R 8 is selected from the group consisting of C 4 -C 8 heterocyclic fluorenyl, C 3 -C 8 cyclodecyl-C 6 fluorenylene, C 4 -C 8 heterocycloalkyl C r C 6 fluorenylene, dC 6 fluorenyl , -COR 9 or -(S0 2 )R 9 , C 4 -C 8 heterocycloalkyl is optionally substituted by one or more R 12 ;
  • R 9 is selected from the group consisting of -C 6 fluorenyl, 3 ⁇ 4 8 cyclodecyl, C 4 -C 8 heterocycloalkyl, C 6 -C 1() aryl, C 5 -. Heteroaryl, C 3 -C 8 cyclodecyl dC 6 -fluorenylene, C 5 -C 8 heterocyclic fluorenyl CC 6 fluorenylene, C 6 -C 1Q aryl CC 6 fluorenylene, C 5 -C 10 wide heteroaryl TJ Ci- e 3 ⁇ 4 ⁇ 3 ⁇ 4 Ci-C 6 3 ⁇ 43 ⁇ 43 ⁇ 4 3 ⁇ 4S3 ⁇ 4 C C 6 3 ⁇ 43 ⁇ 4 C wide C 6 3 ⁇ 43 ⁇ 4, wide C C 6 3 ⁇ 43 ⁇ 4, C 3 -C 8 cycloalkyl group embankment, C 5 -C 8 heterocyclic group optionally embankment
  • the ground is replaced by one or more halogen, hydroxy, dC 6
  • R 1Q is selected from the group consisting of hydrogen, dC 6 fluorenyl, hydroxy, hydroxy dC 6 fluorenylene, CC 6 decyloxy, halogen, nitro, amino, acylamino, cyano, oxo or 3 ⁇ 4 generation-C r C 6
  • Substituent substitution R 11 is selected from the group consisting of hydrogen, -C 6 fluorenyl, C r C 6 decylamino, C r C 6 fluorenyl-C 6 decylamino, hydroxy, hydroxy dC 6 fluorenyl, CC 6 decyloxy, halogen, nitrate Base, amino, acylamino, acyl, cyano, oxo, decyl, hydroxyamino, carboxy, carbamoyl, carbamate, ⁇ H CH ⁇ decyloxy, ⁇ H d-Cs decyl or hydroxy Substituting
  • R 12 is selected from the group consisting of hydrogen, C r C 6 fluorenyl, ⁇ - ⁇ cyclodecyl, C 4 -C 8 heterocycloalkyl, C 3 -C 8 cyclodecyl C r C 6 fluorenylene or C 4 -C 8 heterocyclic fluorenyl CC 6 anthracenyl.
  • R 3 is selected from hydroxy-C 6 fluorenyl
  • X, Y, D, G are selected from CH
  • R 8 , R 11 are not selected from hydrogen or C r C 6 fluorenyl
  • R 3 is selected from C -Co ⁇ Or a hydroxy dC 6 fluorenyl group
  • X, Y, D, G are selected from CH
  • Q is selected from N
  • R 8 is not selected from hydrogen, -C 6 fluorenyl or -COR 9
  • R 11 is not selected from hydrogen, - C 6 thiol or acyl.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from ;
  • R' is selected from -R 7 R 8 ;
  • R 7 is selected from C 4 -C 8 heterocycloalkyl, and C 4 -C 8 heterocycloalkyl is optionally substituted by one or more R 11 ;
  • R 8 is selected from the group consisting of C 4 -C 8 heterocycloalkyl, C 3 -C 8 cyclodecyl-C 6 -fluorenylene, C 4 -C 8 heterocycloalkyl-C 6 -fluorenylene, dC 6 fluorenyl, -COR 9 or -(S0 2 )R 9 , C 4 -C 8 heterocyclic fluorenyl is optionally substituted by one or more R 12 ;
  • R 9 is selected from the group consisting of -C 6 fluorenyl, 3 ⁇ 4 8 cyclodecyl, C 4 -C 8 heterocycloalkyl, C 6 -C 1() aryl, C 5 -. Heteroaryl, C 3 -C 8 cyclodecyl dC 6 -fluorenylene, C 5 -C 8 heterocyclic fluorenyl CC 6 fluorenylene, C 6 -C 1Q aryl CC 6 fluorenylene, C 5 -C 10 heteroaryl Ci-C 6 3 ⁇ 4 ⁇ 3 ⁇ 4 Ci-C 6 3 ⁇ 43 ⁇ 43 ⁇ 4 wide 3 ⁇ 4S3 ⁇ 4 C C 6 3 ⁇ 43 ⁇ 4 C wide C 6 3 ⁇ 43 ⁇ 4, wide C C 6 3 ⁇ 43 ⁇ 4, C 3 -C 8 cycloalkyl group embankment, C 5 -C 8 heterocyclic group optionally embankment
  • the ground is replaced by one or more halogen, hydroxy, dC 6 meth
  • R 11 is selected from hydrogen, alkyl with dC 6, cyano, hydroxyl or optionally substituted by one or more halo, hydroxy substituted firing dC 6-yl;
  • R 12 is selected from the group consisting of hydrogen, dC 6 fluorenyl, C 3 -C 8 cyclodecyl, C 4 -C 8 heterocycloalkyl, C 3 -C 8 cyclodecyl CC 6 fluorenylene, C 4 -C 8 Cyclodecyl-C 6 anthracenyl.
  • R' is preferably m is selected from 0-2, more preferably 0 or 1.
  • R 8 is preferably C 3 -C 6 cyclodecylmethylene, C 4 -C 6 heterocycloalkyl, C 4 -C 6 heterocycloalkylmethylene, dC 6 fluorenyl,
  • C 4 -C 6 heterocyclic fluorenyl is optionally substituted by one or more R 12 , wherein C 4 -C 6 heterocyclic ring
  • W is selected from 0, S or NR 12 ; R 12 is as defined above.
  • R 9 is preferably CC 4 fluorenyl, C 3 -C 6 cyclodecyl, C 4 -C 6 heterocycloalkyl, phenyl, C 5 -C 1 () heteroaryl, C 3 -C 6 cyclodecyl Methylene, C 4 -C 6 heterocyclodeclyl methylene, benzyl, methylamino, dimethylamino, ethylamino, diethylamino, dC 4 fluorenyl, C 3 -C 6 cyclodecyl,
  • the C 4 -C 6 heterocyclic fluorenyl group is optionally substituted by one or more halogen, hydroxy, dC 4 decyloxy groups, and the phenyl group, the phenyl group on the benzyl group, and the C 5 -C 1Q heteroaryl group are selectively One or more halogen, -C 4 fluorenyl, CC 4 decyl
  • R 11 is preferably hydrogen, methyl, ethyl, cyano, hydroxy, -CH 2 F, CHF 2 , CF 3 or CH 2 OH.
  • composition of R 1 is as follows: M is selected from CH or N;
  • R 8 is selected from C 4 -C 8 heterocycloalkyl, C r C 6 fluorenyl, -COR 9 , C 4 -C 8 heterocyclic fluorenyl is optionally substituted by R 12 ;
  • R 9 is selected from C 3 -C 8- ring sulfhydryl;
  • R 12 is selected from the group consisting of hydrogen and -C 6 fluorenyl
  • R 8 is selected from Y 0 CT Or methyl, ethyl, propyl.
  • R 2 is selected from the group consisting of methylethyl and propyl.
  • R 3 is selected from the group consisting of hydrogen, methyl, hydroxymethyl
  • R 4 is selected from cyclopropyl.
  • R 5 is selected from hydrogen or fluorine.
  • X, Y, ⁇ , Q are independently selected from CH.
  • D, G are independently selected from CH or N, but D and G are different at the same time? .
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound of formula (I) in free form or in a pharmaceutically acceptable salt form; one or more pharmaceutically acceptable carrier materials and/or diluents.
  • the compound of the formula (I) of the present invention and a pharmaceutically acceptable carrier, excipient or diluent may also be included.
  • the invention further relates to a combined pharmaceutical composition comprising an effective amount of a compound of the formula (I) in free form or in a pharmaceutically acceptable salt form; one or more pharmaceutically acceptable carrier materials and/or diluents.
  • the application provides a method for treating an inflammatory and/or autoimmune disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a Btk inhibitor compound of any of Formulas I.
  • the application provides a method for treating arthritis comprising administering to a patient in need thereof a therapeutically effective amount of a Btk inhibitor compound of any of Formula I.
  • the application provides a method for treating rheumatoid arthritis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a Btk inhibitor compound of any of the above formulas or variants thereof.
  • the application provides a method for treating asthma comprising administering to a patient in need thereof a therapeutically effective amount of a Btk inhibitor compound of any of Formulas I.
  • the application provides a method of inhibiting B cell proliferation, the method comprising administering to a patient in need thereof a therapeutically effective amount of a Btk inhibitor compound of any of Formulas I.
  • the application provides a method for treating an inflammatory condition, the method comprising co-administering to a patient in need thereof a therapeutically effective amount of an anti-inflammatory compound and a Btk inhibitor compound of any of Formulas I.
  • the application provides a method for treating arthritis comprising co-administering to a patient in need thereof a therapeutically effective amount of an anti-inflammatory compound and a Btk inhibitor compound of any of Formulas I.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a Btk inhibitor compound of any of Formula I in admixture with at least one pharmaceutically acceptable carrier, excipient or diluent.
  • biochemical level enzyme activity assays and cell level enzyme activity assays were employed to determine the level of activity and effect of various compounds of the invention on one or more PKs. Similar experiments can be designed in the same manner for any kinase using methods well known in the art.
  • HTRF High-Resolved Fluorescence
  • FRET fluorescence resonance energy transfer
  • TR time-resolved
  • the fluorescence signal difference is used to determine the inhibitory activity of the test substance on Btk tyrosine kinase at different concentrations.
  • the activity of the compounds of the invention against the biochemical levels of Btk tyrosine kinase can be determined by this method, and similar assays can be used for other protein kinases using methods well known in the art.
  • the determination of enzyme activity at the cellular level is achieved by measuring calcium flux.
  • the experiment used the Fluo-4 DirectTM Calcium Assay Kits kit.
  • the main dye used in the kit is Fluo 4-AM.
  • Fluo 4-AM is a acetyl methyl ester derivative of Fluo 4 that can be easily introduced into cells by culture. When AM enters the cell, it is hydrolyzed by intracellular esterase, and the resulting Fluo 4 then binds to calcium ions and fluoresces.
  • the concentration of intracellular calcium can be measured using a laser confocal microscope or flow cytometry.
  • the pharmacodynamic properties of the compounds in rats can also be examined by using a general test method for pharmacological experiments in rats.
  • the in vivo efficacy of the compound in mice or rats can be examined using a generic mouse Arthus Reaction model or a rat collagen-induced arthritis (rCIA) model.
  • Mercapto refers to a saturated aliphatic hydrocarbon group. A straight or branched chain group of 1 to 20 carbon atoms is included. Preference is given to medium-sized mercapto groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. More preferred are lower fluorenyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like.
  • the fluorenyl group may be substituted or unsubstituted, and when substituted, preferred groups are: halogen, C 2 -C 6 alkenyl, C 6 -C 1Q aryl, C 5 -C 1Q heteroaryl, halogen a -C 6 fluorenyl group, a 4 to 8 membered heteroalicyclic group, a hydroxy group, a CC 6 decyloxy group, a C 6 -C 1Q aryloxy group.
  • Indexlene means a divalent saturated direct hydrocarbon group of 1 to 10 carbon atoms (for example, (CH 2 ) n ) or a branched saturated divalent hydrocarbon group of 2 to 10 carbon atoms (for example, -CHMe), unless otherwise . Except in the case of methylene groups, the open state of the fluorene group is not attached to the same atom. Examples of the fluorenylene group include, but are not limited to, methylene, ethylene, Propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene, 2-ethylbutylene.
  • Cyclopentyl means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6-membered fused or polycyclic fused ring
  • thick means each in the system The ring shares an adjacent pair of carbon atoms in the ring with the other ring in the system, wherein one or more of the rings have a fully connected pi-electron system, and examples of the ring thiol group are not limited to cyclopropene, cyclobutan , cyclopentanyl, cyclopentene, cyclohexanthene, adamantane, cyclohexadiene, cycloheptadene and cycloheptatriene.
  • the cycloalkyl group is a substitutable and substituted.
  • the substituent is preferably one or more groups each selected from the group consisting of: hydrogen, hydroxy, decyl, oxo, lower fluorenyl, lower decyloxy, lower cyclodecyl, lower heterocyclic Base, lower halogenated methoxy, sulfonyl, 3 ⁇ 4, lower 3 ⁇ 4 decyl, lower hydroxydecyl, lower cyclodecyl fluorenyl, lower heterocyclic fluorenylene, aryl, heteroaryl, Alkoxycarbonyl, amino, decylamino, decylsulfonyl, arylsulfonyl, decylaminosulfonyl, arylaminosulfonyl, decylsulfonylamino, arylsulfonylamino, decylaminocarbonyl, Arylaminocarbonyl
  • Aryl means an all-carbon monocyclic or fused polycyclic group of 6 to 14 carbon atoms having a fully conjugated ⁇ -electron system. “Aryl” includes:
  • a six-membered carbon aromatic ring such as benzene
  • the bicyclic ring wherein at least one of the rings is a carbon aromatic ring, such as naphthalene, anthracene and 1,2,3,4-tetrahydroquinoline; and a tricyclic ring, at least one of which is a carbon aromatic ring, such as hydrazine.
  • an aryl group includes a six-membered carbon aromatic ring and a six-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, provided that the point of attachment is on the carbon aromatic ring.
  • the aryl group does not contain, nor does it overlap in any way with the heterocyclic aryl groups respectively defined below.
  • the resulting ring system is a heteroaryl group rather than an aryl group.
  • Non-limiting examples of aryl groups are phenyl, naphthyl.
  • the aryl group can be substituted or unsubstituted.
  • preferred groups are: hydrogen, hydroxy, nitro, cyano, oxo, lower fluorenyl, lower decyloxy, lower cyclodecyl, lower heterocycloalkyl, lower halodecyloxy , thiol, halogen, lower 3 ⁇ 4 decyl, lower hydroxydecyl, lower cyclodecyl fluorenylene, lower heterocyclic fluorenylene, aryl, heteroaryl, decyloxycarbonyl, amino, fluorenyl Amino, decylsulfonyl, arylsulfonyl, decylaminosulfonyl, arylaminosulfonyl, decylsulfonylamino, arylsulfonylamino, fluorenylaminocarbonyl, arylaminocarbonyl, decylcarbonylamino , arylcarbonylamino.
  • Heteroaryl means a monocyclic or fused ring radical of 5 to 14 ring atoms containing one, two, three or four ring heteroatoms selected from fluorene, 0 or S, the remaining ring atoms being C In addition, it has a fully conjugated ⁇ -electron system. Heteroaryl refers to: a 5-8 membered monocyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, 0 and S, such as from 1 to 4 heteroatoms, in some embodiments, from 1 to 3 heteroatoms, other atoms on the ring. Is a carbon atom;
  • a heteroaryl group includes a 5-6 membered heteroaromatic ring and a 5-6 membered ring fluorenyl group.
  • a heterocyclic ring in which the bicyclic rings are combined only one of the rings contains one or more hetero atoms, and the linking site is on the heteroaromatic ring.
  • the total number of sulfur and oxygen atoms on the heteroaryl group exceeds 1, these heteroatoms are not adjacent one another. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group does not exceed two. In some embodiments, the total number of sulfur atoms and oxygen atoms in the heteroaryl group does not exceed one.
  • heteroaryl groups including but not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, triazole, pyrimidine, pyridine, pyridone, pyridine, pyrazine, pyridazine, anthracene, Azaindene, benzimidazole, benzotriazole, porphyrin, anthrone, quinoline, isoquinoline, quinazoline, thienopyridine, thienopyrimidine, and the like.
  • Preferred examples of such groups are pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furyl, oxazolyl, thienyl, thiazolyl, benzimidazolyl, benzotriazole.
  • One or all of the hydrogen atoms in the heteroaryl group may be substituted by hydrogen, hydroxy, nitro, cyano, oxo, lower fluorenyl, lower decyloxy, lower cyclodecyl, lower heterocyclic fluorenyl, Lower halogenated decyloxy, sulfonylthio, 3 ⁇ 4, lower 3 ⁇ 4 thiol, lower hydroxydecyl, lower cyclodecyl fluorenylene, lower heterocyclic fluorenylene, aryl, heteroaryl, oxime Carbocarbonyl, amino, decylamino, decylsulfonyl, arylsulfonyl, decylaminosulfonyl, arylaminosulfonyl, decylsulfonylamino, arylsulfonylamino, decylaminocarbonyl, aryl Aminocarbonyl, decy
  • Heterocyclic fluorenyl means a monovalent saturated cyclic group consisting of one or more rings, preferably 1 to 2 rings, including a spiro ring system, each ring having 3 to 8 atoms in combination with one or a plurality of ring heteroatoms (selected from hydrazine, 0 or S(0) Q _ 2 ), and which may be optionally substituted independently by one or more, preferably one or two substituents, said substituents being selected From: hydrogen, hydroxy, decyl, oxo, lower fluorenyl, lower decyloxy, lower cyclodecyl, lower heterocyclic fluorenyl, lower halodecyloxy, sulfonylthio, halogen, lower halogenated fluorenyl, Lower hydroxymethyl, lower cyclodecyl fluorenyl, lower heterocyclic fluorenyl fluorene, aryl, heteroaryl, decyloxycarbon
  • heterocyclic fluorenyl groups include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl, pyrrolidinyl, hexahydroaza, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl , oxazolyl, thiazolyl, isoxazolyl, tetrahydropyranyl, thio-allinyl,
  • W is selected from 0, S or NR 12 , and each group is as described above, and the example may also be bicyclic, such as, for example, 3, 8-diaza-bicyclo[3.2.1]octane, 2, 5 - diazabicyclo[2. 2. 2] octyl or octahydro-pyrazino[2, 1-c] [1, 4] oxazine. Its heterocyclic thiol group (and derivatives) include its ionic form.
  • Alkoxy means -0- (unsubstituted fluorenyl) and -0 (unsubstituted fluorenyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • Aryloxy means -0-aryl and -0-heteroaryl. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furanoxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.
  • Arylhydrazone means a fluorenyl group, preferably a lower fluorenyl group as defined above, which is substituted by an aryl group as described above, for example -CH 2 phenyl, -(CH 2 ) 2 phenyl, -(CH 2 3 phenyl, CH 3 CH (CH 3 ) CH 2 phenyl and its derivatives.
  • Heteroaryl fluorenyl means a fluorenyl group, preferably a lower fluorenyl group as defined above, which is substituted by a heteroaryl group as described above, for example 3 ⁇ 4 pyridyl, -(03 ⁇ 4) 2 pyrimidinyl, -(CH 2 ) )
  • Haldroxy means a -0H group.
  • Haldroxycarbonyl means - fluorenyl - 0H.
  • Halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • Haloalkyl denotes a fluorenyl group, preferably a lower fluorenyl group as defined above, which is substituted by one or more of the same or different halogen atoms, for example -CH 2 C1, -CF 3 , -CC1 3 , -CH 2 CF 3 , -CH 2 CC1 3, and the like.
  • Cyano means a -CN group.
  • Amino means a -NH 2 group.
  • Neitro means a -N0 2 group.
  • substituted with one or more groups means that one, two, three or four hydrogen atoms in a given atom or group are each selected from a specified range of groups. Replace the same or different groups.
  • a wavy line indicates a connection site
  • “Pharmaceutically acceptable salt” means those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
  • salt formation with an acid obtained by the reaction of a free base of a parent compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, etc.
  • an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, etc.
  • organic acids including acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid
  • malic acid fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid
  • an organic base such as ethanolamine, diethanolamine, or the like.
  • “Pharmaceutical composition” means that one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is mixed with another chemical component, such as a pharmaceutically acceptable carrier. .
  • the purpose of the pharmaceutical composition is to facilitate the administration to the animal.
  • “Pharmaceutically acceptable carrier” refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to, calcium carbonate, calcium phosphate, each Sugar (eg lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymer or methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, Ethylene glycol, castor oil or hydrogenated castor oil or polyethoxy hydrogenated castor oil, sesame oil, corn oil, peanut oil, and the like.
  • the aforementioned pharmaceutical composition may include, in addition to a pharmaceutically acceptable carrier, an adjuvant commonly used in medicine, for example: an antibacterial agent, an antifungal agent, an antimicrobial agent, a shelf life agent, a tone. Toners, solubilizers, thickeners, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, Sweeteners, colors, flavors or combinations thereof.
  • an adjuvant commonly used in medicine for example: an antibacterial agent, an antifungal agent, an antimicrobial agent, a shelf life agent, a tone.
  • Toners solubilizers, thickeners, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, Sweeteners, colors, flavors or combinations thereof.
  • Xantphos (436 mg, 0.752 mmol), tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ) (80.52 mg, 0.188 mmol) were weighed and mixed, and 50 mL of dioxane was added under argon atmosphere.
  • the tert-butyl 3-(4-(6-nitropyridin-3-yl)piperazine-1-yl)azetidinium-1 can be obtained by a similar method to the preparation of the compound intermediate (1e). - Carboxylic ester (1.5 g, 79%).
  • 5-Bromo-1-methyl-3-((5-(4-(1-methylazetidin-3-yl))piperidyl can be prepared by a similar method to the preparation of compound intermediate (1 e ) Pyrazin-1-yl)pyridin-2-yl)amine)pyridine-2(1H)-one amine (550 mg, 63%).
  • 1-methyl-3-((5-(4-(1-methylazetidin-3-yl)piperazine-1-) can be obtained by a similar method to the preparation of compound intermediate (1f).
  • -pyridin-2-yl)amine) -5-(4,4,5,5-tetramethyl-1,3,2-dioxapentan-2-yl)pyridine-2(1H)- Ketone (245 mg, 48%) [M+H]+ 481.3.
  • Soil ⁇ ⁇ 'dwa ⁇ wi yarr ' ⁇ # ⁇ 3 ⁇ 4 ⁇ 3 ⁇ 4 ⁇ ⁇ ' 9 0) ⁇ ⁇ ⁇ ( ⁇ 0 ⁇ 8179 ⁇ ' ⁇ ) hang ⁇ ' s 'l)fli 3 ⁇ 4 ⁇ "93 ⁇ 4 '( ⁇ omm V ' ⁇ ) wake up - ( ⁇ ) ⁇ -foot fti 3 ⁇ 4Mir9 ⁇
  • the compound 2-bromo-6-(6-cyclopropyl-1 -oxo-2,7-naphthyridin-2(1 H)-yl)benzene can be obtained by a similar method to the preparation of the compound intermediate (5a). Formaldehyde (103 mg, 52.2%). MS (ESI) m/z 369.1 [M + H]+.
  • the compound 2-(3-bromo-2-methylphenyl)-6-cyclopropyl-8-fluoroisoquinolin-1 (2H)-one (72) can be obtained by a similar method to the preparation of compound intermediate (5a). Mg, 38.7 %).
  • Example 11 In vitro biochemical level inhibition of protein kinase (PK) activity assay
  • the selected positive drug is RN486, which can be prepared by the existing literature (WO2010100070).
  • the structure is as follows:
  • test compound was formulated into a mother liquor of 0.5-10 mmol/L in DMSO, and stored at -20 ° C after dispensing;
  • the compound to be dispensed is taken out from the refrigerator before the test, diluted with pure DMSO to the desired concentration of 50 Torr; then the compound is diluted to the desired concentration with 4 Torr in deionized water;
  • test solution Dilute 16.67 ⁇ /L of Streptavidin-XL665 to a final concentration of 4 ⁇ with HTRF detection buffer, then mix with an equal volume of Antibody-Cryptate (both from the HTRF kit).
  • Enzyme reaction step 4 ⁇ L ⁇ l of kinase working solution was added to each well of a low volume 384 microplate, and 4 1.33x Enzymatic buffer was added as a negative control (Negative); 2 ⁇ of the compound working solution was added to the well while adding 2% DMSO aqueous solution as a zero compound concentration control (ie positive control, Positive); incubate at 25 V (or 30 V) for 5-10 min; add 2 ⁇ L of substrate working solution to the well to start the enzymatic reaction at 25 ° C (or 30 ° C) Oscillating reaction for 15-60 min.
  • HTRF reagent detection step 8 ⁇ L of test solution is added to the well to terminate the reaction; 25 ° C reaction for 1 h;
  • Reading of HTRF signal Using PHERAstar FS reading detection signal, the instrument is set as follows:
  • the ratio 665 nm / 620 nm
  • Inhibition rate % ( 1- ) 100 %
  • the present invention provides a half-inhibitory concentration (IC 5Q ) of a compound of formula I as shown in Formula I for BTK kinase activity.
  • Example : 12 In vitro cell water, protein kinase (PK) activity assay
  • Cell treatment Wash cells with serum-free medium and remove serum.
  • Dye preparation The 2 ⁇ dye was then diluted to lx with serum free medium. Resuspension of the cells: The washed cells were resuspended with the lx dye prepared above.
  • Cell seeding 200,000/well, 40 ⁇ l/well, 96-well plate, black wall plate required.
  • Room temperature equilibration Take out the test plate and equilibrate for 5 min at room temperature.
  • Baseline determination Baseline was first tested with a PHERStar plate reader before the agonist was added.
  • Add agonist Add IgM, ⁇ /well at a final concentration of l ( ⁇ g/ml).
  • the present invention provides a half-inhibitory concentration (IC 5Q ) of a compound of the formula I for calcium flux in BTK cells.
  • Example 13 Method for determining pharmacokinetic properties in rats
  • SD rats were used as test animals, and the concentration of the drug in plasma at different times after intravenous administration of the compound of Example 1 was measured by LC/MS/MS.
  • the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
  • Example 1 Compound and positive control drug RN486.
  • Sex Male weight: 190-210g Food, water supply: Words, free intake of water during drug administration, 12 hours before blood withdrawal, source of fasting: Shanghai Slack Laboratory Animal Co., Ltd.
  • Compound RN486 Prescription: Compound RN486 is dissolved in 5% DMA and 5% solute solution, and the formulated solution is clear and transparent.
  • Compound 1 Prescription: Compound 1 was dissolved in 5% DMA and 5% solute solution, and the formulated solution was clear and transparent.
  • Rats in the gavage group were collected blood samples at 0 min, 10 min, 20 min, 40 min, 1, 2, 4, 6, 8, 10, 24 h after administration.
  • the intravenous injection group was administered 5 min, 10 min after the administration.
  • 20min, 40min, 1, 2, 4, 6, 8, 10, 24h, respectively take about 0.3ml of blood to the heparinized Eppendorf tube, temporarily stored in the ice bath, whole blood was collected by centrifugation, and the plasma was transferred to 96 wells. In the plate, store at -20 °C until LC-MS/MS detection.
  • the pharmacokinetic parameters of the compounds of the invention are as follows:
  • RN486 The pharmacopoeetic property of RN486 was superior to that of compound RN486.
  • Example 14 In vivo efficacy determination of mouse Arthus Reaction molding
  • Balb/c mice were used as test animals, and the in vivo efficacy of the compounds of the present invention and positive control drugs was evaluated using the Arthus Reaction model.
  • Test drug Dexamethasone: 100701, Jinling Pharmaceutical Co., Ltd.
  • Compound 1 and RN486 3 mL each, at a concentration of 3 mg/mL, placed in an Eppendorf tube,
  • OVA batch number SLBB5992V, sigma; rabbit anti-OVA: 099K4830, sigma; rabbit IgG: SLBD1647V, sigma; Evans blue, 72496LJ, sigma; all reagents were prepared using cold physiological saline (4 ° C) before use. The reagents are stored in an ice bath and are now ready for use.
  • mice SPF grade; C57/BL6, SPF grade;
  • Test protocol Grouping: Animals are randomly grouped.
  • the drug was administered after grouping, and it was set to time point 0 at the time of administration.
  • Anesthetized animals i.p. 1% sodium pentobarbital, dose 70 mg/kg
  • the animal was injected with 0.2 mL of OVA+Evans blue in the tail vein.
  • IgG and antibody were injected intradermally, 30 ⁇ per point, and 3 points per skin injection.
  • Example 15 In vivo pharmacodynamic assay on rat collagen-induced arthritis (rCIA) model
  • Modeling DAY0, take 10 ml of incomplete Freund's adjuvant IFA and 10 ml of collagen, emulsified with a homogenizer on ice, Until the emulsion is dripped into the water. Multiple injections were made in the tail of the rat, and each rat was injected with 0.3 ml of emulsion to form a local bulge on the skin surface.
  • Grouping Observe the onset of the model, after the onset (about Dayl4), measure the volume of the hind limbs of each rat, and randomly group the disease model rats according to the volume.
  • Dosing and measurement According to the above group, it lasted for 14 days. The body weight of the rats was weighed twice a week during the administration, and the foot volume of the hind limbs of the rats was measured with an ankle tester and scored.
  • Measurement indicators and methods Animal weight: twice a week weighing records;
  • Animal hindlimb volume measured and recorded twice a week with an ankle tester
  • the indicator is as follows

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Abstract

L'invention concerne un dérivé de 2-phényl-isoquinoline-1-cétone qui possède une structure de formule (I), et des utilisations associées. Le composé a un effet inhibiteur efficace sur l'activité de la tyrosine kinase de Bruton, et la concentration inhibitrice médiane du composé est généralement inférieure à 10-7 mol.L-1. Le composé de structure de formule (I) et préparé dans un mode de réalisation de la présente invention présente une nette activité anti-inflammatoire sur différents modèles animaux.
PCT/CN2014/077570 2013-05-22 2014-05-15 Inhibiteurs de la tyrosine kinase de bruton WO2014187262A1 (fr)

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EP3246317A4 (fr) * 2015-01-14 2018-10-24 Hubei Bio-Pharmaceutical Industrial Technological Institute Inc. Inhibiteur btk
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2022140246A1 (fr) 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Procédés et composés destinés à l'autophagie ciblée
US11590167B2 (en) 2016-12-03 2023-02-28 Juno Therapeutic, Inc. Methods and compositions for use of therapeutic T cells in combination with kinase inhibitors

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CN108658976B (zh) * 2017-03-31 2021-02-19 南京科技职业学院 一类新型吡唑并[4,3-c]吡啶-4(5)-酮布鲁顿激酶抑制剂
CN110283171A (zh) * 2019-07-17 2019-09-27 鼎泰(南京)临床医学研究有限公司 一类含有吡啶并嘧啶-4-胺类结构的化合物、药物组合物以及其应用

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WO2022140246A1 (fr) 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Procédés et composés destinés à l'autophagie ciblée

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