[go: up one dir, main page]

WO2019001461A1 - Inhibiteur d'irak4 - Google Patents

Inhibiteur d'irak4 Download PDF

Info

Publication number
WO2019001461A1
WO2019001461A1 PCT/CN2018/093090 CN2018093090W WO2019001461A1 WO 2019001461 A1 WO2019001461 A1 WO 2019001461A1 CN 2018093090 W CN2018093090 W CN 2018093090W WO 2019001461 A1 WO2019001461 A1 WO 2019001461A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
acid
group
pharmaceutically acceptable
synthesis
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2018/093090
Other languages
English (en)
Chinese (zh)
Inventor
张杨
王一恺
陈琳琳
周丽莉
方勇波
冯韬
陈曙辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medshine Discovery Inc
Original Assignee
Medshine Discovery Inc
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 Medshine Discovery Inc filed Critical Medshine Discovery Inc
Publication of WO2019001461A1 publication Critical patent/WO2019001461A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • the present invention relates to a class of IRAK4 inhibitors and their use in the manufacture of a medicament for the treatment of diseases associated with IRAK4. Specifically, it relates to a compound of the formula (I) and a pharmaceutically acceptable salt thereof.
  • Interleukin-1 receptor kinase 4 is a serine/threonine-specific protein kinase belonging to the tyrosine-like kinase (TLK) family of interleukin-1, 18, 33 receptors and Toll-like receptors.
  • TLK tyrosine-like kinase
  • the extracellular signal molecule binds to the interleukin receptor or Toll-like receptor, it recruits to form the MyD88:IRAK4:IRAK1/2 polyprotein complex, which leads to phosphorylation of IRAK1/2, mediating a series of downstream signaling, thereby activating p38 and JNK.
  • the NF-kB signaling pathway ultimately leads to the expression of pro-inflammatory cytokines.
  • IRAK4 has become an important therapeutic target and has attracted a wide range of research and development interests.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • n is selected from: 1 or 2;
  • n is selected from: 0, 1, 2 or 3;
  • R 1 is selected from H, CN, OH, or selected from those optionally substituted by R
  • R 2 is selected from the group consisting of: H, F, Cl, Br, I;
  • R 3 is selected from OH, NH 2 , CN, halogen, or selected from C 1 1-3 alkyl, C 1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • L is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -;
  • L 1 is selected from: O or NH
  • Ring A is selected from a 4-6 membered heterocycloalkyl group
  • R is selected from F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkyl, C 1-3 heteroalkyl optionally substituted by 1, 2 or 3 R';
  • R' is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CN, CF 3 ;
  • hetero of the C 1-3 heteroalkyl group and the 4-6 membered heterocycloalkyl group are each independently selected from: N, O, S, NH;
  • the number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
  • R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, R' The invention is defined.
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et,
  • R 1 is selected from the group consisting of: H, CN, OH,
  • the structural unit Selected from: H, CN, OH, R 1 is as defined in the present invention.
  • the structural unit From:
  • the ring A is selected from the group consisting of morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl.
  • R 3 is selected from the group consisting of OH, NH 2 , CN, halogen, or selected from the group consisting of 1, 2 or 3 R: Me, Et, -NHCH 3 , R, as in the present invention definition.
  • R 3 is selected from the group consisting of OH, NH 2 , CN, F, Cl, Br, I, Me, Et, -NHCH 3 ,
  • the structural unit From: R 3 and m are as defined by the present invention.
  • the structural unit From:
  • the two R 3s are connected together, the structural unit Selected from
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, other variables such as As defined above.
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et, Other variables are as defined above.
  • R 1 is selected from the group consisting of: H, CN, OH, Other variables are as defined above.
  • the above ring A is selected from the group consisting of morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, and other variables are as defined above.
  • R 3 is selected from the group consisting of OH, NH 2 , CN, halogen, or selected from the group consisting of: 1, 2 or 3 R: Me, Et, -NHCH 3 , other variables as described above definition.
  • R 3 is selected from the group consisting of OH, NH 2 , CN, F, Cl, Br, I, Me, Et, -NHCH 3 , Other variables are as defined above.
  • the two R 3s are connected together, the structural unit Selected from Other variables are as defined above.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • the present invention also provides a compound of the formula: or a pharmaceutically acceptable salt thereof:
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a medicament for treating IRAK4.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acids such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A.
  • the substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a hetero atom which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (i.e., C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, anthracycline, benzimidazolyl, benzofuranyl, benzofurylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl, ind
  • heteroalkyl by itself or in conjunction with another term denotes a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • a heteroatom or heteroatom can be located at any internal position of a heteroalkyl group, including where the heteroalkyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thio) Alkoxy) is a conventional expression and refers to those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Examples include, but are not limited to, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S -CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 .
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • heterocycloalkyl a heteroatom
  • heterocycloalkyl groups include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • the invention obtains a series of 4 fused ring compounds with greatly improved permeability and improved metabolic stability, and has better drug properties and higher kinase selectivity.
  • a solution of the compound A1-3 (90 g, 304.72 mmol, 1.00 eq) of formamide (395.50 g, 8.78 mol, 350.00 mL, 28.82 eq) was placed in an oil bath at 180 ° C for 24 hours. After the reaction was completed, the reaction solution was lowered. To the room temperature, slowly add water (400 mL) and ethyl acetate (200 mL), stir well, and then stand to separate the layers. After liquid separation, the aqueous phase was extracted with ethyl acetate (150 mL ⁇ 5) for 5 times, and the organic phase was combined.
  • reaction mixture was cooled to room temperature, and then added with 20 mL of brine, and the mixture was combined with ethyl acetate (20 mL ⁇ 3), and the organic phase was combined, and the organic phase was washed with saturated brine (20 mL ⁇ 2) Filtration and removal of the filtrate by rotary evaporation under reduced pressure afforded crude material.
  • Diisopropylethylamine (12.60 g, 97.47 mmol, 16.98 mL, 1.5 eq) was added sequentially to a solution of compound WX001-4 (5.8 g, crude) in N,N-dimethylformamide (300 mL) HATU (37.06 g, 97.47 mmol, 1.5 eq) and aqueous ammonia (11.39 g, 97.47 mmol, 12.51 mL, 1.5 eq). After the reaction was completed, 150 mL of water was added to the reaction solution to quench the reaction, and the quenched reaction liquid was evaporated under reduced pressure to remove the solvent to obtain a crude product.
  • HATU 54.91 mg, 144.40 umol, 2.00 eq
  • 2,2,2-trifluoroethylamine 14.30 mg, 144.40 umol, 11.35 uL, 2.00 eq
  • WX001-4 30.00 mg
  • acetonitrile 1.00mL
  • the crude product was prepared by high performance liquid chromatography column (column: Boston Green ODS 150*30) 5u; mobile phase: [water (0.1% trifluoroacetic acid)-ACN]; B%: 18%-48%, 8 min) isolated WX002.
  • the compound W1003 was synthesized from the intermediates A1 and B5.
  • the compound WX004-1 was synthesized from the intermediates A1 and B6, and subjected to preparative liquid chromatography (column: Boston Green ODS 150 mm*30 mm 5 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)- ACN]; B%: 28%-38%, 8min) After separation, most of the products were tested as WX004, and the separated solution was concentrated under reduced pressure, then 1 drop of trifluoroacetic acid was added, stirred for 1 hour, and then decompressed again. The solvent was removed by rotary evaporation to give WX004.
  • Triethylamine (464.47 mg, 4.59 mmol, 636.26 uL, 2.00 eq), 4-dimethylaminopyridine (28.04 mg, 229.50 umol, 0.10 eq) and p-toluenesulfonyl chloride (656.32 mg, 3.44 mmol) at 0 °C , 1.50 eq) was added to a solution of WX005-1 (580.00 mg, 2.30 mmol, 1.00 eq) in dichloromethane (1 mL), and the reaction mixture was slowly warmed to room temperature. After stirring for 2 hours, the reaction solution was poured into 3 mL of 0.5 M.
  • WX008 was synthesized using the intermediates A1 and B7 as raw materials.
  • the crude product was separated by high performance liquid chromatography (column: Phenomenex Synergi C18 150mm*25mm*10 ⁇ m; mobile phase: water (0.1% trifluoroacetic acid)-ACN]; B%: 9%-39%, 13min), and WX011 was obtained.
  • Zinc powder (3.19 g, 48.72 mmol, 2.00 eq) and triethyl chlorosilane (8.00 g, 53.10 mmol, 8.99 mL, 2.18 eq) were sequentially added to 20 mL of acetonitrile at -20 ° C and stirred for 10 minutes.
  • Ethyl dibromofluoroacetate (16.07 g, 60.90 mmol, 2.50 eq) was added to the reaction mixture.
  • 2-cyclopenten-1-one (2.00 g, 24.36 mmol, 2.04 mL, 1.00 eq. ) was added to the reaction solution.
  • Phosphorus oxychloride (941.97 mg, 6.14 mmol, 570.89 ⁇ L, 3.5 eq) was added to compound WX012-3 (0.55 g, 1.76 mmol, 1 eq) and formamide (5.65 g, 125.44 mmol, 5 mL). In a mixture of 71.47 eq), the temperature was slowly raised to 25 ° C and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into water (10 mL), and the pH was adjusted to 9 with a saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate (10 mL ⁇ 3) three times, and the organic phase was combined, and the mixture was washed with saturated brine.
  • the aqueous phase was adjusted to pH 2 with dilute hydrochloric acid (1M), and ethyl acetate (10 mL ⁇ 4) The extraction was carried out four times, and the aqueous phase was evaporated to remove the solvent by evaporation under reduced pressure to give compound WX ⁇ /RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ RTIgt;
  • Diisopropylethylamine (49.76 mg, 385.02 ⁇ mol, 67.24 ⁇ L, 1.50 eq) was added to a solution of compound WX013-2 (110.00 mg, 256.68 ⁇ mol, 1.00 eq) in DMF (3.00 mL).
  • HATU 146.40 mg, 385.02 ⁇ mol, 1.50 eq
  • aqueous ammonia 44.98 mg, 385.02 umol, 49.43 ⁇ L, 1.50 eq
  • the quenched reaction mixture was extracted with ethyl acetate (10 mL ⁇ 8), and the organic phase was combined, and the organic phase was washed with saturated brine (50 mL) Dry over sodium sulfate, filter, and remove the solvent by rotary evaporation under reduced pressure to give a crude material.
  • Example 14 the synthesis was carried out using the intermediate A2, the compound 3,3-difluoropyrrolidine hydrochloride as a starting material.
  • the crude product was separated by preparative high performance liquid chromatography (column: Phenomenex Synergi C18 150*25*10 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)-ACN]; B%: 9%-39%, 13 min), and WX014A was obtained. And WX014B.
  • HPLC XBridge C18UPLC column: 3.5um, 3.0 *50mm, method: 10-80CD_4min, retention time: 2.260min
  • HPLC XBridge C18UPLC column: 3.5 ⁇ m, 3.0*50 mm, method: 10-80 CD_4 min, retention time: 2.197
  • Example 14 the intermediate A2 and the compound 4,4-difluoropiperidine were synthesized as raw materials, and the crude product was separated by preparative high performance liquid chromatography (column: Phenomenex Gemini 150*25 mm*10 ⁇ m; mobile phase: [water ( 0.05% ammonia water v/v)-ACN]; B%: 30%-60%, 12min), obtained WX015, and then separated by SFC (column: AD (250mm*30mm, 10 ⁇ m); mobile phase: [0.1% ammonia water methanol ]; B%: 30%-30%, 4min; 100min), obtain WX015-P1&P2, WX015-P3, WX015-P4, and then separate by SFC (column: AS (250mm*30mm, 5 ⁇ m); mobile phase: [ 0.1% ammonia water methanol]; B%: 30%-30%, 4.4min; 60min), preparative high performance liquid chromatography separation (column: Phenomenex Gemini 150
  • Example 14 the synthesis was carried out using the intermediates A2 and B8 as raw materials, and the crude product was prepared by high performance liquid chromatography (column: Phenomenex Synergi C18 150 mm*25 mm*10 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile) ]; B%: 16%-43%, 12 min) WX016 was obtained after separation.
  • Test Example 1 In vitro evaluation
  • Buffer conditions 20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij 35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO.
  • Test procedure The test compound was dissolved in DMSO at room temperature to prepare a 10 mM solution for use.
  • the substrate is dissolved in a freshly prepared buffer, and the kinase to be tested is added thereto and mixed well.
  • a DMSO solution in which the test compound was dissolved was added to the above mixed reaction solution by an acoustic technique (Echo 550).
  • the concentration of the compound in the reaction mixture was 10 ⁇ M, 3.33 ⁇ M, 1.11 ⁇ M, 0.370 ⁇ M, 0.123 ⁇ M, 41.2 nM, 13.7 nM, 4.57 nM, 1.52 nM, 0.508 nM.
  • the kinase activity data was expressed as an alignment of the kinase activity of the test compound and the kinase activity of the blank group (DMSO only), and the IC50 value was obtained by curve fitting by Prism4 software (GraphPad), and the experimental results are shown in Table 2.
  • Table 1 Information on kinases, substrates and ATP in in vitro assays.
  • the compounds of the invention exhibit good inhibitory activity against IRAK4.
  • Human liver microsomes were purchased from BD and mouse liver microsomes were purchased from Xenotech. Positive controls were testosterone (3A4 substrate), propafenone (2D6 substrate) and diclofenac (2C9 substrate).
  • the test compound and the positive drug were incubated at a concentration of 1 ⁇ M, and were incubated with liver microparticles at 37 ° C, and the liver microsomal protein concentration was 0.5 mg/ml. After incubation for 0, 5, 10, 20, 30 and 60 minutes, respectively, a cold acetonitrile containing an internal standard was added to stop the reaction. The test compound and the microsomes were incubated for 60 minutes without the action of the NADPH regeneration system. Samples were analyzed by LC/MS/MS and the elimination of the compounds was evaluated by the peak area ratio of the analyte to the internal standard.
  • Test Example 3 Two-way permeability study of MDR1-MDCK cells
  • MDR1-MDCKII cells introduced from the Netherlands Cancer Institute (NKI) were used, and the cells were seeded at BD Falcon's Transwell-96 well plate at a density of 2.3 ⁇ 10 5 cells/cm 2 and placed in a carbon dioxide culture incubator. The medium was cultured for 4 to 7 days and used for experiments.
  • test compound was diluted to 2 ⁇ M with 10 mM DSMO stock solution in HBSS transport buffer and used on the apical or basal side of the monolayer.
  • the permeability of the compound from the top side to the substrate side or from the substrate side to the top side was tested using a two sample.
  • the positive drug digoxin was also tested for permeability from the apical side to the basal side or from the basal side to the apical side at an incubation concentration of 2 ⁇ M, but not from the apical side to the basal side when the incubation concentration was 2 ⁇ M for Norbert and Propranolol. Permeability.
  • the cell plates were incubated for 150 minutes in a cell incubator at 37 ⁇ 1 ° C, 5% CO 2 and saturated relative humidity. In addition, the efflux ratio of the test compound was simultaneously tested. Semi-quantitative analysis of the test substance and the reference compound was carried out by LC-MS/MS method based on the peak area ratio of the analyte and the internal standard.
  • the integrity of the MDR1-MDCK II cell membrane was measured using a Lucifer Yellow Rejection Assay.
  • the buffer at the top side and the base side was removed, then 75 ⁇ L of 100 ⁇ M fluorescent yellow buffer was added, and 250 ⁇ L of HBSS transport buffer was added to the top side and the base side, respectively.
  • the relative fluorescence unit (RFU) of the fluorescent yellow in the sample was detected at the 425/528 nm (excitation/emission) spectrum using an M2 e plate reader.
  • dC r /d t is the cumulative concentration of the compound at the receiving end per unit time ( ⁇ M/s); the volume of the solution at the receiving end of Vr (the volume of the solution at the top and the base end are 0.075 and 0.25 mL, respectively; A is the relative surface area of the cell monolayer ( 0.0804 cm 2 ); C 0 is the initial concentration (nM) of the test article at the drug delivery end or the peak area ratio of the control.
  • the efflux is calculated using the following formula:
  • the recovery rate is calculated using the following formula:
  • C 0 is the initial concentration (nM) of the test end or the peak area ratio of the control
  • V d is the volume of the drug end (0.075 mL on the top side and 0.25 mL on the basal side)
  • C d and C r The final concentration (nM) of the test sample and the peak area ratio of the reference substance for the drug delivery end and the receiving end, respectively.
  • Test Example 4 Study on pharmacokinetic parameters
  • mice Six healthy adult female Lewis rats (7-9 weeks old, purchased from pharmacokinetic parameters) were selected, 3 were intravenous injection group, and 3 were oral group.
  • the candidate compound was mixed with an appropriate amount of intravenous vehicle (5% dimethyl sulfoxide + 10% HP- ⁇ -CD + 0.5% sodium carboxymethylcellulose + 84.5% deionized water), vortexed and sonicated to prepare 0.5
  • the clear solution was mg/mL, and the microporous membrane was filtered and used; the oral medium was 0.5% methylcellulose aqueous solution, and the candidate compound was mixed with the solvent, vortexed and sonicated to prepare a 0.5 mg/mL uniform suspension for use.
  • mice After 1 mg/kg of mice were administered intravenously or 2.5 mg/kg orally, whole blood was collected for a certain period of time, plasma was prepared, and the drug concentration was analyzed by LC-MS/MS method and calculated by Phoenix WinNonlin software (Pharsight, USA). Pharmacokinetic parameters. As shown in Table 5 below:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé polycyclique tenant lieu d'inhibiteur d'IRAK4 ainsi que son utilisation dans la préparation d'un médicament pour le traitement de maladies associées à IRAK4. L'invention concerne plus particulièrement un composé de formule I et son sel pharmaceutiquement acceptable. (I)
PCT/CN2018/093090 2017-06-27 2018-06-27 Inhibiteur d'irak4 Ceased WO2019001461A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710502669 2017-06-27
CN201710502669.4 2017-06-27

Publications (1)

Publication Number Publication Date
WO2019001461A1 true WO2019001461A1 (fr) 2019-01-03

Family

ID=64740397

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/093090 Ceased WO2019001461A1 (fr) 2017-06-27 2018-06-27 Inhibiteur d'irak4

Country Status (1)

Country Link
WO (1) WO2019001461A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014011902A1 (fr) * 2012-07-11 2014-01-16 Nimbus Iris, Inc. Inhibiteurs d'irak et leurs utilisations
US20140018361A1 (en) * 2012-07-11 2014-01-16 Nimbus Iris, Inc. Irak inhibitors and uses thereof
CN104582705A (zh) * 2012-01-10 2015-04-29 林伯士艾瑞斯公司 白介素-1受体相关激酶(irak)抑制剂和其用途
CN105142639A (zh) * 2013-01-10 2015-12-09 林伯士艾瑞斯公司 Irak抑制剂和其用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104582705A (zh) * 2012-01-10 2015-04-29 林伯士艾瑞斯公司 白介素-1受体相关激酶(irak)抑制剂和其用途
WO2014011902A1 (fr) * 2012-07-11 2014-01-16 Nimbus Iris, Inc. Inhibiteurs d'irak et leurs utilisations
US20140018361A1 (en) * 2012-07-11 2014-01-16 Nimbus Iris, Inc. Irak inhibitors and uses thereof
CN105142639A (zh) * 2013-01-10 2015-12-09 林伯士艾瑞斯公司 Irak抑制剂和其用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KELLY, P.N ET AL.: "Selective Interleukin 1 Receptor Associated Kinase 4 Inhibitors for the Treatment of Autoimmune Disorders and Lymphoid Malignancy", J. EXP. MED., vol. 212, no. 13, 31 December 2015 (2015-12-31), pages 2189 - 2201, XP055562600 *
SCOTT, J.S. ET AL.: "Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin 1 Receptor Associated Kinase 4 ( IRAK 4) for the Treatment of Mutant MYD88L265P Diffuse Large B Cell Lymphoma", J. MED. CHEM., vol. 60, 27 November 2017 (2017-11-27), pages 10071 - 10091, XP055562599 *

Similar Documents

Publication Publication Date Title
CN110944989B (zh) 作为egfr激酶抑制剂的芳基磷氧化合物
JP6600365B2 (ja) Ｊａｋ阻害剤
CN110198943B (zh) 作为Wee1抑制剂的1,2-二氢-3H-吡唑[3,4-d]嘧啶-3-酮衍生物
JP7008064B2 (ja) Ｆｇｆｒ４阻害剤としてのヘテロ環式化合物
CN111683928B (zh) 作为fgfr抑制剂的吡嗪-2(1h)-酮类化合物
BRPI0910690B1 (pt) derivados de 1-heterociclil-1,5-di-hidro-pirazolo[3,4-d]pirimidin-4-ona
CN111372937B (zh) 噻吩并二氮杂卓衍生物及其应用
KR102513448B1 (ko) Cdk4/6 억제제
CN111655689B (zh) 吡唑并吡啶酮化合物
CN111655690B (zh) 吡唑并吡啶酮化合物
ES2996878T3 (en) New quinolinone compounds
WO2019034075A1 (fr) Inhibiteur de fgfr et egfr
CN112243438B (zh) 作为IRAK4抑制剂的异噻唑并[5,4-d]嘧啶类化合物
WO2023071998A1 (fr) Nouveau composé pyrido ou pyrido hétérocyclique à substitution triazine
CN113227100B (zh) 噻吩并吡啶酮化合物
WO2019001461A1 (fr) Inhibiteur d'irak4
CN115991681B (zh) 亲脂性5-ht2b拮抗剂
CN106905315B (zh) 四氢吡啶并[3,4-d]嘧啶类化合物及其制备方法和应用
RU2827549C2 (ru) Соединения тиенопиридинона
WO2019001460A1 (fr) Composé polycyclique tenant lieu d'inhibiteur d'irak4
WO2017213210A1 (fr) Composé hétérocyclique
CN111362928A (zh) 2,4-二氨基嘧啶衍生物
HK40026523B (en) Thienodiazepine derivatives and application thereof
HK40026523A (en) Thienodiazepine derivatives and application thereof
HK40037152B (en) Pyrazolopyridinone compounds

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: 18823880

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: 18823880

Country of ref document: EP

Kind code of ref document: A1