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WO2018052058A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

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Publication number
WO2018052058A1
WO2018052058A1 PCT/JP2017/033199 JP2017033199W WO2018052058A1 WO 2018052058 A1 WO2018052058 A1 WO 2018052058A1 JP 2017033199 W JP2017033199 W JP 2017033199W WO 2018052058 A1 WO2018052058 A1 WO 2018052058A1
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Prior art keywords
group
compound
acid
aromatic heterocyclic
salt
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English (en)
Japanese (ja)
Inventor
雅都 吉田
祐介 冨成
善右 塩川
章人 渋谷
和明 ▲高▼見
ギブソン、トニー
新吉 鈴木
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero 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
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention has an interleukin 1 receptor-related kinase 4 (IRAK-4) inhibitory action and is useful for the prevention and treatment of inflammatory diseases, autoimmune diseases, bone / joint degenerative diseases, neoplastic diseases and the like.
  • IRAK-4 interleukin 1 receptor-related kinase 4
  • the present invention relates to an expected heterocyclic compound and a medicine containing the same.
  • IRAK-4 is a member of the IRAK family of protein kinases, all Toll-like receptors (TLRs) except TLR3 and interleukin 1, 18, 33 receptors (IL-1R, IL-18R, IL-33R) ) Downstream (Non-Patent Document 1).
  • TLRs Toll-like receptors
  • IL-1R, IL-18R, IL-33R interleukin 1, 18, 33 receptors
  • IRAK-4 and MyD88 are thought to contribute to physiological responses such as defense against pathogens, control of inflammation, innate and acquired immunity, cell survival, and cell proliferation by controlling the production of inflammatory mediators. . Furthermore, in addition to acute and chronic inflammatory diseases, it is also involved in autoimmune diseases such as rheumatoid arthritis (Non-patent document 3), systemic lupus erythematosus (Non-patent document 4), and multiple sclerosis (Non-patent document 5) ( Non-patent document 6).
  • Non-patent Document 7 Non-patent Document 7
  • IRAK-4 inhibitors may have high efficacy in the treatment of acute and chronic inflammatory diseases, autoimmune diseases and cancer.
  • Examples of the compound having a structure similar to the compound described in the present specification include the following.
  • An IRAK-4 inhibitor which is useful for the prevention or treatment of inflammatory diseases, autoimmune diseases, etc.
  • IRAK-4 inhibitor which is useful for the prevention or treatment of inflammatory diseases, autoimmune diseases, etc.
  • R 1 represents an optionally substituted aromatic heterocyclic group or an optionally substituted C 6-14 aryl group
  • R 2 represents a hydrogen atom or a substituent
  • R 3 and R 4 independently represent a hydrogen atom or a substituent, or R 3 and R 4 may be combined to form an optionally substituted ring
  • R 5 and R 6 independently represent a hydrogen atom or a substituent, or R 5 and R 6 may be combined to form an optionally substituted ring
  • X represents CR 7 R 8 , NR 9 , O or S
  • R 7 and R 8 independently represent a hydrogen atom or a substituent, or R 7 and R 8 may be combined to form an optionally substituted ring
  • R 9 represents a hydrogen atom or a substituent.
  • An object of the present invention is a heterocyclic compound that has IRAK-4 inhibitory action and is expected to be useful for the prevention and treatment of inflammatory diseases, autoimmune diseases, bone / joint degenerative diseases, neoplastic diseases, and the like, and It is to provide a medicament containing it.
  • the present inventors have found that the compound represented by the following formula (I) has an excellent IRAK-4 inhibitory action, and therefore, inflammatory diseases, autoimmune diseases,
  • the present inventors have found that it can be useful for the prevention and treatment of bone / joint degenerative diseases, neoplastic diseases and the like, and have completed the present invention. That is, the present invention is as follows.
  • R 1 represents an optionally substituted aromatic heterocyclic group or an optionally substituted C 6-14 aryl group
  • R 2 , R 3 , R 4 , R 5 and R 6 independently represent a hydrogen atom or a substituent.
  • a salt thereof hereinafter also referred to as compound (I)).
  • R 1 is an optionally substituted aromatic heterocyclic group
  • R 2 is a C 1-6 alkyl group
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom
  • R 5 is a hydrogen atom or a C 1-6 alkyl group
  • R 6 is a hydrogen atom or a C 1-6 alkyl group
  • R 1 is (1) a 5- to 14-membered aromatic heterocyclic group optionally substituted with 1 to 3 mono- or di-C 1-6 alkylamino groups optionally substituted with 1 to 3 halogen atoms, and (2) optionally substituted with 1 to 3 substituents selected from (i) an oxo group, and (ii) a C 1-6 alkyl group optionally substituted with 1 to 3 amino groups
  • the medicament according to [8] above which is an interleukin 1 receptor-related kinase 4 inhibitor.
  • a method for inhibiting interleukin 1 receptor-related kinase 4 in a mammal comprising administering an effective amount of the compound or salt thereof according to [1] to the mammal.
  • a method for preventing or treating an autoimmune disease and / or inflammatory disease in a mammal comprising administering an effective amount of the compound or salt thereof according to [1] to the mammal.
  • Compound (I) has an excellent IRAK-4 inhibitory action, and may be useful as a preventive or therapeutic agent for inflammatory diseases, autoimmune diseases, bone / joint degenerative diseases, neoplastic diseases, and the like.
  • each substituent has the following definition.
  • examples of the “halogen atom” include fluorine, chlorine, bromine and iodine.
  • examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl.
  • Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2- Difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tri Examples include fluoropentyl, hexyl, and 6,6,6-trifluorohexyl.
  • examples of the “C 2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- Examples include methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
  • examples of the “C 2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Examples include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl.
  • examples of the “C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] octyl, and adamantyl.
  • the "optionally halogenated C 3-10 also be cycloalkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 3- A 10 cycloalkyl group.
  • examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • examples of the “C 3-10 cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • examples of the “C 6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.
  • examples of the “C 7-16 aralkyl group” include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.
  • examples of the “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • the "optionally halogenated C 1-6 alkoxy group” for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkoxy group is mentioned.
  • Examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyl.
  • Examples include oxy and hexyloxy.
  • examples of the “C 3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
  • examples of the “C 1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
  • the "optionally halogenated C 1-6 alkylthio group optionally" for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkylthio group is mentioned.
  • examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio.
  • examples of the “C 1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2- Examples include dimethylpropanoyl, hexanoyl, and heptanoyl.
  • examples of the “ optionally halogenated C 1-6 alkyl-carbonyl group” include C 1 optionally having 1 to 7, preferably 1 to 5 halogen atoms.
  • a -6 alkyl-carbonyl group is mentioned. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
  • examples of the “C 1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, Examples include pentyloxycarbonyl and hexyloxycarbonyl.
  • examples of the “C 6-14 aryl-carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
  • examples of the “C 7-16 aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl.
  • examples of the “5- to 14-membered aromatic heterocyclic carbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.
  • examples of the “3- to 14-membered non-aromatic heterocyclic carbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.
  • examples of the “mono- or di-C 1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl.
  • examples of the “mono- or di-C 7-16 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.
  • examples of the “C 1-6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
  • the "optionally halogenated C 1-6 alkyl sulfonyl group” for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1- 6 alkylsulfonyl group is mentioned.
  • examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl.
  • examples of the “C 6-14 arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.
  • examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, and a substituted group.
  • An optionally substituted amino group an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl ( SH) group and optionally substituted silyl group.
  • examples of the “hydrocarbon group” include, for example, a C 1-6 alkyl group, a C 2-6 alkenyl group, Examples thereof include a C 2-6 alkynyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group, and a C 7-16 aralkyl group.
  • examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group which may have a substituent selected from the following substituent group A.
  • substituent group A (1) a halogen atom, (2) Nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C 1-6 alkoxy group, (7) C 6-14 aryloxy group (eg, phenoxy, naphthoxy), (8) C 7-16 aralkyloxy group (eg, benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy), (10) 3 to 14-membered non-aromatic heterocyclic oxy group (eg, morpholinyloxy, piperidinyloxy), (11) C 1-6 alkyl-carbonyloxy group (eg, acetoxy, propanoyloxy), (12) C 6-14 aryl-carbony
  • the number of the substituents in the “optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
  • examples of the “heterocyclic group” include, for example, a nitrogen atom, a sulfur atom and a ring atom other than a carbon atom.
  • an aromatic heterocyclic group (ii) a non-aromatic heterocyclic group, and (iii) a 7 to 10-membered heterocyclic bridge group each containing 1 to 4 heteroatoms selected from oxygen atoms .
  • the “aromatic heterocyclic group” (including the “5- to 14-membered aromatic heterocyclic group”) is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • Suitable examples of the “aromatic heterocyclic group” include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1 5-, 6-membered monocyclic aromatic heterocyclic groups such as 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl; Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyri
  • non-aromatic heterocyclic group examples include, for example, a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom 3 to 14-membered (preferably 4 to 10-membered) non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from Suitable examples of the “non-aromatic heterocyclic group” include aziridinyl, oxiranyl, thiylyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolidinyl, pyra
  • preferable examples of the “7 to 10-membered heterocyclic bridged ring group” include quinuclidinyl and 7-azabicyclo [2.2.1] heptanyl.
  • examples of the “nitrogen-containing heterocyclic group” include those containing at least one nitrogen atom as a ring-constituting atom among the “heterocyclic groups”.
  • examples of the “optionally substituted heterocyclic group” include a heterocyclic group which may have a substituent selected from the substituent group A described above.
  • the number of substituents in the “optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
  • acyl group is, for example, “1 selected from a halogen atom, an optionally halogenated C 1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group.
  • the “acyl group” also includes a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclic-sulfinyl group.
  • the hydrocarbon-sulfonyl group is a sulfonyl group to which a hydrocarbon group is bonded
  • the heterocyclic-sulfonyl group is a sulfonyl group to which a heterocyclic group is bonded
  • the hydrocarbon-sulfinyl group is a hydrocarbon group.
  • a sulfinyl group to which is bonded and a heterocyclic-sulfinyl group mean a sulfinyl group to which a heterocyclic group is bonded.
  • the “acyl group” a formyl group, a carboxy group, a C 1-6 alkyl-carbonyl group, a C 2-6 alkenyl-carbonyl group (eg, crotonoyl), a C 3-10 cycloalkyl-carbonyl group ( Examples, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 cycloalkenyl-carbonyl group (eg, 2-cyclohexenecarbonyl), C 6-14 aryl-carbonyl group, C 7-16 aralkyl- Carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered
  • Diallylcarbamoyl mono- or di-C 3-10 cycloalkyl-carbamoyl group (eg, cyclopropylcarbamoyl), mono- or di-C 6-14 aryl-carbamoyl group (eg, phenylcarbamoyl), mono- or Di-C 7-16 aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6 alkyl-thiocarbamoyl group (eg, methylthio) Carbamoyl, N-ethyl-N-methyl Okarubamoiru), mono - or di -C 2-6 alkenyl - thiocarbamoyl group (e.g., diallyl thio carbamoyl), mono - or di cycl
  • examples of the “optionally substituted amino group” include, for example, a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A” C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7 -16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl Groups, mono- or di-C 1-6 alkyl-carbamoyl groups, mono- or di-C 7-16 aralkyl-carbamoyl groups, C 1-6 alkylsulfonyl groups and C 6- And an amino
  • Suitable examples of the optionally substituted amino group include an amino group, a mono- or di- (optionally halogenated C 1-6 alkyl) amino group (eg, methylamino, trifluoromethylamino, Dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 alkenylamino groups (eg, diallylamino), mono- or di-C 3-10 cycloalkylamino groups (eg, Cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 arylamino group (eg, phenylamino), mono- or di-C 7-16 aralkylamino group (eg, benzylamino, dibenzylamino), mono - or di - (optionally halogenated C 1-6 alkyl) - carbonyl amino group (e.g., a Chiru
  • examples of the “optionally substituted carbamoyl group” include, for example, a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A” C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7 -16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di -C 1-6 alkyl - carbamoyl group and mono- - or di -C 7-16 aralkyl - 1 or 2 substituents selected from a carbamoyl group
  • Suitable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group, a mono- or di-C 2-6 alkenyl-carbamoyl group (eg, diallylcarbamoyl group).
  • Mono- or di-C 3-10 cycloalkyl-carbamoyl groups eg cyclopropylcarbamoyl, cyclohexylcarbamoyl
  • mono- or di-C 6-14 aryl-carbamoyl groups eg phenylcarbamoyl
  • mono- or Di-C 7-16 aralkyl-carbamoyl group mono- or di-C 1-6 alkyl-carbonyl-carbamoyl group (eg acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 aryl-carbonyl-carbamoyl Groups (eg, benzoylcarbamoyl)
  • a 5- to 14-membered aromatic heterocyclic carbamoyl group eg, pyridylcarbamoyl
  • pyridylcarbamoyl pyridylcarb
  • examples of the “optionally substituted thiocarbamoyl group” include, for example, “C 1-6 alkyl each optionally having 1 to 3 substituents selected from Substituent Group A” Group, C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di -C 1-6 alkyl - carbamoyl group and mono- - or di -C 7-16 aralkyl - one or two location selected from a carbamoyl
  • thiocarbamoyl group which may be substituted include a thiocarbamoyl group, a mono- or di-C 1-6 alkyl-thiocarbamoyl group (eg, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthio).
  • examples of the “optionally substituted sulfamoyl group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”.
  • the optionally substituted sulfamoyl group include sulfamoyl group, mono- or di-C 1-6 alkyl-sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethyl).
  • examples of the “optionally substituted hydroxy group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”.
  • Suitable examples of the optionally substituted hydroxy group include a hydroxy group, a C 1-6 alkoxy group, a C 2-6 alkenyloxy group (eg, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy).
  • C 3-10 cycloalkyloxy group eg, cyclohexyloxy
  • C 6-14 aryloxy group eg, phenoxy, naphthyloxy
  • C 7-16 aralkyloxy group eg, benzyloxy, phenethyloxy
  • C 1-6 alkyl-carbonyloxy group eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy
  • C 6-14 aryl-carbonyloxy group eg, benzoyloxy
  • C 7-16 aralkyl- A carbonyloxy group eg benzylcarbonyloxy)
  • 5 to 14-membered aromatic heterocyclic carbonyloxy group e.g., nicotinoyl oxy
  • 3 to 14-membered non-aromatic heterocyclic carbonyloxy group e.g., piperidinylcarbonyl oxy
  • examples of the “optionally substituted sulfanyl group” include a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A”.
  • C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group and 5 to Examples thereof include a sulfanyl group optionally having a substituent selected from a 14-membered aromatic heterocyclic group and a halogenated sulfanyl group.
  • the optionally substituted sulfanyl group include a sulfanyl (—SH) group, a C 1-6 alkylthio group, a C 2-6 alkenylthio group (eg, allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 cycloalkylthio group (eg, cyclohexylthio), C 6-14 arylthio group (eg, phenylthio, naphthylthio), C 7-16 aralkylthio group (eg, benzylthio, phenethylthio), C 1-6 alkyl-carbonylthio group (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 aryl-carbonylthio group (eg, benzoylthio), 5-
  • examples of the “optionally substituted silyl group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”
  • a silyl group optionally having 1 to 3 substituents selected from a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group and a C 7-16 aralkyl group ” Can be mentioned.
  • Preferable examples of the optionally substituted silyl group include a tri-C 1-6 alkylsilyl group (eg, trimethylsilyl, tert-butyl (dimethyl) silyl).
  • the “5- or 6-membered nitrogen-containing monocyclic aromatic heterocyclic group” is a 5- or 6-membered monocyclic “heterocyclic group” and has at least one ring-constituting atom. The thing containing the above nitrogen atoms is mentioned.
  • non-aromatic heterocyclic group includes the above “3- to 8-membered monocyclic non-aromatic heterocyclic group” and “9- to 14-membered condensed polycyclic (preferably 2- or 3-cyclic).
  • Non-aromatic heterocyclic group triazaspirononyl (eg, 1,3,7-triazaspiro [4.4] nonyl), thiadiazaspirononyl (eg, 7-thia-1,3- Diazaspiro [4.4] nonyl), dioxide thiadiazaspirononyl (eg, 7,7-dioxide-7-thia-1,3-diazaspiro [4.4] nonyl), etc.
  • a cyclic group is mentioned.
  • R 1 represents an optionally substituted aromatic heterocyclic group or an optionally substituted C 6-14 aryl group.
  • aromatic heterocyclic group of the “optionally substituted aromatic heterocyclic group” represented by R 1 is preferably a 5- to 14-membered aromatic heterocyclic group, more preferably 5 or A 6-membered monocyclic aromatic heterocyclic group, more preferably a 5- or 6-membered monocyclic nitrogen-containing aromatic heterocyclic group, more preferably oxazolyl (eg, oxazolyl-4-yl) or pyridyl It is.
  • R 1 in the "optionally substituted C 6-14 aryl group" as the “C 6-14 aryl group” is preferably phenyl.
  • each “group” may have 1 to 3 substituents at substitutable positions. When a plurality of substituents are present, each substituent may be the same or different.
  • R 1 aromatic heterocyclic group of the “optionally substituted aromatic heterocyclic group”
  • C 6-14 aryl optionally substituted C 6-14 aryl group
  • substituent for example, a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group (the “heterocyclic group” A substituent selected from group A (which may further be substituted with a substituent selected from substituent group A)), an acyl group, or a substituent A good amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) ) Group, and position It includes a silyl group which may optionally be.
  • R 1 aromatic heterocyclic group of the “optionally substituted aromatic heterocyclic group”
  • C 6-14 aryl optionally substituted C 6-14 aryl group
  • the “substituent” of the “group” include an optionally substituted heterocyclic group (for example, a substituent selected from the substituent group A (the substituent is further selected from the substituent group A). And a heterocyclic group optionally having a substituent).
  • R 1 is preferably an optionally substituted aromatic heterocyclic group, more preferably an optionally substituted 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group. More preferably, it is an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, and even more preferably, an optionally substituted 5- or 6-membered nitrogen-containing monocyclic aromatic heterocyclic ring A group (preferably oxazolyl (eg, oxazolyl-4-yl) or pyridyl).
  • R 1 is preferably an optionally substituted aromatic heterocyclic group, more preferably an optionally substituted 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group. More preferably, it is an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group, and even more preferably, an optionally substituted 5- or 6-membered nitrogen-containing monocyclic aromatic heterocyclic ring A group (preferably oxazolyl (eg, ox
  • R 1 is preferably (1) 1 to 3 substituted by mono- or di-C 1-6 alkylamino group (eg, ethylamino) optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom)
  • a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
  • (2) (i) an oxo group, and (ii) a C 1-6 alkyl group optionally substituted with 1 to 3 amino groups (eg, methyl)
  • a 3- to 14-membered non-aromatic heterocyclic group preferably a 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, imidazolidinyl)
  • To 14-membered spiro-type heterocyclic group eg, 1,3,7-triazaspir
  • R 2 , R 3 , R 4 , R 5 and R 6 independently represent a hydrogen atom or a substituent.
  • R 2 is preferably an optionally substituted C 1-6 alkyl group (eg, methyl).
  • R 2 is more preferably a C 1-6 alkyl group (eg, methyl).
  • R 3 and R 4 are preferably both hydrogen atoms.
  • R 5 and R 6 are preferably independently a hydrogen atom or an optionally substituted C 1-6 alkyl group (eg, methyl).
  • R 5 and R 6 are more preferably independently a hydrogen atom or a C 1-6 alkyl group (eg, methyl).
  • Preferred examples of compound (I) include the following:
  • R 1 is an optionally substituted aromatic heterocyclic group (preferably a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group);
  • R 2 is a C 1-6 alkyl group;
  • R 3 is a hydrogen atom;
  • R 4 is a hydrogen atom;
  • R 5 is a hydrogen atom or a C 1-6 alkyl group;
  • R 6 is a hydrogen atom or a C 1-6 alkyl group, Compound (I).
  • R 1 is (1) 1 to 3 substituted by mono- or di-C 1-6 alkylamino group (eg, ethylamino) optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom)
  • a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
  • (2) (i) an oxo group, and (ii) a C 1-6 alkyl group optionally substituted with 1 to 3 amino groups (eg, methyl)
  • a 3- to 14-membered non-aromatic heterocyclic group preferably a 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, imidazolidinyl)
  • R 1 is (1) 1 to 3 substituted by mono- or di-C 1-6 alkylamino group (eg, ethylamino) optionally substituted by
  • salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like.
  • metal salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salt with organic acid examples include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene And salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • the raw materials and reagents used in each step in the following production method and the obtained compound may each form a salt.
  • Examples of such salts include those similar to the salts of the aforementioned compound of the present invention.
  • the compound obtained in each step is a free compound, it can be converted into a target salt by a method known per se.
  • the compound obtained in each step is a salt, it can be converted into a free form or other types of desired salts by a method known per se.
  • the compound obtained in each step remains in the reaction solution or is obtained as a crude product and can be used in the next reaction.
  • the compound obtained in each step is concentrated from the reaction mixture according to a conventional method. , Crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography and the like, and can be isolated and / or purified.
  • the reaction time may vary depending on the reagent and solvent to be used, but unless otherwise specified, is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.
  • the reaction temperature may vary depending on the reagent and solvent to be used, but is usually ⁇ 78 ° C. to 300 ° C., preferably ⁇ 78 ° C. to 150 ° C. unless otherwise specified.
  • the pressure may vary depending on the reagent and solvent used, but unless otherwise specified, is usually 1 to 20 atmospheres, preferably 1 to 3 atmospheres.
  • a Microwave synthesizer such as an initiator manufactured by Biotage may be used.
  • the reaction temperature may vary depending on the reagent and solvent to be used, but unless otherwise specified, is usually room temperature to 300 ° C., preferably 50 ° C. to 250 ° C.
  • the reaction time may vary depending on the reagent and solvent to be used, but unless otherwise specified, is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.
  • the reagent is used in an amount of 0.5 equivalent to 20 equivalents, preferably 0.8 equivalent to 5 equivalents, relative to the substrate.
  • the reagent is used in an amount of 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate.
  • the reagent also serves as a reaction solvent, the amount of solvent is used as the reagent.
  • these reactions are performed without solvent or dissolved or suspended in a suitable solvent.
  • the solvent include the solvents described in the examples or the following.
  • Alcohols methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc .
  • Ethers diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc .
  • Aromatic hydrocarbons chlorobenzene, toluene, xylene, etc .
  • Saturated hydrocarbons cyclohexane, hexane, etc .
  • Amides N, N-dimethylformamide, N-methylpyrrolidone, etc .
  • Halogenated hydrocarbons dichloromethane, carbon tetrachloride, etc .
  • Nitriles acetonitrile, etc.
  • Sulfoxides dimethyl sulfoxide and the like; Aromatic organic bases: pyridine, etc .; Acid anhydrides: acetic anhydride, etc .; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc .; Inorganic acids: hydrochloric acid, sulfuric acid, etc .; Esters: ethyl acetate and the like; Ketones: acetone, methyl ethyl ketone, etc .; water. Two or more of the above solvents may be mixed and used at an appropriate ratio.
  • Inorganic bases sodium hydroxide, magnesium hydroxide, etc .
  • Basic salts sodium carbonate, calcium carbonate, sodium bicarbonate, etc .
  • Organic bases triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]- 7-undecene, imidazole, piperidine and the like
  • Metal alkoxides sodium ethoxide, potassium tert-butoxide and the like
  • Alkali metal hydrides sodium hydride, etc .
  • Metal amides sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc .
  • Organic lithiums n-butyllithium and the
  • an acid or an acidic catalyst is used in the reaction in each step, for example, the following acids and acidic catalysts, or acids and acidic catalysts described in the examples are used.
  • Inorganic acids hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc .
  • Organic acids acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc .
  • Lewis acid boron trifluoride Diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.
  • reaction in each step is a method known per se, for example, the 5th edition Experimental Chemistry Course, Volumes 13 to 19 (Edited by The Chemical Society of Japan); New Experimental Chemistry Course, Volumes 14 to 15 (Japan) Chemistry Association); Fine Organic Chemistry Revised 2nd Edition (L.F.Tietze, Th.Eicher, Nanedo); Revised Organic Name Reaction, its mechanism and points (by Hideo Togo, Kodansha); ORGANIC SYNTHES Collective Volume I-VII ( John Wiley & Sons Inc); Modern Organic Synthesis in the Laboratory A Collection of Standard Exploratory Procedures (Jie Jack Li, UFFOR by JJFORD) VERSITY publication); Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol.
  • the protection or deprotection reaction of the functional group is carried out according to a method known per se, for example, “Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M., et al., Wiley-Interscience). The method described in Thimeme's 2004 “Protecting Groups 3rd Ed.” (By PJ Kocienski) or the like, or the method described in the examples.
  • protecting groups for hydroxyl groups such as alcohol and phenolic hydroxyl groups
  • ether-type protecting groups such as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether, and tetrahydropyranyl ether
  • carboxylate-type protecting groups such as acetate Sulfonic acid ester type protecting groups such as methanesulfonic acid ester
  • carbonic acid ester type protecting groups such as t-butyl carbonate.
  • the protecting group for the carbonyl group of the aldehyde include an acetal-type protecting group such as dimethylacetal; and a cyclic acetal-type protecting group such as cyclic 1,3-dioxane.
  • Examples of the protecting group for the carbonyl group of the ketone include a ketal-type protecting group such as dimethyl ketal; a cyclic ketal-type protecting group such as cyclic 1,3-dioxane; an oxime-type protecting group such as O-methyloxime; N, N— And hydrazone-type protecting groups such as dimethylhydrazone.
  • Examples of the protecting group for carboxyl group include ester-type protecting groups such as methyl ester; amide-type protecting groups such as N, N-dimethylamide.
  • thiol-protecting group examples include ether-type protecting groups such as benzylthioether; ester-type protecting groups such as thioacetate ester, thiocarbonate, and thiocarbamate.
  • protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole and indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamines such as N-triphenylmethylamine Type protecting groups, and sulfonamide type protecting groups such as methanesulfonamide.
  • the protecting group can be removed by a method known per se, for example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (for example, trimethylsilyl iodide). And trimethylsilyl bromide) or a reduction method.
  • a method known per se for example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (for example, trimethylsilyl iodide). And trimethylsilyl bromide) or a reduction method.
  • the reducing agent used is lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride
  • Metal hydrides such as hydrogenated triacetoxy boron tetramethylammonium; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid and the like.
  • a catalyst such as palladium-carbon or a Lindlar catalyst.
  • the oxidizing agent used includes peracids such as m-chloroperbenzoic acid (MCPBA), hydrogen peroxide and t-butyl hydroperoxide; tetrabutylammonium perchlorate, etc.
  • Perchlorates such as sodium chlorate; Chlorites such as sodium chlorite; Periodic acids such as sodium periodate; High-valent iodine reagents such as iodosylbenzene; Manganese dioxide; Reagents having manganese such as potassium manganate; Leads such as lead tetraacetate; Reagents having chromium such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent; N-bromosuccinimide (NBS) Halogen compounds such as oxygen; ozone; sulfur trioxide / pyridine complex; male tetroxide Um; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.
  • PCC pyridinium chlorochromate
  • PDC pyridinium dichromate
  • NBS N-bromosuccinimide
  • the radical initiator used is an azo compound such as azobisisobutyronitrile (AIBN); 4-4′-azobis-4-cyanopentanoic acid (ACPA) Water-soluble radical initiators such as triethylboron in the presence of air or oxygen, and benzoyl peroxide.
  • AIBN azobisisobutyronitrile
  • ACPA 4-4′-azobis-4-cyanopentanoic acid
  • Water-soluble radical initiators such as triethylboron in the presence of air or oxygen, and benzoyl peroxide.
  • the radical reaction reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide.
  • Examples of Wittig reagents used include alkylidene phosphoranes.
  • the alkylidene phosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.
  • the reagents used include phosphonoacetate esters such as methyl dimethylphosphonoacetate and ethyl ethyl diethylphosphonoacetate; bases such as alkali metal hydrides and organolithiums Can be mentioned.
  • the reagent used includes a combination of Lewis acid and acid chloride, or a combination of Lewis acid and an alkylating agent (eg, alkyl halides, alcohols, olefins, etc.). Can be mentioned.
  • an organic acid or an inorganic acid can be used in place of the Lewis acid, and an acid anhydride such as acetic anhydride can be used in place of the acid chloride.
  • a nucleophile eg, amines, imidazole, etc.
  • a base eg, basic salts, organic bases, etc.
  • a nucleophilic addition reaction with a carbanion In each step, a nucleophilic addition reaction with a carbanion, a nucleophilic 1,4-addition reaction with a carbanion (Michael addition reaction), or a nucleophilic substitution reaction with a carbanion, a base used to generate a carbanion Examples thereof include organic lithiums, metal alkoxides, inorganic bases, and organic bases.
  • examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide; alkylmagnesium halides such as methylmagnesium bromide.
  • the Grignard reagent can be prepared by a method known per se, for example, by reacting alkyl halide or aryl halide with metal magnesium using ether or tetrahydrofuran as a solvent.
  • reagents include an active methylene compound (eg, malonic acid, diethyl malonate, malononitrile, etc.) sandwiched between two electron-withdrawing groups and a base (eg, organic bases, Metal alkoxides and inorganic bases) are used.
  • active methylene compound eg, malonic acid, diethyl malonate, malononitrile, etc.
  • a base eg, organic bases, Metal alkoxides and inorganic bases
  • phosphoryl chloride and an amide derivative eg, N, N-dimethylformamide, etc.
  • examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, and sodium azide.
  • DPPA diphenylphosphoryl azide
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like.
  • examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone.
  • examples of amines used include primary amines such as ammonia and methylamine; secondary amines such as dimethylamine and the like.
  • azodicarboxylic acid esters eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.
  • triphenylphosphine eg, triphenylphosphine
  • the reagents used include acyl halides such as acid chloride and acid bromide; acid anhydrides, active ester compounds, and sulfate ester compounds. And activated carboxylic acids.
  • carboxylic acid activators include carbodiimide condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD); 4- (4,6-dimethoxy-1,3,5- Triazine condensing agents such as triazin-2-yl) -4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenyl Azide phosphate (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukayama reagent); thionyl chloride; haloformates such as ethyl chloroformate Lower alkyl; O- (7-azabenzotriazol-1-yl) -N, N, N ′, N
  • additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) may be further added to the reaction.
  • HOBt 1-hydroxybenzotriazole
  • HOSu N-hydroxysuccinimide
  • DMAP dimethylaminopyridine
  • the metal catalyst used is palladium acetate (II), tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethyl).
  • Palladium compounds such as phosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride, palladium (II) acetate; tetrakis (tri Nickel compounds such as phenylphosphine) nickel (0); rhodium compounds such as tris (triphenylphosphine) rhodium (III) chloride; cobalt compounds; copper compounds such as copper oxide and copper iodide (I); platinum compounds and the like It is done. Furthermore, a base may be added to the reaction, and examples of such a base include inorganic bases and basic salts.
  • diphosphorus pentasulfide is typically used as the thiocarbonylating agent.
  • 2,4-bis (4-methoxyphenyl) is used.
  • a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as -1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson reagent) It may be used.
  • halogenating agents used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Is mentioned.
  • the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.
  • the halogenating agent used is an acid halide of hydrohalic acid and an inorganic acid.
  • bromination such as phosphorus chloride include 48% hydrobromic acid.
  • a method of obtaining an alkyl halide from alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide may be used.
  • a method of synthesizing an alkyl halide through a two-step reaction in which an alcohol is converted into a sulfonate ester and then reacted with lithium bromide, lithium chloride, or sodium iodide may be used.
  • examples of the reagent used include alkyl halides such as ethyl bromoacetate; phosphites such as triethyl phosphite and tri (isopropyl) phosphite.
  • examples of the sulfonylating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic acid anhydride, and p-toluenesulfonic acid anhydride.
  • each step when a hydrolysis reaction is performed, an acid or a base is used as a reagent.
  • acid hydrolysis reaction of t-butyl ester is performed, formic acid or triethylsilane may be added in order to reductively trap the t-butyl cation produced as a by-product.
  • examples of the dehydrating agent used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N, N'-dicyclohexylcarbodiimide, alumina, and polyphosphoric acid.
  • the nitrating agent used includes nitric acid, fuming nitric acid, copper nitrate, and the like, and is activated with concentrated sulfuric acid, acetic anhydride, or the like.
  • examples of the diazonium agent used include sodium nitrite and isoamyl nitrite, which are activated by concentrated sulfuric acid, concentrated hydrobromic acid, concentrated hydrochloric acid, and the like.
  • examples of the halogenating agent for the diazonium salt include potassium iodide, copper (I) bromide, and copper (I) chloride.
  • Compound (I) can be produced from compound (1) or compound (7) by the method shown in Scheme A or Scheme B, a method analogous thereto or the method described in Examples.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each have the same meaning as described above, and X represents a halogen atom.
  • halogen atom represented by X is preferably an iodine atom, a bromine atom, or a chlorine atom.
  • Compound (1), Compound (2), and Compound (7) can all be commercially available products, or can be produced by a method known per se or a method analogous thereto.
  • Compound (6) may be a commercially available product, or can be produced by a method known per se, a method analogous thereto, or a method described in Examples.
  • R 1 , R 3 , R 4 , R 5 , R 6 may be converted to other substituents by a method known per se or a method analogous thereto.
  • compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and synthetic methods and separation methods known per se (for example, , Concentration, solvent extraction, column chromatography, recrystallization, etc.), each can be obtained as a single product.
  • synthetic methods and separation methods known per se for example, , Concentration, solvent extraction, column chromatography, recrystallization, etc.
  • the optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.
  • a method known per se for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.
  • Chiral column method A method in which a racemate or a salt thereof is separated through a column for separation of optical isomers (chiral column).
  • a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Chemical Industries), and water, various buffer solutions (eg, phosphorus
  • the optical isomers are separated by developing the solution as an acid buffer or the like and an organic solvent (eg, ethanol, methanol, 2-propanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) alone or as a mixed solution.
  • an organic solvent eg, ethanol, methanol, 2-propanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.
  • separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).
  • Diastereomer method A racemic mixture is converted into a diastereomer mixture by chemical reaction with an optically active reagent, and this is converted into a single substance through ordinary separation means (for example, fractional recrystallization, chromatography, etc.). And then obtaining an optical isomer by separating the optically active reagent site by chemical treatment such as hydrolysis reaction.
  • the compound (I) when the compound (I) has hydroxy or primary or secondary amino in the molecule, the compound and an optically active organic acid (for example, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], ( -)-Menthoxyacetic acid etc.) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively.
  • an amide or ester diastereomer can be obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
  • Compound (I) may be a crystal. Crystals of compound (I) can be produced by applying crystallization methods known per se to compound (I) for crystallization.
  • the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, a crystallization method from a melt, and the like.
  • the “crystallization from solution” includes a state in which the compound is not saturated by changing factors relating to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent.
  • a method of shifting from a supersaturated state to a supersaturated state is exemplified, and specific examples include a concentration method, a slow cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, and a flux method.
  • solvent used examples include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane).
  • aromatic hydrocarbons eg, benzene, toluene, xylene, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • saturated hydrocarbons eg, hexane, heptane, cyclohexane.
  • Etc. ethers
  • ethers eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.
  • nitriles eg, acetonitrile, etc.
  • ketones eg, acetone, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • acid amides Eg, N, N-dimethylformamide, etc.
  • esters eg, ethyl acetate, etc.
  • alcohols eg, methanol, ethanol, 2-propanol, etc.
  • water and the like eg, water and the like.
  • solvents may be used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)).
  • a seed crystal can also be used as needed.
  • Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, a chemical transport method, and the like.
  • crystallization from the melt examples include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method). , Liquid phase epitaxy method) and the like.
  • compound (I) is dissolved in an appropriate solvent (eg, alcohol such as methanol, ethanol, etc.) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved.
  • an appropriate solvent eg, alcohol such as methanol, ethanol, etc.
  • Examples thereof include a method of cooling to a temperature or lower (for example, 0 to 50 ° C., preferably 0 to 20 ° C.).
  • the crystals of the present invention thus obtained can be isolated by, for example, filtration.
  • a method for analyzing the obtained crystal a crystal analysis method by powder X-ray diffraction is generally used. Further, examples of the method for determining the crystal orientation include a mechanical method and an optical method.
  • the crystals of compound (I) obtained by the above production method have high purity and high quality, low hygroscopicity, do not change even when stored for a long time under normal conditions, and are extremely excellent in stability. In addition, it has excellent biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), expression of drug efficacy, etc.) and is extremely useful as a medicine.
  • a prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, it is enzymatically oxidized, reduced, hydrolyzed, etc.
  • Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated and phosphorylated [eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated.
  • prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.
  • compound (I) and prodrugs of compound (I) may be collectively abbreviated as “the compound of the present invention”.
  • Compound (I) may be a hydrate, a non-hydrate, a solvate, or a non-solvate.
  • Compounds labeled with isotopes eg, 3 H, 14 C, 35 S, 125 I, etc.
  • a deuterium converter obtained by converting 1 H into 2 H (D) is also encompassed in compound (I).
  • Tautomers are also encompassed in compound (I).
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • Compound (I) may be used as a PET tracer.
  • the compound of the present invention has an excellent IRAK-4 inhibitory action, it can be useful as a safe pharmaceutical based on this action. Since the compound of the present invention has an IL-1R inhibitory action, an IL-18R inhibitory action and an IL-33R inhibitory action in addition to the TLR1-9 inhibitory action excluding TLR3, it is also useful as a safe pharmaceutical based on this action. possible.
  • the medicament of the present invention comprising the compound of the present invention is related to IRAK-4 against mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.) It can be used as a preventive or therapeutic agent for diseases, more specifically, the diseases described in (1) to (4) below.
  • Inflammatory diseases eg, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis Systemic inflammatory response syndrome (SIRS), inflammation after surgery or trauma, pneumonia (such as idiopathic interstitial pneumonia including idiopathic pulmonary fibrosis (IPF)), nephritis, meningitis, cystitis, pharyngopharyngitis , Gastric mucosal damage, central nervous disease (neurodegenerative diseases such as Alzheimer's disease, depression, etc.), spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, ischemia reperfusion injury Gout (eg, acute gout, etc.), hay fever, acute kidney injury, cryopyrin-related periodic syndrome (
  • the medicament of the present invention is preferably an autoimmune disease, inflammatory disease, bone / joint degenerative disease or neoplastic disease, particularly preferably psoriasis, rheumatoid arthritis, inflammatory bowel disease (preferably Crohn's disease or ulcerative colon) ), Sjogren's syndrome, Behcet's disease, multiple sclerosis, or systemic lupus erythematosus.
  • an autoimmune disease preferably an autoimmune disease, inflammatory disease, bone / joint degenerative disease or neoplastic disease, particularly preferably psoriasis, rheumatoid arthritis, inflammatory bowel disease (preferably Crohn's disease or ulcerative colon) ), Sjogren's syndrome, Behcet's disease, multiple sclerosis, or systemic lupus erythematosus.
  • the medicament of the present invention can be preferably used as an agent for preventing or treating autoimmune diseases and / or inflammatory diseases, particularly preferably multiple sclerosis, systemic lupus erythematosus, gout or hay fever. .
  • prevention of the disease refers to, for example, a patient who has not developed the disease, which is expected to have a high risk of onset due to some factor related to the disease, or who has developed the subjective symptom. This means that a drug containing the compound of the present invention is administered to a patient who is not, or that a drug containing the compound of the present invention is administered to a patient who is concerned about recurrence of the disease after treatment of the disease.
  • the medicament of the present invention has excellent pharmacokinetics (eg, blood drug half-life), low toxicity (eg, HERG inhibition, CYP inhibition, CYP induction, cytotoxicity, etc.), and side effects (eg, drug interaction, body weight). Reduction).
  • the compound of the present invention is mixed with a pharmacologically acceptable carrier as it is or according to a method known per se generally used in the production of pharmaceutical preparations to form a pharmaceutical composition, which is used as the medicament of the present invention. obtain.
  • the medicament of the present invention is given orally or parenterally to mammals (eg, humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, etc.). Can be safely administered.
  • the medicament containing the compound of the present invention is a pharmacologically acceptable compound of the present compound alone or with the compound of the present invention according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). It can be used as a pharmaceutical composition mixed with a carrier.
  • examples of the medicament containing the compound of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules).
  • controlled release formulations
  • the content of the compound of the present invention in the medicament of the present invention is about 0.01% to about 100% by weight of the whole medicament.
  • the dose varies depending on the administration subject, administration route, disease and the like, but for example, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis or systemic lupus erythematosus (body weight about 60 kg)
  • the active ingredient (compound (I)) is about 0.01 mg / kg body weight to about 500 mg / kg body weight, preferably about 0.1 mg / kg body weight to about 50 mg / kg body weight per day, Preferably, about 1 mg / kg body weight to about 30 mg / kg body weight can be administered once to several times a day.
  • Examples of the pharmacologically acceptable carrier that may be used in the production of the medicament of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials.
  • excipients and lubricants in solid preparations Binders and disintegrants, solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffers and soothing agents.
  • additives such as usual preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • the compound of the present invention When the compound of the present invention is used as an ointment, the compound of the present invention is used in a concentration of about 0.001 to 3% (W / W), preferably about 0.01 to 1% (W / W). To be mixed and manufactured.
  • the production of an ointment preferably includes a powdering step of the compound of the present invention and a sterilization step of the preparation.
  • the ointment may be administered 1 to 4 times a day depending on the patient's condition.
  • ointment base purified lanolin, white petrolatum, macrogol, plastibase, liquid paraffin and the like are appropriately used.
  • excipient examples include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
  • hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like.
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • Examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellow Nos.
  • water-insoluble lake dyes examples include aluminum salts of the aforementioned water-soluble edible tar pigments), natural pigments (eg, ⁇ -carotene, chlorophyll, bengara, etc.) and the like.
  • the sweetener include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
  • the adsorbent include porous starch, calcium silicate (trade name: Florite RE), magnesium aluminate metasilicate (trade name: Neusilin), and light anhydrous silicic acid (trade name: Silicia).
  • the wetting agent include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, polyoxyethylene lauryl ether, and the like.
  • the compound of the present invention can be used together with other drugs.
  • the pharmaceutical used when the compound of the present invention is used in combination with another drug is referred to as “the combination agent of the present invention”.
  • the combination agent of the present invention when the compound of the present invention is used as an IRAK-4 inhibitor, a TLR1-9 inhibitor excluding TLR3, an IL-1R inhibitor, an IL-18R inhibitor, or an IL-33R inhibitor, it can be used in combination with the following drugs: .
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) (I) Classic NSAIDs Arcofenac, aceclofenac, sulindac, tolmetine, etodolac, fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam, teoxicam, lornoxicam, nabumetone, acetaminophen, phenacetin, ethenamide, sulpyrine, antipyrine, migrenin, aspirin, fefenamic acid, mefenamic acid Diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, fructaphenine, piroxicam, epilisol, thiaramide hydrochloride, zal
  • cyclooxygenase inhibitors COX-1 selective inhibitors, COX-2 selective inhibitors, etc.
  • Salicylic acid derivatives eg, celecoxib, aspirin
  • etoroxib etoroxib
  • valdecoxib diclofenac
  • indomethacin loxoprofen
  • Nitric Oxide Free NSAIDs Iv) JAK inhibitors Tofacitinib (Tofacitinib), Ruxolitinib (Ruxolitinib) and the like.
  • DMARDs Disease-modifying anti-rheumatic drugs
  • Amino salicylic acid preparation Sulfasalazine, mesalazine, olsalazine, balsalazide and the like.
  • V pyrimidine synthesis inhibitor leflunomide and the like.
  • Anti-cytokine drug protein preparation
  • TNF inhibitor etanercept TNF inhibitor etanercept, infliximab, adalimumab, certolizumab Pegor, golimumab, PASSTNF- ⁇ , soluble TNF- ⁇ receptor, TNF- ⁇ binding protein, anti-TNF- ⁇ antibody etc.
  • Interleukin-1 inhibitor Anakinra interleukin-1 receptor antagonist
  • soluble interleukin-1 receptor and the like.
  • Interleukin-6 inhibitor Tocilizumab anti-interleukin-6 receptor antibody
  • Iv Interleukin-10 drug Interleukin-10 and the like.
  • V Interleukin-12 / 23 inhibitor Ustekinumab, briakinumab (anti-interleukin-12 / 23 antibody) and the like.
  • II Non-protein preparation
  • Iv TNF- ⁇ converting enzyme inhibitor
  • VX-765 interleukin-1 ⁇ converting enzyme inhibitor
  • Interleukin-6 antagonist HMPL-004 and the like.
  • Interleukin-8 inhibitor IL-8 antagonist CXCR1 & CXCR2 antagonist, reparexin and the like.
  • Chemokine antagonist CCR9 antagonist CCX-282, CCX-025), MCP-1 antagonist and the like.
  • Ix Interleukin-2 receptor antagonist Denileukine, Defuchitox and the like.
  • Therapeutic vaccines TNF- ⁇ vaccine and the like.
  • Gene therapy drug Gene therapy drug for enhancing expression of genes having anti-inflammatory activity such as interleukin-4, interleukin-10, soluble interleukin-1 receptor, soluble TNF- ⁇ receptor .
  • Immunomodulatory drugs immunosuppressive drugs
  • Methotrexate Methotrexate, cyclophosphamide, MX-68, atiprimmod dihydrochloride, BMS-188667, CKD-461, limexolone, cyclosporine, tacrolimus, gusperimus, azathioprine, anti-lymphocera, dry sulfonated immunoglobulin, erythropoietin, colony stimulation Factors, interleukins, interferons, etc.
  • Steroid drugs Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, estriol propionate, etc.
  • Angiotensin converting enzyme inhibitor enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril and the like.
  • Angiotensin II receptor antagonist candesartan, candesartan cilexetil, azilsartan, azilsartan medoxomil, valsartan, irbesartan, olmesartan, eprosartan, and the like.
  • Diuretics Hydrochlorothiazide, spironolactone, furosemide, indapamide, bendrofluazide, cyclopenthiazide and the like.
  • (11) ⁇ receptor antagonist carvedilol, metoprolol, atenolol and the like.
  • Contraceptives Sex hormones or derivatives thereof Progesterone or derivatives thereof (progesterone, 17 ⁇ -hydroxyprogesterone, medroxyprogesterone, medroxyprogesterone acetate, norethisterone, norethisterone enanthate, norethindrone, norethindrone acetate, norethinodrel, levonorgestrel , Norgestrel, etinodiol diacetate, desogestrel, norgestimate, guestden, progestin, etonogestrel, drospirenone, dienogest, trimegestone, nestron, chromadianone acetate, mifepristone, nomegestrol acetate, Org-30659, TX-525, EMM-310525) or Progesterone or its derivative and follicular hormone or its derivative (Ladiol, estradiol benzoate,
  • T cell inhibitor Inosine monophosphate dehydrogenase (IMPDH) inhibitor Mycophenolate mofetil and the like.
  • thalidomide v) cathepsin inhibitor
  • MMPs matrix metalloprotease
  • V-85546 Glucose-6-phosphate dehydrogenase inhibitor
  • DHODH Dihydrorotate dehydrogenase
  • PDEIV Phosphodiesterase IV
  • X Phospholipase A 2 inhibitor
  • xi iNOS inhibitor VAS-203 and the like.
  • Xii Microtubule stimulant paclitaxel and the like.
  • Xiii Microtubule inhibitor Rheumacon and the like.
  • Xiv MHC class II antagonist
  • xv Prostacyclin agonist iloprost and the like.
  • CD4 antagonist zanolimumab and the like.
  • Xvii CD23 antagonist
  • xviii LTB4 receptor antagonist DW-1305 and the like.
  • Xix 5-lipoxygenase inhibitor zileuton and the like.
  • Xx Cholinesterase inhibitor galantamine and the like.
  • Xxi tyrosine kinase inhibitor Tyk2 inhibitor (WO20101422752) and the like.
  • Cathepsin B inhibitor xxiii) Adenosine deaminase inhibitor Pentostatin and the like.
  • osteogenesis stimulating agent xxv) dipeptidyl peptidase inhibitor (xxvi) collagen agonist
  • xxvii) capsaicin cream xxviii) hyaluronic acid derivative synbisc (hylan GF 20), orthobisque and the like.
  • concomitant drugs other than the above include, for example, antibacterial drugs, antifungal drugs, antiprotozoal drugs, antibiotics, antitussives and expectorants, sedatives, anesthetics, antiulcer drugs, antiarrhythmic drugs, antihypertensive diuretics, anticoagulants Drugs, tranquilizers, antipsychotics, antitumor drugs, antihyperlipidemic drugs, muscle relaxants, antiepileptic drugs, antidepressants, antiallergic drugs, cardiotonic drugs, antiarrhythmic drugs, vasodilators, vasoconstriction Drugs, antihypertensive diuretics, antidiabetics, narcotic antagonists, vitamins, vitamin derivatives, anti-asthma, frequent urinary / urinary incontinence, antidiarrheal, atopic dermatitis, allergic rhinitis, pressurization
  • examples include drugs, endotoxin antagonists or antibodies, signal transduction inhibitors, inflammatory mediator action inhibitor
  • Antibacterial drugs sulfa drugs sulfamethizole, sulfisoxazole, sulfamonomethoxine, salazosulfapyridine, silver sulfadiazine and the like.
  • Quinoline antibacterial agents Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.
  • Antituberculosis drugs Isoniazid, ethambutol (ethambutol hydrochloride), paraaminosalicylic acid (calcium paraaminosalicylate), pyrazinamide, etionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like.
  • Mycobacterial drugs Diaphenylsulfone, rifampicin and the like.
  • Antiviral drugs idoxuridine, acyclovir, vitarabine, ganciclovir and the like.
  • Anti-HIV drugs zidovudine, didanosine, zarcitabine, indinavir sulfate ethanol adduct, ritonavir and the like.
  • Antispiro carte drugs (viii) Antibiotics Tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, cannendomycin, libidomycin, tobramycin, amikacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, loritetracycline, doxycycline, ticarcillin, cephalitin, cephalidine, cephalidine , Cefaclor, cephalexin, cefloxazine, cefadroxyl, cefamandol, cephoeum, cefuroxime, cefothiam, cefothium hexetyl, cefuroxime axetil, cefdinir, cefdit
  • Antifungal drugs Polyethylene antibiotics (eg, amphotericin B, nystatin, tricomycin) (ii) Griseofulvin, pyrrolnitrin, etc. (iii) cytosine antimetabolite (eg, flucytosine) (iv) Imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole) (v) Triazole derivatives (eg, fluconazole, itraconazole) (vi) thiocarbamic acid derivatives (eg, trinaphthol) and the like. (3) Antiprotozoal drugs Metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate and the like.
  • Ephedrine hydrochloride noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, methylephedrine hydrochloride, aloclamide, chlorfedianol, picoperidamine, cloperastine, protochelol, isoproterenol, salbutamol Terbutaline, oxymethebanol, morphine hydrochloride, dextromethorphan hydrobromide, oxycodone hydrochloride, dimemorphan phosphate, tipepidine hibenzate, pentoxyberine citrate, clofedanol hydrochloride, benzonate, guaifenesin, bromhexine hydrochloride, ambrox hydrochloride Sole, acetylcysteine, ethylcysteine hydrochloride, carbocysteine and the like.
  • Anesthetic (6-1) Local anesthetic Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxesazein and the like.
  • Anti-ulcer drugs Histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastron, oxesazein, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, teprenone, prostaglandin, etc.
  • Arrhythmia drug (i) sodium channel blockers (eg, quinidine, procainamide, disopyramide, azimarin, lidocaine, mexiletine, phenytoin), (ii) ⁇ -blockers (eg, propranolol, alprenolol, bufetrol, hydrochloride, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol hydrochloride), (iii) potassium channel blockers (eg, amiodarone), (iv) Calcium channel blockers (eg, verapamil, diltiazem) and the like.
  • sodium channel blockers eg, quinidine, procainamide, disopyramide, azimarin, lidocaine, mexiletine, phenytoin
  • ⁇ -blockers eg, prop
  • Anticoagulant heparin sodium sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dalteparin sodium, warfarin potassium, argatroban, gabexate, ozagrel sodium, icosapentarate ethyl, beraprost sodium, al Prostadil, ticlopidine hydrochloride, pentoxifylline, dipyridamole, tisokinase, urokinase, streptokinase, etc.
  • Muscle relaxants Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, clozoxazone, eperisone, tizanidine and the like.
  • Antiepileptic drugs Phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trimetadione, carbamazepine, phenobarbital, primidone, sultiam, sodium valproate, clonazepam, diazepam, nitrazepam and the like.
  • Antiallergic drugs diphenhydramine, chlorpheniramine, tripelenamine, methodiramine, clemizole, diphenylpyraline, methoxyphenamine, cromoglycate sodium, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine hydrochloride, epinastine hydrochloride , Pranlukast hydrate, seratrodast, etc.
  • Cardiotonic drugs Transbioxocamphor, telephilol, aminophylline, ethylephrine, dopamine, dobutamine, denopamine, vesnarinone, amrinone, pimobendan, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophantin and the like.
  • Vasodilators Oxyfedrine, diltiazem, trazoline, hexobenzine, bamethane, clonidine, methyldopa, guanabenz and the like.
  • Vasoconstrictor dopamine, dobutamine, denopamine and the like are examples of vasis, aminophene, and the like.
  • Antihypertensive diuretics Hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine and the like.
  • Antidiabetic drugs Tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide, acarbose, epalrestat, troglitazone, glucagon, grimidine, glipizide, phenformin, buformin, metformin and the like.
  • Vitamin A vitamin A 1 , vitamin A 2 and retinol palmitate
  • Vitamin D Vitamin D 1 , D 2 , D 3 , D 4 and D 5
  • Vitamin E ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, nicotinic acid D1- ⁇ -tocopherol
  • Vitamin Ks Vitamin K 1 , K 2 , K 3 and K 4
  • Folic acid vitamin M
  • Vitamin derivatives Various derivatives of vitamins, for example, vitamin D 3 derivatives such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1- ⁇ -hydroxycholecalciferol, 5,6- Vitamin D 2 derivatives such as trans-ergocalciferol.
  • Anti-asthma drugs Isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimethoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, iprotropium bromide, oxitropium bromide, bromide Flutropium, theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, amlexanone, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, dexamethasone, prednisolone hydrocolicone , Beclomethasone prop
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered to the administration subject at the same time or may be administered with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the combination is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) obtained by separately formulating the compound of the present invention and the concomitant drug.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight based on the whole preparation. %, More preferably about 0.5 to about 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight, based on the whole preparation, Preferably, it is about 0.5 to about 20% by weight.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to about 99.99% by weight, preferably about 10 to about 90% by weight, based on the whole preparation. It is. The same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
  • the dose varies depending on the type of the compound of the present invention, the administration route, symptoms, the age of the patient, etc.
  • Body weight When administered orally to a patient (body weight of about 60 kg), about 0.1 mg / kg body weight to about 50 mg / kg body weight, preferably about 1 mg / kg body weight to about 30 mg / kg of compound (I) per kg body weight per day Body weight can be administered once to several times daily.
  • the dosage is the type and content of compound (I), the dosage form, the duration of drug release, the animal to be administered (for example, mouse, rat, hamster, guinea pig) Mammals such as rabbits, cats, dogs, cows, horses, pigs, sheep, monkeys, humans, etc.), depending on the purpose of administration, for example, about 0.1 per week when applied by parenteral administration About 100 mg of compound (I) may be released from the dosage formulation.
  • the animal to be administered for example, mouse, rat, hamster, guinea pig
  • Mammals such as rabbits, cats, dogs, cows, horses, pigs, sheep, monkeys, humans, etc.
  • about 100 mg of compound (I) may be released from the dosage formulation.
  • the amount of the concomitant drug can be set as long as side effects do not become a problem.
  • the daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, weight, sensitivity difference, timing of administration, interval, nature of the pharmaceutical preparation, formulation, type, type of active ingredient, etc.
  • the amount of the drug is usually about 0.001 to about 2000 mg, preferably about 0.01 to about 500 mg, more preferably about 0.1 to about 100 mg per kg body weight of the mammal by oral administration. This can usually be administered in 1 to 4 divided doses per day.
  • the compound of the present invention and the concomitant drug may be administered at the same time, or may be administered with a time difference.
  • the time difference varies depending on the active ingredient, dosage form, and administration method to be administered.
  • Examples include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
  • the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention. Is mentioned.
  • room temperature usually indicates about 10 ° C. to about 35 ° C.
  • the ratio shown in the mixed solvent is a volume ratio unless otherwise specified. Unless otherwise indicated, “%” indicates “% by weight”.
  • silica gel column chromatography when described as NH, aminopropylsilane-bonded silica gel was used, and when described as Diol, 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel was used.
  • HPLC high performance liquid chromatography
  • octadecyl-bonded silica gel was used.
  • the ratio of elution solvent indicates a volume ratio unless otherwise specified.
  • a peak from which H 2 O is eliminated may be observed as a fragment ion.
  • a free molecular ion peak or a fragment ion peak is usually observed.
  • the unit of sample concentration (c) in optical rotation ([ ⁇ ] D ) is g / 100 mL.
  • the reaction mixture was stirred at 80 ° C. for 2 hours under a nitrogen atmosphere, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (Diol, ethyl acetate / hexane) to give the title compound (2.0 g).
  • a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 15-Crown 5-ether (0.026 mL) was added to a DMF (3.0 mL) solution of the residue and sodium azide (28 mg), and the mixture was stirred at 80 ° C. for 16 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (26 mg). MS (ESI +), found: 439.1.
  • Example compounds are shown in the following table. MS in the table indicates actual measurement.
  • Test example 1 IRAK-4 enzyme inhibition test
  • the IRAK-4 enzyme inhibition activity of the test compound was measured by the LANCE method (Perkin Elmer). First, 2 ⁇ L of a test compound diluted with an assay buffer (50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA) was added to each 384 well plate. .
  • an assay buffer 50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA
  • IRAK-4 (Karna Bioscience) was added in an amount of 240 ng / mL, and a fluorescence-labeled peptide substrate (ULight-ACC peptide, Perkin Elmer) diluted with an assay buffer to 37.5 nM was added in an amount of 2 ⁇ L each.
  • the enzyme reaction was started by adding 2 ⁇ L of ATP solution prepared with assay buffer to 1.5 mM. After reacting at room temperature for 1 hour, 6 ⁇ L of Detection Buffer (PerkinElmer) prepared to become 20 mM EDTA, 1 nM europium-labeled anti-phosphorylated ACC antibody (PerkinElmer) was added.
  • fluorescence intensity (excitation wavelength: 340 nm, fluorescence wavelength: 665 nm, delay time: 100 microseconds) was measured with a plate reader Envision (Perkin Elmer).
  • the inhibitory activity of each compound was calculated as a relative activity value with 100% inhibition of the fluorescence intensity of wells without enzyme.
  • the IRAK-4 enzyme inhibition rate when the concentration of the test compound is 1 ⁇ M is shown below.
  • Formulation Example 1 (Manufacture of capsules) 1) 30 mg of the compound of Example 1 2) Fine powder cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 60 mg total 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
  • Formulation Example 2 Manufacture of tablets
  • Formulation Example 3 Manufacture of ointments
  • the obtained product is dispensed and filled into a tube to obtain an ointment.
  • the compound of the present invention has an excellent IRAK-4 inhibitory action and can be useful as a preventive or therapeutic agent for inflammatory diseases, autoimmune diseases, bone / joint degenerative diseases, neoplastic diseases and the like.

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  • Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention concerne : un composé hétérocyclique qui a une activité d'inhibition d'IRAK -4 et est supposé être utile pour la prévention/le traitement de maladies inflammatoires, des maladies auto-immunes, des maladies dégénératives ostéoarticulaires, des maladies néoplasiques et analogues ; et un médicament contenant le composé hétérocyclique. La présente invention concerne un composé représenté par la formule (I) [dans laquelle chaque symbole est tel que défini dans la description] ou un sel de celui-ci.
PCT/JP2017/033199 2016-09-15 2017-09-14 Composé hétérocyclique Ceased WO2018052058A1 (fr)

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US10874743B2 (en) 2017-12-26 2020-12-29 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11117889B1 (en) 2018-11-30 2021-09-14 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11292792B2 (en) 2018-07-06 2022-04-05 Kymera Therapeutics, Inc. Tricyclic CRBN ligands and uses thereof
US11358948B2 (en) 2017-09-22 2022-06-14 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
US11485743B2 (en) 2018-01-12 2022-11-01 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US11512080B2 (en) 2018-01-12 2022-11-29 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
US11591332B2 (en) 2019-12-17 2023-02-28 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11623932B2 (en) 2017-09-22 2023-04-11 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US11685750B2 (en) 2020-06-03 2023-06-27 Kymera Therapeutics, Inc. Crystalline forms of IRAK degraders
US11707457B2 (en) 2019-12-17 2023-07-25 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US12091411B2 (en) 2022-01-31 2024-09-17 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
US12150995B2 (en) 2020-12-30 2024-11-26 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US12171768B2 (en) 2021-02-15 2024-12-24 Kymera Therapeutics, Inc. IRAK4 degraders and uses thereof
US12187744B2 (en) 2021-10-29 2025-01-07 Kymera Therapeutics, Inc. IRAK4 degraders and synthesis thereof
US12454520B2 (en) 2018-07-06 2025-10-28 Kymera Therapeutics, Inc. Protein degraders and uses thereof

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US10414753B2 (en) * 2016-10-26 2019-09-17 Rigel Pharmaceuticals, Inc. Amide compounds and method for making and using
US10370367B2 (en) * 2016-10-26 2019-08-06 Rigel Pharmaceuticals, Inc. IRAK inhibitors and method for making and using

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US11623932B2 (en) 2017-09-22 2023-04-11 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US11358948B2 (en) 2017-09-22 2022-06-14 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
US10874743B2 (en) 2017-12-26 2020-12-29 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US12168057B2 (en) 2017-12-26 2024-12-17 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11723980B2 (en) 2017-12-26 2023-08-15 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11318205B1 (en) 2017-12-26 2022-05-03 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11485743B2 (en) 2018-01-12 2022-11-01 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US12006329B2 (en) 2018-01-12 2024-06-11 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US11512080B2 (en) 2018-01-12 2022-11-29 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
US11932635B2 (en) 2018-01-12 2024-03-19 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
US12454520B2 (en) 2018-07-06 2025-10-28 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US11292792B2 (en) 2018-07-06 2022-04-05 Kymera Therapeutics, Inc. Tricyclic CRBN ligands and uses thereof
US11897882B2 (en) 2018-07-06 2024-02-13 Kymera Therapeutics, Inc. Tricyclic crbn ligands and uses thereof
US11352350B2 (en) 2018-11-30 2022-06-07 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US12258341B2 (en) 2018-11-30 2025-03-25 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11117889B1 (en) 2018-11-30 2021-09-14 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11807636B2 (en) 2018-11-30 2023-11-07 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11707457B2 (en) 2019-12-17 2023-07-25 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11779578B2 (en) 2019-12-17 2023-10-10 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11591332B2 (en) 2019-12-17 2023-02-28 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11685750B2 (en) 2020-06-03 2023-06-27 Kymera Therapeutics, Inc. Crystalline forms of IRAK degraders
US12150995B2 (en) 2020-12-30 2024-11-26 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US12171768B2 (en) 2021-02-15 2024-12-24 Kymera Therapeutics, Inc. IRAK4 degraders and uses thereof
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
US12187744B2 (en) 2021-10-29 2025-01-07 Kymera Therapeutics, Inc. IRAK4 degraders and synthesis thereof
US12091411B2 (en) 2022-01-31 2024-09-17 Kymera Therapeutics, Inc. IRAK degraders and uses thereof

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