WO2012005299A1 - Inhibiteur de ros de tyrosine kinase - Google Patents

Inhibiteur de ros de tyrosine kinase Download PDF

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WO2012005299A1
WO2012005299A1 PCT/JP2011/065492 JP2011065492W WO2012005299A1 WO 2012005299 A1 WO2012005299 A1 WO 2012005299A1 JP 2011065492 W JP2011065492 W JP 2011065492W WO 2012005299 A1 WO2012005299 A1 WO 2012005299A1
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fluorophenyl
pyrazin
ylamino
ethylamino
ethyl
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Japanese (ja)
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正輝 野河
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日本新薬株式会社
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    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to a novel ROS tyrosine kinase inhibitor containing an aminopyrazine derivative as an active ingredient.
  • ROS tyrosine kinase is a receptor-type protein tyrosine kinase similar to the EGF receptor, and is considered to be involved in signal transduction related to cell proliferation and differentiation (see, for example, Non-Patent Document 1).
  • changes in the gene level of ROS tyrosine kinase have been reported in several malignant tumors.
  • overexpression of ROS tyrosine kinase is reported in glioma, meningioma, etc. (see, for example, Non-Patent Documents 2 and 3), and patient cells of chronic myelomonocytic leukemia (for example, see Non-Patent Document 4).
  • FIG-ROS fusion gene in a glioblastoma cell line see, for example, Non-Patent Document 5
  • an SLC34A2-ROS fusion gene in a non-small cell lung cancer cell line see, for example, Non-Patent Document 6
  • a non-small cell lung cancer see, for example, Non-Patent Document 6
  • a CD74-ROS fusion gene has been found in clinical specimens (see, for example, Non-Patent Document 6).
  • the FIG-ROS fusion gene has properties as an oncogene (see, for example, Non-Patent Document 7).
  • ROS tyrosine kinase is a homologue of the oncogene v-ROS of a virus that infects birds (see, for example, Non-Patent Document 8), and activation of ROS tyrosine kinase is thought to lead to canceration. More recently, a FIG-ROS fusion gene has been found in cholangiocarcinoma (see, for example, Non-Patent Document 9), suggesting the possibility of abnormal ROS in liver cancer, kidney cancer, pancreatic cancer, and testicular cancer. (For example, refer to Patent Document 1). From the above, it is considered that the ROS tyrosine kinase inhibitor is effective as a therapeutic agent for the diseases described above.
  • the main object of the present invention is to provide a novel ROS tyrosine kinase inhibitor.
  • the compound of the present invention a compound represented by the following general formula [1] (hereinafter referred to as “the compound of the present invention”) or a pharmaceutically acceptable product thereof, which is either of the following (I) or (II): ROS tyrosine kinase inhibitors containing a salt as an active ingredient.
  • X represents CH or N.
  • R 1 represents halogen.
  • R 2 is (1) H, (2) halogen, (3) cyano, (4) a group represented by the following general formula [2],
  • R C , R D and R E are the same or different and each represents (a) H, or (b) alkyl optionally substituted with hydroxy or alkoxy.
  • R C , R D and R E are combined with adjacent C, and the remaining one group is H to represent a saturated heterocyclic group containing one N.
  • a saturated heterocyclic group may be substituted with an alkylsulfonyl), (5) a group represented by the following general formula [3],
  • R F and R G are the same or different, and (a) H, (b) hydroxy, amino, dialkylamino, saturated cyclic amino group, alkylcarbonylamino, alkyl (C) alkylcarbonyl, (c) alkyl optionally substituted with one or two groups selected from the group consisting of sulfonylamino, aryl, heteroaryl optionally substituted with alkyl, tetrahydrofuranyl, and carbamoyl d) represents alkylsulfonyl, (e) carbamoyl, or (f) heteroaryl optionally substituted with alkyl, or R F and R G together with adjacent N to form a saturated cyclic amino group
  • saturated cyclic amino groups include (a) halogen, (b) cyano, (c) hydroxy, (d) hydroxy, alcohol Alkyl optionally substituted with one or two groups selected from the group consisting of cis, amino, alkyl (C) alkylcarbon
  • R H represents alkyl or aryl
  • j a group represented by the following general formula [5],
  • R I and R J are the same or different and represent H, alkyl, carbamoyl, alkylcarbonyl, or alkylsulfonyl), (k) the following general formula [ 6],
  • R K is alkyl, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, (cycloalkyl) alkylamino, (hydroxyalkyl) amino, (alkoxyalkyl) (Represents an amino, alkoxy, alkylsulfonylamino, or saturated cyclic amino group), and (l) substituted with one or two groups selected from the group consisting of a saturated cyclic amino group optionally substituted with hydroxy Or may be spiro-bonded to a group represented by the following general formula [7A] or [7B].
  • R L is a saturated cyclic amino group optionally substituted with (a) alkyl, (b) hydroxy, (c) alkoxy, (d) alkyl or alkylsulfonyl. Or (e) optionally substituted with one or two groups selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, alkoxyalkyl, and hydroxyalkyl Represents amino), (7) a group represented by the following general formula [9],
  • R M , R N and R O are the same or different and represent H, halogen, cyano, alkoxy, carbamoyl, sulfamoyl, monoalkylaminosulfonyl, or alkylsulfonyl. Or two groups of R M , R N and R O together represent methylenedioxy).
  • R P is selected from hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and alkyl substituted with a group selected from the group consisting of cycloalkyl, or, optionally substituted by hydroxy Or a saturated cyclic group which may contain one O.) or (9) cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl Represents heteroaryl optionally substituted with one or two groups selected from the group consisting of hydroxycarbonyl and alkoxyalkyl.
  • R 3 represents H or hydroxy.
  • R 4 represents H or alkyl.
  • R 5 represents H or alkyl.
  • X represents —CR A.
  • R A is a group represented by the following general formula [10],
  • R B is substituted with 1 or 2 groups selected from the group consisting of (a) alkyl, cycloalkyl, (cycloalkyl) alkyl, and alkoxyalkyl). Which represents an optionally substituted amino, (b) alkoxy, (c) hydroxy, or (d) a saturated cyclic amino group.)
  • R 1 represents halogen.
  • R 2 represents H.
  • R 3 represents H or hydroxy.
  • R 4 represents H or alkyl.
  • R 5 represents H or alkyl.
  • a compound represented by the general formula [1] which is any of the following [i] or [ii], or a pharmaceutically acceptable salt thereof is preferable.
  • [I] X is CH or N
  • R 2 is (1) a group represented by the following general formula [11]
  • R F1 and R G1 are the same or different and (a) H, (b) hydroxy, amino, dialkylamino, saturated cyclic amino group, alkylcarbonylamino, alkyl (C) alkylcarbonyl, (c) alkyl optionally substituted with one or two groups selected from the group consisting of sulfonylamino, aryl, heteroaryl optionally substituted with alkyl, tetrahydrofuranyl, and carbamoyl d) represents alkylsulfonyl, (e) carbamoyl, or (f) heteroaryl optionally substituted with alkyl, or R F1 and R G1 together with adjacent N form a saturated cyclic amino group
  • saturated cyclic amino groups are (a) halogen, (b) cyano, (c) hydroxy, (d) hydroxy Alkyl optionally substituted with one or two groups selected from the group consisting of alkoxy, amino, al
  • R P1 represents alkyl optionally substituted with a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl), or ( 5) substituted with 1 or 2 groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl Optionally heteroaryl.
  • X is -CR A
  • R A is a group represented by the following general formula [10]:
  • R 2 is H.
  • X is CH
  • R 2 is (1) a group represented by the following general formula [11]
  • R P1 is as defined above
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is more preferably a heteroaryl optionally substituted with one or two groups selected from the group consisting of aralkyl, hydroxycarbonyl and alkoxyalkyl.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is useful as a medicament.
  • each term according to the present invention will be described in detail.
  • halogen examples include fluorine, chlorine, bromine and iodine.
  • Alkyl is, for example, a linear or branched one having 1 to 8 carbon atoms, specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Examples thereof include tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl. Of these, those having 1 to 6 carbon atoms are preferred, and those having 1 to 3 carbon atoms are more preferred.
  • haloalkyl examples include linear or branched alkyl having 1 to 8 carbon atoms substituted at any position where one or more halogen atoms can be substituted.
  • alkyl part and the halogen part of “haloalkyl” include those similar to the above “alkyl” and “halogen”, respectively.
  • cycloalkyl examples include those having 3 to 8 carbon atoms, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • cycloalkyl moiety of “(cycloalkyl) alkyl”, “cycloalkylamino”, and “(cycloalkyl) alkylamino” include those similar to the above “cycloalkyl”.
  • Alkoxy is, for example, linear or branched one having 1 to 8 carbon atoms, specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy. , T-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy and n-octyloxy.
  • alkoxyalkyl examples include those similar to the above “alkoxy”.
  • aryl examples include those having 6 to 10 carbon atoms, such as phenyl, 1-naphthyl and 2-naphthyl. Of these, phenyl is preferred.
  • the “aralkyl” is, for example, a linear or branched alkyl having 1 to 8 carbon atoms substituted at any position where an aryl having 6 to 10 carbon atoms can be substituted, such as benzyl, phenylethyl ( For example, 1-phenylethyl, 2-phenylethyl), phenylpropyl (1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, etc.), naphthylmethyl (eg, 1-naphthylmethyl, 2-naphthylmethyl, etc.) Can be mentioned.
  • the “saturated cyclic amino group” includes, for example, a 4-membered to 7-membered saturated cyclic amino group having one or two N, which may have one O or S as a ring-constituting atom, Examples include 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, piperidino, 1-piperazinyl, 1-tetrahydropyrimidinyl, morpholino, thiomorpholino, and 1-homopiperazinyl.
  • saturated heterocyclic group containing 1 N for example, a 5-membered or 6-membered saturated heterocyclic group having 1 N as a ring-constituting atom, specifically, for example, 2-pyrrolidinyl , 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl.
  • saturated cyclic group optionally containing one O for example, a 5-membered or 6-membered saturated cyclic group optionally having 1 O as a ring-constituting atom, specifically, Can include, for example, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl.
  • Heteroaryl is, for example, 5-membered or 6-membered having 1 to 4 N, O, S as ring-constituting atoms, specifically, for example, furyl (for example, 2-furyl, 3 -Furyl), thienyl (eg 2-thienyl, 3-thienyl), pyrrolyl (eg 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg 1-imidazolyl, 2-imidazolyl, 4-imidazolyl) Pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (eg 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2, 4-triazol-4-yl), tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (eg 2 Oxazo
  • tetrahydrofuranyl examples include 2-tetrahydrofuranyl and 3-hydrofuranyl.
  • tetrahydropyranyl examples include 2-tetrahydropyranyl, 3-tetrahydropyranyl and 4-tetrahydropyranyl.
  • the compound of the present invention can be produced from a known compound or an easily synthesizeable intermediate, for example, according to the following method.
  • the reaction is generally carried out after the raw material is protected with a suitable protecting group by a known method in advance.
  • the protecting group can be removed after the reaction by a known method.
  • R 2 is halogen (R 1 and R 5 are as defined above.
  • X 1 represents CH or N.
  • Hal 1 and Hal 2 are the same or different and represent halogen.)
  • This reaction is a condensation reaction of the compound [12] and the compound [13] using a palladium catalyst, and therefore can be performed by a method known per se as a condensation reaction.
  • Solvents that can be used are not particularly limited as long as they are not involved in the reaction.
  • hydrocarbons such as toluene and xylene
  • ethers such as 1,4-dioxane and tetrahydrofuran
  • N N-dimethylformamide
  • examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • the reaction is carried out in the range of 20 ° C. to 200 ° C. in the presence of a base.
  • the palladium catalyst that can be used include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate.
  • the amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide.
  • the ligand of the palladium catalyst that can be used include 1,1′-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, and 2-dicyclohexylphosphino- 2 ′, 4 ′, 6′-triisopropylbiphenyl, ( ⁇ ) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis Mention may be made of [2- (diphenylphosphino) phenyl] ether and tri-t-butylphosphine.
  • Examples of the base that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
  • the reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually in the range of 10 minutes to 24 hours.
  • Compound [12] which is a raw material compound, is produced according to a known method (Bioorg. Med. Chem. Lett., 14, 2004, 4249-4252, Org. Lett., 6, 2004, 3671-3675, etc.). be able to.
  • R 2 is -OR P (wherein, R P has the same meaning as defined above.)
  • Production method 2-1 (X 1 , R 1 , R 5 , Hal 2 are as defined above.
  • R P is substituted with a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl. And represents a saturated cyclic group which may be substituted with alkyl or hydroxy and may contain one O.)
  • This reaction is carried out by a condensation reaction of compound [1a] and alcohol compound [14] using a palladium catalyst.
  • Solvents that can be used are not particularly limited as long as they are not involved in the reaction.
  • hydrocarbons such as toluene and xylene
  • ethers such as 1,4-dioxane and tetrahydrofuran
  • N N-dimethylformamide
  • examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • This reaction can be carried out in the range of 20 ° C. to 200 ° C. in the presence of a base.
  • the palladium catalyst include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate.
  • the amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide.
  • the palladium catalyst ligand that can be used include 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, ( ⁇ ) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis [2- (diphenylphosphino) phenyl] ether be able to.
  • the base that can be used include sodium t-butoxide and tripotassium phosphate.
  • the reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually in the range of 10 minutes to
  • Manufacturing method 2-2 (X 1 , R 1 , R 5 , R P , and Hal 1 are as defined above.) This reaction is a condensation reaction of compound [15] and compound [13] using a palladium catalyst, and can be carried out by the same method as in Production Method 1.
  • Compound [15] which is a raw material compound, can be produced, for example, according to the following method.
  • Process 1 Compound [18] can be produced by reacting compound [16] with alcohol compound [17] in the presence of a base in the range of ⁇ 20 ° C. to 100 ° C.
  • a base in the range of ⁇ 20 ° C. to 100 ° C.
  • the base include sodium hydride and sodium hydroxide.
  • Solvents that can be used are not particularly limited as long as they are not involved in the reaction.
  • hydrocarbons such as toluene and xylene
  • ethers such as 1,4-dioxane and tetrahydrofuran
  • N N-dimethylformamide
  • Examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, water, or a mixed solvent thereof.
  • the reaction time varies depending on the type of raw materials used and the reaction temperature, but usually 30 minutes to 24 hours is appropriate.
  • This reaction is a condensation reaction of the compound [18] and the compound [19] using a palladium catalyst, and therefore can be performed by a method known per se as a condensation reaction.
  • Solvents that can be used are not particularly limited as long as they are not involved in the reaction. For example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N, N-dimethylformamide, N, Examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • This reaction can be carried out in the range of 20 ° C. to 200 ° C. in the presence of a base.
  • Examples of the palladium catalyst that can be used include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate.
  • the amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide.
  • Examples of the palladium catalyst ligand that can be used include 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, ( ⁇ ) -2,2′-bis (diphenylphosphino) -1,1.
  • Examples include '-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis [2- (diphenylphosphino) phenyl] ether, and tri-t-butylphosphine.
  • Examples of the base that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
  • the reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually in the range of 10 minutes to 24 hours.
  • R 2 is a group represented by the following general formula [9], (Wherein R M , R N , R O and * are as defined above), or Substituted with one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl In the case of a good heteroaryl (provided that the bond is from C)
  • R 6 and R 7 all represent hydroxy, or R 6 and R 7 together represent —O—C ( It represents CH 3 ) 2 —C (CH 3 ) 2 —O—, —O— (CH 2 ) 3 —O—, or —O—CH 2 —C (CH 3 ) 2 —CH 2 —O—.
  • R 8 is a group represented by the following general formula [9],
  • R M , R N , R O and * are as defined above
  • Substituted with one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl Represents a good heteroaryl (provided that the bond is from C).
  • This reaction is a cross-coupling reaction using compound [1a] and organoboron compound [20], and can be carried out by a method known per se. This reaction can be carried out, for example, at 20 to 200 ° C.
  • a palladium catalyst examples include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex.
  • the amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide.
  • the reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction.
  • ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, N
  • amides such as N-dimethylformamide and N, N-dimethylacetamide
  • hydrocarbons such as benzene and toluene, water, or a mixed solvent thereof.
  • base examples include sodium hydroxide, potassium carbonate, and sodium carbonate.
  • the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 30 minutes to 24 hours.
  • This reaction is a condensation reaction of compound [21] and compound [13] using a palladium catalyst, and is performed by a method known per se.
  • Solvents that can be used are not particularly limited as long as they do not participate in the reaction.
  • hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N, N-dimethylformamide, N, N Examples thereof include amides such as dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • This reaction can be carried out in the range of 20 ° C.
  • the palladium catalyst examples include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate.
  • the amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide.
  • Examples of the ligand of the palladium catalyst that can be used include 1,1′-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, and 2-dicyclohexylphosphino- 2 ′, 4 ′, 6′-triisopropylbiphenyl, ( ⁇ ) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis Mention may be made of [2- (diphenylphosphino) phenyl] ether and tri-t-butylphosphine.
  • Examples of the base that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
  • the reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually in the range of 10 minutes to 24 hours.
  • Compound [21] which is a raw material compound, can be produced, for example, according to the following three methods.
  • Process 1 This reaction is a cross-coupling reaction using compound [22] and organoboron compound [20], and can be performed by a method known per se. This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at a temperature in the range of 20 to 200 ° C.
  • Examples of the palladium catalyst that can be used include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex. Can do.
  • the amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide.
  • the reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction.
  • ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, N
  • amides such as N-dimethylformamide and N, N-dimethylacetamide
  • hydrocarbons such as benzene and toluene, water, or a mixed solvent thereof.
  • base examples include sodium hydroxide, potassium carbonate, and sodium carbonate.
  • the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 30 minutes to 24 hours.
  • This reaction is a condensation reaction of the compound [23] and the compound [19] using a palladium catalyst, and therefore can be performed by a method known per se as a condensation reaction.
  • Solvents that can be used are not particularly limited as long as they are not involved in the reaction. For example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N, N-dimethylformamide, N, Examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • This reaction can be carried out in the range of 20 ° C. to 200 ° C. in the presence of a base.
  • Examples of the palladium catalyst that can be used include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate.
  • the amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide.
  • Examples of the palladium catalyst ligand that can be used include 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, ( ⁇ ) -2,2′-bis (diphenylphosphino) -1,1.
  • Examples include '-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis [2- (diphenylphosphino) phenyl] ether, and tri-t-butylphosphine.
  • Examples of the base that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
  • the reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually in the range of 10 minutes to 24 hours.
  • Method B (X 1 , R 1 , R 8 , Hal 1 and Hal 2 are as defined above. R 9 , R 10 and R 11 are the same or different and represent alkyl.)
  • This reaction is a cross-coupling reaction using compound [12] and organotin compound [24] and can be carried out by a method known per se. This reaction can be carried out, for example, at 20 to 200 ° C. in a suitable solvent in the presence of a palladium catalyst.
  • Examples of the palladium catalyst that can be used include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex, and palladium acetate. Can be mentioned.
  • the amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide.
  • the reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction.
  • ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, N, N -Amides such as dimethylacetamide, hydrocarbons such as benzene and toluene, or mixed solvents thereof.
  • Additives such as copper oxide and silver oxide can also be added.
  • the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 1 to 24 hours.
  • This reaction is a cross-coupling reaction using compound [12] and organoboron compound [20], and can be carried out by a method known per se.
  • This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at a temperature in the range of 20 to 200 ° C.
  • Examples of the palladium catalyst that can be used include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex. Can do.
  • the amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide.
  • the reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction.
  • ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, N
  • amides such as N-dimethylformamide and N, N-dimethylacetamide
  • hydrocarbons such as benzene and toluene, water, or a mixed solvent thereof.
  • base examples include sodium hydroxide, potassium carbonate, and sodium carbonate.
  • the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 30 minutes to 24 hours.
  • R 2 is a group represented by the following general formula [3] (Wherein, R F and R G are as defined above)
  • Manufacturing method 4-1 (X 1 , R 1 , R 5 and Hal 2 have the same meanings as described above.
  • R 12 represents a group represented by the following general formula [3].
  • This reaction is a cross-coupling reaction using compound [1a] and compound [25] and can be carried out by a method known per se.
  • Solvents that can be used are not particularly limited as long as they are not involved in the reaction. For example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N, N-dimethylformamide, N, Examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at a temperature in the range of 20 to 200 ° C.
  • a palladium catalyst examples include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate.
  • the amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide.
  • Examples of the ligand of the palladium catalyst that can be used include 1,1′-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, and 2-dicyclohexylphosphino- 2 ′, 4 ′, 6′-triisopropylbiphenyl, ( ⁇ ) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis Mention may be made of [2- (diphenylphosphino) phenyl] ether and tri-t-butylphosphine.
  • Examples of the base that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
  • the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 30 minutes to 24 hours.
  • This reaction is a condensation reaction of compound [26] and compound [13] using a palladium catalyst and can be carried out by a method known per se.
  • Solvents that can be used are not particularly limited as long as they are not involved in the reaction. For example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N, N-dimethylformamide, N, Examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof. This reaction can be carried out in the range of 20 ° C.
  • the palladium catalyst examples include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate.
  • the amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide.
  • Examples of the ligand of the palladium catalyst that can be used include 1,1′-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, and 2-dicyclohexylphosphino- 2 ′, 4 ′, 6′-triisopropylbiphenyl, ( ⁇ ) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis Mention may be made of [2- (diphenylphosphino) phenyl] ether and tri-t-butylphosphine.
  • Examples of the base that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
  • the reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually in the range of 10 minutes to 24 hours.
  • Compound [26] which is a raw material compound, can be produced, for example, according to the following two methods.
  • Method a Compound [26] can be produced by reacting compound [12] and compound [25] in a suitable solvent in the presence of a base within the range of 20 ° C to 200 ° C.
  • a base within the range of 20 ° C to 200 ° C. Examples of the base that can be used include pyridine, triethylamine, N, N-diisopropylethylamine, potassium carbonate, and sodium hydrogen carbonate.
  • Solvents that can be used are not particularly limited as long as they do not participate in the reaction, but alcohols such as 1-butanol and 2-methoxyethanol, ethers such as tetrahydrofuran and 1,4-dioxane, N, N-dimethylformamide, Examples thereof include amides such as N, N-dimethylacetamide, hydrocarbons such as benzene and toluene, acetonitrile, or a mixed solvent thereof.
  • the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 1 to 24 hours.
  • Method b Compound [26] is a condensation reaction of compound [12] and compound [25] using a palladium catalyst and can be carried out by a method known per se.
  • Solvents that can be used are not particularly limited as long as they are not involved in the reaction. Examples thereof include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, and mixed solvents thereof. it can. This reaction can be carried out in the range of 20 ° C. to 200 ° C. in the presence of a base.
  • the palladium catalyst examples include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate.
  • the amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide.
  • Examples of the ligand of the palladium catalyst that can be used include 1,1′-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, and 2-dicyclohexylphosphino- 2 ′, 4 ′, 6′-triisopropylbiphenyl, ( ⁇ ) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis Mention may be made of [2- (diphenylphosphino) phenyl] ether and tri-t-butylphosphine.
  • Examples of the base that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
  • the reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually in the range of 10 minutes to 24 hours.
  • R 2 is one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl.
  • X 1 , R 1 , R 5 , Hal 1 are as defined above.
  • R 13 is cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, Heteroaryl optionally substituted with one or two groups selected from the group consisting of hydroxycarbonyl and alkoxyalkyl (provided that the bond is from N)
  • This reaction is a condensation reaction of compound [27] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in the above production method 4-2.
  • Compound [27] which is a raw material compound, can be produced according to the following method.
  • This reaction is a cross-coupling reaction using compound [12] and compound [28] and can be carried out by a method known per se.
  • This reaction can be carried out, for example, in the range of 20 to 200 ° C. in a suitable solvent in the presence or absence of a copper catalyst.
  • the copper catalyst examples include copper iodide and copper acetate.
  • the amount of the copper catalyst that can be used is suitably in the range of 0.01 to 0.2 mole per mole of aryl halide.
  • Examples of copper ligands include trans-N, N′-dimethylcyclohexane-1,2-diamine, trans-1,2-cyclohexanediamine, and 1,10-phenanthroline.
  • the reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction.
  • ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, N
  • Examples thereof include amides such as N-dimethylformamide and N, N-dimethylacetamide, hydrocarbons such as benzene and toluene, and mixed solvents thereof.
  • Examples of the base that can be used include tripotassium phosphate, potassium carbonate, sodium carbonate, cesium carbonate and the like.
  • the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 30 minutes to 24 hours.
  • Compound [29] which is a raw material compound, can be produced according to the following method. (X 1 , R 1 , R 14 , Hal 1 , Hal 3 are as defined above.) This reaction is a condensation reaction of the compound [30] and the compound [19] using a palladium catalyst, and can be performed by the same method as in Step 2 of the production method of the compound [15] as the raw material compound.
  • This reaction is a hydrolysis reaction of the compound [1f] and can be carried out by a method known per se.
  • compound [1g] can be produced by hydrolyzing compound [1f] in the presence of an acid or a base.
  • the acid used in this reaction include inorganic acids such as hydrochloric acid and sulfuric acid, and examples of the base include inorganic bases such as sodium hydroxide and potassium hydroxide.
  • reaction solvent examples include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and 1,4-dioxane, water, and a mixed solvent thereof.
  • the reaction temperature is 0 to 100 ° C., and the reaction time is usually 30 minutes to 24 hours.
  • R 2 is (a) a saturated cyclic amino group optionally substituted with alkyl or alkylsulfonyl, or (b) alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, alkoxyalkyl
  • aminocarbonyl optionally substituted with one or two groups selected from the group consisting of hydroxyalkyl (X 1 , R 1 , R 5 are as defined above.
  • R 15 , R 16 are the same or different, and H, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, (Represents alkoxyalkyl or hydroxyalkyl, or together with the adjacent N represents a saturated cyclic amino group, which may be substituted with alkyl or alkylsulfonyl).
  • This reaction is a condensation reaction between compound [1g] and compound [31] and can be carried out by a method known per se as a condensation reaction.
  • Compound [1h] can be synthesized by reacting carboxylic acid represented by compound [1g] or a reactive derivative thereof with compound [31].
  • Examples of the reactive derivative of the compound [1g] include acid halides (for example, acid chloride, acid bromide), mixed acid anhydrides, imidazolides, active amides, and the like that are commonly used in amide condensation formation reactions. .
  • the reaction can be performed at ⁇ 20 to 100 ° C. using a condensing agent in the presence or absence of a base.
  • condensing agent examples include 1,1′-oxalyldiimidazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphonate, O- (benzotriazole).
  • 1,1′-oxalyldiimidazole 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphonate
  • O- (benzotriazole) examples include 1,1′-oxalyldiimidazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphonate, O- (benzotriazole).
  • Examples of the base that can be used in this reaction include organic bases such as triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, pyridine, and 1,8-diazabicyclo [5,4,0] -7-undecene. Can be mentioned. Solvents that can be used are not particularly limited as long as they are not involved in the reaction. For example, ethers such as tetrahydrofuran, 1,4-dioxane and diethyl ether, N, N-dimethylformamide, N, N-dimethylacetamide and the like can be used.
  • Examples thereof include amides, nitriles such as acetonitrile and propiononitrile, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and methylene chloride, and mixed solvents thereof.
  • an additive can be used as needed.
  • additives that can be used include 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole.
  • the reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually in the range of 10 minutes to 24 hours.
  • the amount of compound [31] and condensing agent used is, for example, suitably in the range of 1 to 3 mol per mol of compound [1g].
  • R 2 is H, an alkylcarbonyl, a saturated heterocyclic group containing 1 N optionally substituted with alkylsulfonyl, or an alkyl optionally substituted with hydroxy or alkoxy
  • R 17 is a saturated heterocyclic group containing 1 N optionally substituted with H, alkylcarbonyl, or alkylsulfonyl; Or represents an alkyl optionally substituted with hydroxy or alkoxy
  • This reaction is a condensation reaction of compound [32] and compound [13] using a palladium catalyst, and can be carried out by the same method as in Production Method 1.
  • This reaction is a cyanation reaction of compound [1a] and can be carried out by a method known per se. This reaction can be carried out, for example, in the presence or absence of a palladium catalyst, in a suitable solvent, with a cyano compound and in the range of 20 to 200 ° C., if necessary, using a microwave.
  • Examples of the palladium catalyst that can be used include tetrakis (triphenylphosphine) palladium, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex, tris (dibenzylideneacetone) dipalladium (0 ).
  • the amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide.
  • a palladium ligand 4,5-bis (diphenylphosphino) -9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, 2-dicyclohexyl Phosphino-2 ′, 6′-dimethoxybiphenyl and the like can be used.
  • cyano compounds that can be used include copper (I) cyanide, zinc (II) cyanide, potassium cyanide, and sodium cyanide.
  • the reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction.
  • ethers such as tetrahydrofuran and 1,4-dioxane
  • alcohols such as methanol and ethanol
  • N, N-dimethylformamide N
  • examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, hydrocarbons such as benzene and toluene, dimethyl sulfoxide, water, and a mixed solvent thereof.
  • the reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 30 minutes to 24 hours.
  • Compound [33] which is a raw material compound, can be produced according to the following method. (R 1 , R 18 , Hal 1 , Hal 3 are as defined above.) This reaction is a condensation reaction of compound [34] and compound [19] using a palladium catalyst, and can be carried out in the same manner as in production method 3-2 and method A, step 2.
  • R 19 and R 20 are the same or different and each represents H, alkyl, cycloalkyl, (cycloalkyl) alkyl, or alkoxyalkyl, or adjacent N. Together with a saturated cyclic amino group.
  • This reaction is a condensation reaction of compound [1j] and compound [36] and can be carried out by the same method as in Production Method 8.
  • Compound [37] which is a raw material compound, can be produced according to the following method. (X 1 , R 1 , R 2 , R 21 and Hal 1 are as defined above. Hal 4 represents halogen.)
  • This step can be produced by reacting compound [38] and compound [39] in an appropriate solvent at 20 ° C. to 200 ° C. in the presence of a base, if necessary, using a microwave.
  • a base examples include sodium hydride, lithium diisopropylamide, n-butyllithium and the like.
  • Solvents that can be used are not particularly limited as long as they are not involved in the reaction.
  • ethers such as tetrahydrofuran and 1,4-dioxane
  • amides such as N, N-dimethylformamide and N, N-dimethylacetamide
  • hydrocarbons such as benzene and toluene, acetonitrile, or a mixed solvent thereof.
  • the reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 10 minutes to 24 hours.
  • Compound [40] which is a raw material compound, can be produced according to the following method.
  • X 1 , R 1 , R 2 , Hal 1 , Hal 3 have the same meanings as described above.
  • Process 1 Compound [42] can be produced according to a known method (J. Org. Chem., 65, 2000, 9059-9068, etc.).
  • Process 2 This step is a condensation reaction of the compound [42] and the compound [43] using a palladium catalyst, and can be performed, for example, by the same method as the production method 1.
  • the compound of the present invention can be used as a medicine as it is, but can also be used in the form of a pharmaceutically acceptable salt by a known method.
  • Such salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, Mention may be made of salts of organic acids such as methanesulfonic acid.
  • the hydrochloride of the compound of the present invention can be obtained by dissolving the compound of the present invention in an alcohol solution of hydrogen chloride, an ethyl acetate solution or a diethyl ether solution.
  • optical isomers are known, for example, from the racemates obtained as described above, using optically active acids (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) utilizing the basicity. It can be optically resolved by the above method or can be produced using a previously prepared optically active compound as a raw material. In addition, it can also be produced by optical resolution or asymmetric synthesis using a chiral column. In addition, when a geometric isomer or tautomer exists in the compound of the present invention, not only one isomer but also a mixture thereof is also included in the compound of the present invention.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has a high ROS tyrosine kinase inhibitory activity as shown in the following test examples, and is useful as a medicine.
  • a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is a disease involving ROS tyrosine kinase, such as glioma, meningioma, non-small cell lung cancer, glioblastoma, It can be used as a prophylactic or therapeutic agent for chronic myelomonocytic leukemia, cholangiocarcinoma, liver cancer, kidney cancer, pancreatic cancer, or testicular cancer.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical
  • the compound of the present invention or a pharmaceutically acceptable salt thereof as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, A pharmaceutical composition containing 0.001% to 99.5%, preferably 0.1% to 90%, is administered to mammals including humans.
  • the pharmaceutical composition according to the present invention is desirably administered in a dosage unit form.
  • the pharmaceutical composition can be administered intra-tissue, oral, intravenous, topical (transdermal, ophthalmic, etc.) or rectally. Of course, it is administered in a dosage form suitable for these administration methods.
  • the dosage as a pharmaceutical is adjusted in consideration of the patient's condition such as age, weight, type of disease, degree of administration, etc., and the route of administration.
  • the amount of the effective component of the salt to be administered is 0.1 mg to 5 g / adult, preferably 1 mg to 500 mg / adult, per day for oral administration. In some cases, less than this may be sufficient, and vice versa. Usually, it can be administered once or divided into several times a day, or can be continuously administered intravenously over 1 to 24 hours.
  • the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 960 mg of the title compound as a pale yellow powder.
  • Example 11 (S) -N 2 - [ 1- (4- fluorophenyl) ethyl] -N 4 - (pyrazin-2-yl)-6-(1H-pyrazol-4-yl) pyrimidine-2,4 Diamine hydrochloride
  • 4- (methylsulfonyl) phenylboronic acid 4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl )-1H-pyrazole -1-carbamic acid t- butyl
  • (S) -N 2 - [ 1- (4- fluorophenyl) ethyl] -N 4 - (pyrazin-2-yl) -6- ( 1H-pyrazol-4-yl) pyrimidine-2,4-diamine was obtained.
  • Step 2 (S) -N 2 - [ 1- (4- fluorophenyl) ethyl] -N 4 - (pyrazin-2-yl) -6- (pyridin-3-yl) pyrimidine-2,4-diamine (S ) -4-chloro-N- [1- (4-fluorophenyl) ethyl] -6- (pyridin-3-yl) pyrimidin-2-amine 100 mg, 2-aminopyrazine 35 mg, 4,5-bis (diphenylphos) Fino) -9,9′-dimethylxanthene 18 mg, tripotassium phosphate 129 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 2 ml were added with 2 ml of 1,4-dioxane, deaerated and purged with argon.
  • Step 2 (S) -N 2 - [ 1- (4- fluorophenyl) ethyl] -N 4 - (pyrazin-2-yl) -6- (pyridin-2-yl) pyrimidine-2,4-diamine (S ) -4-chloro-N- [1- (4-fluorophenyl) ethyl] -6- (pyridin-2-yl) pyrimidin-2-amine 62 mg, 2-aminopyrazine 22 mg, 4,5-bis (diphenylphos) (Fino) -9,9'-dimethylxanthene (22 mg), tripotassium phosphate (80 mg) and tris (dibenzylideneacetone) (chloroform) dipalladium (2 ml) were added with degassed and
  • Step 2 (S) -1- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ pyrrolidin-2-one Degassed 1,4 -To 3 ml of dioxane, 104 mg of (S) -1- ⁇ 6-chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl ⁇ pyrrolidin-2-one, 33 mg of 2-aminopyrazine, 4 mg , 5-bis (diphenylphosphino) -9,9′-dimethylxanthene, 132 mg of tripotassium phosphate and 17 mg of tris (dibenzylideneacetone) (chloroform) dipalladium were added successively, and the mixture was stirred at 100 ° C.
  • N-diisopropylethylamine 122 ⁇ l was added and stirred at 80 ° C. for 32 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, 136 mg of the title compound was obtained as a white powder.
  • Step 2 (S) -4- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ piperazin-2,6-dione Degassed 1 , 4-dioxane in 2.5 ml, (S) -4- ⁇ 6-chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl ⁇ piperazine-2,6-dione, 119 mg, -Aminopyrazine 34 mg, 4,5-bis (diphenylphosphino) -9,9'-dimethylxanthene 19 mg, tripotassium phosphate 139 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 17 mg were sequentially added, and an argon atmosphere The mixture was stirred at 100 ° C.
  • Example 21 (S) -1- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ imidazolidin-2-one hydrochloride degassed to 1,4-dioxane 5 ml, (S)-6-chloro -N 2 - [1- (4- fluorophenyl) ethyl] -N 4 - (pyrazin-2-yl) pyrimidine-2,4-diamine ( Example 9) 150 mg, 2-imidazolidinone 224 mg, 4,5-bis (diphenylphosphino) -9,9'-dimethylxanthene 26 mg, tripotassium phosphate 185 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 23 mg was sequentially added, and the mixture was stirred at 100 ° C.
  • Step 2 (S) -N 2 - [ 1- (4- fluorophenyl) ethyl] -6- (oxazol-5-yl) -N 4 - (pyrazin-2-yl) pyrimidine-2,4-diamine hydrochloride (S) -N 2 - [1- (4- fluorophenyl) ethyl] -N 4 - (pyrazin-2-yl) -6- [2- (triisopropylsilyl) oxazol-5-yl] pyrimidin-2, 122 mg of 4-diamine was dissolved in 1.2 ml of tetrahydrofuran, and 1M tetrabutylammonium fluoride.
  • Step 2 (S) -4- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ pyridin-2-ol
  • S -N 2 - [1- (4-fluorophenyl) ethyl] -6- (2-fluoropyridin-4-yl) -N 4 - (pyrazin-2-yl) pyrimidine-2,4-diamine 80mg in 1,2-dimethoxyethane Ethane (1 ml) and 10% aqueous hydrochloric acid solution (1 ml) were added, and the mixture was stirred at 85 ° C. for 2 hours.
  • reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 90 mg of the title compound.
  • Step 3 (S) -6-Chloro-N- [1- (4-fluorophenyl) ethyl] -4- (1- ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ -1H-pyrazol-4-yl) pyridine -2-amine
  • 100 mg of 2,6-dichloro-4- (1- ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ -1H-pyrazol-4-yl) pyridine obtained in Step 2 44 mg of (S)-( ⁇ )-1- (4-fluorophenyl) ethylamine, 17 mg of 2- (di-t-butylphosphino) biphenyl, 70 mg of sodium t-butoxide and 6 mg of palladium acetate were successively added in an argon atmosphere.
  • the mixture was stirred at 85 ° C. for 1.5 hours.
  • the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 70 mg of the title compound as a colorless oil.
  • Step 4 (S) —N 2- [1- (4-Fluorophenyl) ethyl] -N 6- (pyrazin-2-yl) -4- (1- ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ -1H -Pyrazol-4-yl) pyridine-2,6-diamine (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -4 obtained in Step 3 was added to 2 ml of degassed toluene.
  • Step 5 (S) -N 2- [1- (4-Fluorophenyl) ethyl] -N 6- (pyrazin-2-yl) -4- (1H-pyrazol-4-yl) pyridin-2,6-diamine
  • S —N 2- [1- (4-Fluorophenyl) ethyl] -N 6- (pyrazin-2-yl) -4- (1- ⁇ [2- (trimethylsilyl) ethoxy] obtained in Step 4
  • a mixed solution of 1 ml of trifluoroacetic acid and 0.1 ml of water was added to 53 mg of methyl ⁇ -1H-pyrazol-4-yl) pyridine-2,6-diamine, and the mixture was stirred at room temperature for 3 hours.
  • the solvent was distilled off under reduced pressure, diluted with water, and made alkaline with a saturated aqueous sodium hydrogen carbonate solution. Extraction operation was performed with ethyl acetate, and the organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain 15 mg of the title compound as a pale yellow amorphous.
  • Step 2 1- (2,6-Dichloropyridin-4-yl) ethanone 490 mg of 2,6-dichloro-N-methoxy-N-methylisonicotinamide was dissolved in tetrahydrofuran, and 3M methylmagnesium bromide at 0 ° C. Tetrahydrofuran solution (2.1 ml) was added dropwise and stirred at 0 ° C.
  • N, N-dimethylformamide diethyl acetal was distilled off, and 5 ml of ethanol and 91 ⁇ l of hydrazine monohydrate were added to the resulting residue, followed by heating under reflux for 1 hour.
  • the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 320 mg of the title compound.
  • the mixture was stirred at 85 ° C. for 1 hour.
  • the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 130 mg of the title compound as a brown oil.
  • Step 6 (S) —N 2- [1- (4-Fluorophenyl) ethyl] -N 6- (pyrazin-2-yl) -4- (1- ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ -1H -Pyrazol-3-yl) pyridine-2,6-diamine
  • S -6-Chloro-N- [1- (4-fluorophenyl) ethyl] -6 obtained in Step 5 was added to 3 ml of degassed toluene.
  • Step 7 (S) -N 2- [1- (4-Fluorophenyl) ethyl] -N 6- (pyrazin-2-yl) -4- (1H-pyrazol-3-yl) pyridin-2,6-diamine
  • S —N 2- [1- (4-Fluorophenyl) ethyl] -N 6- (pyrazin-2-yl) -4- (1- ⁇ [2- (trimethylsilyl) ethoxy] obtained in step 6
  • a mixed solution of 3 ml of trifluoroacetic acid and 0.3 ml of water was added to 95 mg of (methyl ⁇ -1H-pyrazol-3-yl) pyridine-2,6-diamine, and the mixture was stirred at 60 ° C.
  • Example 31 (S) -N 2 - [ 1- (4- fluorophenyl) ethyl] -6-morpholino -N 4 - (pyrazin-2-yl) pyrimidine-2,4-diamine maleate
  • Example 20 It was synthesized by the method (S) -N 2 - [1- (4- fluorophenyl) ethyl] -6-morpholino -N 4 - a (pyrazin-2-yl) pyrimidine-2,4-diamine, example 30 A maleate was obtained by the same method.
  • Step 3 (S) -6-Chloro-N- [1- (4-fluorophenyl) ethyl] -4- (1-isopropyl-1H-pyrazol-4-yl) pyridin-2-amine
  • 145 mg of 2,6-dichloro-4- (1-isopropyl-1H-pyrazol-4-yl) pyridine obtained in step 2 87 mg of (S)-( ⁇ )-1- (4-fluorophenyl) ethylamine, 34 mg of 2- (di-t-butylphosphino) biphenyl, 109 mg of sodium t-butoxide and 13 mg of palladium acetate were sequentially added, followed by stirring at 85 ° C.
  • Step 4 (S) —N 2- [1- (4-Fluorophenyl) ethyl] -4- (1-isopropyl-1H-pyrazol-4-yl) -N 6- (pyrazin-2-yl) pyridine-2 , 6-diamine hydrochloride
  • Example 41 (S) -3- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl ⁇ propan-1-ol hydrochloride
  • Example 12 In the same manner as described above, 1,3-propanediol was used in place of ethylene glycol to obtain the title compound as a yellow powder.
  • the mixture was diluted with ethyl acetate, washed successively with 5% aqueous citric acid solution and saturated brine, and dried over magnesium sulfate.
  • the solvent was distilled off under reduced pressure to obtain 146 mg of a brown oil. This was dissolved in 2.5 ml of methylene chloride, 1 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. After evaporating the solvent under reduced pressure, 66 mg of N- (azetidin-3-yl) acetamide trifluoroacetate was obtained.
  • reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 17 mg of the title compound as a bright yellow powder.
  • Step 2 (S) -N 2 - [ 1- (4- fluorophenyl) ethyl] -N 4 - (pyrazin-2-yl) -6- (thiazol-5-yl) pyrimidine-2,4-diamine (S ) -4-chloro-N- [1- (4-fluorophenyl) ethyl] -6- (thiazol-5-yl) pyrimidin-2-amine 155 mg, 2-aminopyrazine 53 mg, 4,5-bis (diphenylphos) Fino) -9,9'-dimethylxanthene 72 mg, tripotassium phosphate 196 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 4 ml was added with 4 ml of 1,4-dioxane, degassed and purged with argon, 100 ° C.
  • Step 2 1- ⁇ 2-[(S) -1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ pyrrolidin-3-ol hydrochloride Degassed 1 , 4-dioxane 3 ml, 1- ⁇ 6-chloro-2-[(S) -1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl ⁇ pyrrolidin-3-ol 119 mg, 2-aminopyrazine 40 mg 4,5-bis (diphenylphosphino) -9,9'-dimethylxanthene, 150 mg of tripotassium phosphate and 19 mg of tris (dibenzylideneacetone) dipalladium were added in that order, and 2.
  • Example 51 (S) -N 2 - [ 1- (4- fluorophenyl) ethyl] -N 4 - (5- methylthiazol-2-yl) -N 6 - (pyrazin-2-yl) pyrimidin-2, 4,6-Triamine
  • 2-amino-5-methylthiazole was used in place of 2-pyrrolidone to obtain the title compound as a pale yellow powder.
  • Step 2 (S) —N 2- [1- (4-Fluorophenyl) ethyl] -N 6- (pyrazin-2-yl) -4,5′-bipyrimidine-2,6-diamine
  • S -6- Chloro-N- [1- (4-fluorophenyl) ethyl] -4,5′-bipyrimidin-2-amine 90 mg, 2-aminopyrazine 31 mg, 4,5-bis (diphenylphosphino) -9,9′-
  • To 4 mg of dimethylxanthene, 116 mg of tripotassium phosphate and 28 mg of tris (dibenzylideneacetone) (chloroform) dipalladium was added 2 ml of 1,4-dioxane, deaerated, purged with argon, and stirred at 100 ° C.
  • reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 285 mg of the title compound as a colorless oil.
  • Step 2 (S) -4-Chloro-6- (thiazol-2-yl) pyrimidin-2-yl [1- (4-fluorophenyl) ethyl] carbamate t-butyl
  • Degassed toluene (5 ) -4,6-dichloropyrimidin-2-yl) [1- (4-fluorophenyl) ethyl] carbamate 270 mg, 2- (tributylstannyl) thiazole 314 mg and tetrakis (triphenylphosphine) palladium 81 mg
  • the mixture was added sequentially and stirred at 100 ° C. for 3 hours under an argon atmosphere.
  • Trifluoroacetic acid was distilled off, diluted with water, and made alkaline with a saturated aqueous sodium hydrogen carbonate solution. Extraction operation was performed with ethyl acetate, and the organic layer was washed with water and dried over magnesium sulfate. After distilling off the solvent, the title compound was obtained as a pale yellow powder.
  • Example 61 (S) -2-( ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ (2-hydroxyethyl) amino) ethane -1-ol hydrochloride
  • diethanolamine instead of piperazin-2-one, diethanolamine was used and (S) -2-( ⁇ 2- [1- (4-fluorophenyl) ethylamino] -6- (Pyrazin-2-ylamino) pyrimidin-4-yl ⁇ (2-hydroxyethyl) amino) ethane-1-ol was obtained.
  • Step 2 (S) -N 2 - [ 1- (4- fluorophenyl) ethyl] -N 4 - (pyrazin-2-yl)-6-(1H-pyrrol-3-yl) pyrimidine-2,4-diamine
  • S (S) -N 2 - [1- (4-fluorophenyl) ethyl] -N 4 - (pyrazin-2-yl) -6- [1- (triisopropylsilyl)-1H-pyrrol-3-yl] pyrimidine -2,4-diamine (305 mg) was dissolved in tetrahydrofuran (3 ml), and 1M tetrabutylammonium fluoride / tetrahydrofuran solution (0.86 ml) was added under ice water cooling, followed by stirring at room temperature for 15 minutes.
  • Example 71 (S) -1- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ piperidin-4-ol hydrochloride
  • Example 1 (S) -1- ⁇ 2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2) using 4-hydroxypiperidine instead of piperazin-2-one -Iylamino) pyrimidin-4-yl ⁇ piperidin-4-ol was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a pale yellow powder.
  • Step 3 ((S) -5- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ nicotinonitrile
  • (S) -5- ⁇ 6-Chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl ⁇ nicotinonitrile 55 mg
  • 2-aminopyrazine 16 mg, 2-dicyclohexylphosphino-2 ′ , 4 ′, 6′-triisopropylbiphenyl 15 mg, sodium t-butoxide 21 mg, and tris (dibenzylideneacetone) (chloroform) dipalladium 8 mg were sequentially added, followed by stirring in an argon atmosphere at 100 ° C.
  • Step 2 (S) -N 2 - [ 1- (4- fluorophenyl) ethyl] -N 4 - (pyrazin-2-yl)-6-(2H-tetrazol-5-yl) pyrimidine-2,4-diamine
  • S -6- [2- (benzyloxymethyl) -2H- tetrazol-5-yl] N 2 - [1- (4- fluorophenyl) ethyl] -N 4 - (pyrazin-2-yl) pyrimidine -
  • 50 mg of 2,4-diamine was dissolved in 1.5 ml of methanol, 1.5 ml of a 10% hydrochloric acid aqueous solution was added, and the mixture was stirred at 80 ° C.
  • the organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was dissolved in 3 ml of tetrahydrofuran, 223 ⁇ l of diisopropylethylamine and 23 ⁇ l of acetyl chloride were added at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. Water was added to the reaction solution, and extraction with ethyl acetate was performed. The organic layer was washed with saturated brine and dried over magnesium sulfate.
  • Example 81 (S) -3- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ benzonitrile
  • 3-cyanophenylboronic acid in place of 4- (methylsulfonyl) phenylboronic acid, the title compound was obtained as a pale yellow amorphous.
  • the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 51 mg of the title compound as a white powder.
  • the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 196 mg of the title compound as a white powder.
  • Example 101 (1S, 2S) -2- ⁇ 2-[(S) -1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yloxy ⁇ cyclohexanol hydrochloride
  • (1S, 2S) -trans-1,2-cyclohexanediol was used instead of tetrahydrofurfuryl alcohol, and (1S, 2S) -2- ⁇ 2-[(S)- 1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yloxy ⁇ cyclohexanol was obtained.
  • step 1 4- (hydroxymethyl) piperidin-4-ol hydrochloride 1-benzyl-4- (hydroxymethyl) piperidin-4-ol 500mg (J.Med.Chem, 1988,486-491 Was synthesized in 10 ml of ethanol, 300 mg of 10% palladium carbon and 0.38 ml of concentrated hydrochloric acid were added, and hydrogenated at room temperature overnight. The insoluble material was filtered off, washed with ethanol and water, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue to form a powder, and 374 mg of the desired product was obtained as a white powder.
  • Step 2 (S) -1- ⁇ 6-Chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl ⁇ -4- (hydroxymethyl) piperidin-4-ol (S) -4 , 6-dichloro-N- [1- (4-fluorophenyl) ethyl] pyrimidin-2-amine 150 mg and 4- (hydroxymethyl) piperidin-4-ol hydrochloride 97 mg are dissolved in 3 ml of 2-ethoxyethanol, , N-diisopropylethylamine (274 ⁇ l) was added, and the mixture was stirred at 135 ° C. for 20 hours.
  • reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, 194 mg of the title compound was obtained as a brown oil.
  • Step 3 (S) -1- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ -4- (hydroxymethyl) piperidine-4-
  • Decan-8-yl) pyrimidin-2,4-diamine was used instead of piperazin-2-one, and In Step 1, the reaction was conducted at 135 ° C. using 2-ethoxyethanol as a reaction solvent to obtain the title compound as a brown powder.
  • Step 2 (S) -N 2- [1- (4-Fluorophenyl) ethyl] -N 6- (pyrazin-2-yl) pyridin-2,6-diamine dihydrochloride
  • Step 2 (S) -N 2 - [ 1- (4- fluorophenyl) ethyl] -6- (4-methyl -1H- imidazol-1-yl) -N 4 - (pyrazin-2-yl) pyrimidin-2 , 4-diamine hydrochloride
  • (S) -4-chloro-N- [1- (4-fluorophenyl) ethyl] -6- (4-methyl-1H-imidazolyl-1-yl) Pyrimidin-2-amine 60 mg, 2-aminopyrazine 19 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 17 mg, sodium t-butoxide 35 mg and tris (dibenzylideneacetone) dipalladium 9 mg successively The mixture was added and stirred at 100 ° C.
  • Example 121 (S) -N 2 - [ 1- (4- fluorophenyl) ethyl] -4-methyl -N 6 - (pyrazin-2-yl) pyridine-2,6-diamine hydrochloride ⁇ br/> step 1 (S) -6-Chloro-N- [1- (4-fluorophenyl) ethyl] -4-methylpyridin-2-amine To 6 ml of degassed N, N-dimethylformamide, add 2,6-dichloro-4 -500 mg of iodopyridine, 0.51 ml of trimethylboroxine, 1.0 g of potassium carbonate and 208 mg of tetrakis (triphenylphosphine) palladium were sequentially added and stirred at 110 ° C for 3 hours under an argon atmosphere.
  • the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 330 mg of a pale yellow solid. This was dissolved in 6 ml of degassed toluene, 253 mg of (S)-( ⁇ )-1- (4-fluorophenyl) ethylamine, 147 mg of bis [2- (diphenylphosphino) phenyl] ether, 244 mg of sodium t-butoxide and 40 mg of palladium acetate was sequentially added, and the mixture was stirred at 80 ° C.
  • Step 2 (S) —N 2- [1- (4-Fluorophenyl) ethyl] -4-methyl-N 6- (pyrazin-2-yl) pyridin-2,6-diamine hydrochloride
  • S degassed toluene
  • S -6-chloro-N- [1- (4-fluorophenyl) ethyl] -4-methylpyridin-2-amine
  • 2-aminopyrazine 40 mg, 2-dicyclohexylphosphino-2 ′, 4 ′ , 6′-triisopropylbiphenyl 34 mg, sodium t-butoxide 48 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 19 mg were sequentially added, and the mixture was stirred at 100 ° C.
  • Example 131 (S) -N 2 - [ 1- (4- fluorophenyl) ethyl] -N 6 - (pyrazin-2-yl) -N 4 - (pyrimidin-2-yl) pyridine-2,4,6 -Triamine
  • 2-aminopyrimidine instead of (S) -N- (pyrrolidin-3-yl) acetamide and 1,4-dioxane
  • Step 2 (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinic acid methyl ester
  • (S) -2-chloro- 4.4-g of 6- [1- (4-fluorophenyl) ethylamino] isonicotinic acid 1.3 g of 2-aminopyrazine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 2 .67 g, tripotassium phosphate 5.0 g and tris (dibenzylideneacetone) dipalladium 1.28 g were sequentially added, and the mixture was stir
  • 2,4,6-Trichloropyridine 400 mg was added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and extraction with ethyl acetate was performed. The organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 133 mg of the title compound as a colorless oil.
  • Step 2 (S) -6-Chloro-4- (cyclopropylmethoxy) -N- [1- (4-fluorophenyl) ethyl] pyridin-2-amine
  • 2,6-dichloro-4 -(Cyclopropylmethoxy) pyridine 130 mg
  • sodium t-butoxide 144 mg and palladium acetate 14 mg was sequentially added, and the mixture was stirred at 80 ° C. for 15 minutes under an argon atmosphere.
  • reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 122 mg of the title compound as a colorless oil.
  • Step 3 (S) -4- (Cyclopropylmethoxy) -N 2- [1- (4-fluorophenyl) ethyl] -N 6- (pyrazin-2-yl) pyridin-2,6-diamine Degassed 1 , 4-dioxane in 2 ml, (S) -6-chloro-4- (cyclopropylmethoxy) -N- [1- (4-fluorophenyl) ethyl] pyridin-2-amine 112 mg, 2-aminopyrazine 43 mg, -Dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl 67 mg, sodium t-butoxide 51 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 36 mg were sequentially added, and the mixture was added at 100 ° C.
  • Example 141 (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinic acid (S) -2- [1- (4-fluorophenyl) ethyl 5 ml of methanol was added to 500 mg of amino] -6- (pyrazin-2-ylamino) isonicotinic acid methyl ester (Example 134), followed by 2.7 ml of 2N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 6 hours. After diluting with ethyl acetate and water and extracting the aqueous layer, 2N hydrochloric acid was added.
  • the reaction mixture was diluted with water and extracted with ethyl acetate.
  • the organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 140 mg of brown amorphous.
  • 5 ml of triethyl orthoformate and 7 mg of p-tosylic acid were added and stirred at 60 ° C. for 4 hours.
  • the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
  • the organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate.
  • Step 2 (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) methyl nicotinate
  • 4.09 g of tripotassium phosphate and 475 mg of tris (dibenzylideneacetone) (chloroform) dipalladium were sequentially added, and the mixture was stirred at 100 ° C.
  • the mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over magnesium sulfate. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography to obtain 45 mg of the title compound as a pale yellow powder.
  • Example 151 (S) —Nt-butyl-2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinamide
  • dimethyl T-Butylamine was used in place of amine hydrochloride to give the title compound as a white powder.
  • Example 161 (S)- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl ⁇ (morpholino) methanone
  • morpholino morpholino methanone
  • Example 171 (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) -N- (2,2,2, -trifluoroethyl) isonicotinamide
  • 2,2,2, -trifluoroethylamine was used instead of ethylamine hydrochloride to give the title compound as a pale yellow powder.
  • the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 158 mg of the title compound.
  • Step 2 (S) -1- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ -N-methylazetidine-3-carboxamide 1 -150 mg of benzhydryl-N-methylazetidine-3-carboxamide was dissolved in 6 ml of methanol, 535 ⁇ l of 4N hydrochloric acid / ethyl acetate solution and 150 mg of 20% palladium hydroxide were added, and hydrogenated at room temperature and 4 atm overnight. Palladium hydroxide was filtered off and the solvent was distilled off under reduced pressure to obtain 150 mg of a pale yellow oil.
  • the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 12 mg of the title compound as a pale yellow powder.
  • the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, 610 mg of the title compound was obtained as a pale yellow oil.
  • Step 2 3- [6-Chloro-4- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl] -4- (4-fluorophenyl) oxazolidine-2-one Degassed 1,4 -To 10 ml of dioxane, 379 mg of 2,6-dichloro-4- (1-methyl-1H-pyrazol-4-yl) pyridine, 300 mg of 4- (4-fluorophenyl) oxazolidine-2-one, 4,5-bis ( Diphenylphosphino) -9,9'-dimethylxanthene (192 mg), tripotassium phosphate (705 mg) and tris (dibenzylideneacetone) (chloroform) dipalladium (172 mg) were sequentially added, and the mixture was stirred at 90 ° C.
  • Step 3 2- (4-Fluorophenyl) -2- [4- (1-methyl-1H-pyrazol-4-yl) -6- (pyrazin-2-ylamino) pyridin-2-ylamino] ethanol Degassed 1 , 4-dioxane in 2.5 ml, 3- [6-chloro-4- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl] -4- (4-fluorophenyl) oxazolidine-2- ON 80mg, 2-aminopyrazine 20mg, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl 20mg, sodium t-butoxide 41mg and tris (dibenzylideneacetone) (chloroform) dipalladium 22mg And stirred at 90 ° C.
  • Example 181 (S) -N, N-diethyl-1- ⁇ 2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ azetidine-3- Carboxamide
  • diethylamine instead of methylamine hydrochloride
  • the reaction solution was concentrated under reduced pressure to remove methanol.
  • the obtained aqueous layer was washed with diethyl ether, adjusted to pH 3 with 10% hydrochloric acid, and the precipitated solid was collected by filtration and washed with water. Drying under reduced pressure gave 880 mg of the title compound as a pale yellow powder.
  • Step 2 (S) -2- [1- (4-Fluorophenyl) ethylamino] -N-methyl-6- (pyrazin-2-ylamino) nicotinamide
  • S -2- [1- (4-Fluorophenyl) ) Ethylamino] -6- (pyrazin-2-ylamino) nicotinic acid (80 mg) was dissolved in 1 ml of tetrahydrofuran, and O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexa 86 mg of fluorophosphate (HBTU) and 59 mg of triethylamine were added.
  • HBTU fluorophosphate
  • reaction solution was concentrated under reduced pressure, 5 ml of concentrated aqueous ammonia was added, and the mixture was stirred at 100 ° C. for 30 minutes. After allowing to cool, the reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 13 mg of the title compound as a brown powder.
  • Example 191 (S) -1- ⁇ 2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ -N-isopropylazetidine-3-carboxamide
  • isopropylamine instead of methylamine hydrochloride
  • Example 201 (S) -1- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ -3-isopropylazetidin-3-ol Hydrochloride salt
  • 3-isopropylazetidin-3-ol hydrochloride (synthesized according to US2007 / 275930) was used, and (S) -1- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ -3-isopropylazetidin-3-ol was obtained.
  • the reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (S) -1- ⁇ 2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazine-2 78 mg of -ylamino) pyridin-4-yl ⁇ azetidin-3-ol were obtained. Furthermore, the hydrochloride was obtained according to a conventional method to obtain 60 mg of the title compound as a brown powder.
  • Example 205 (S) -1- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl ⁇ -3-methylazetidin-3-ol Hydrochloride
  • 3-methylazetidin-3-ol hydrochloride was used instead of 3-hydroxyazetidine hydrochloride, and toluene was used instead of 1,4-dioxane as the solvent.
  • Example 206 (S) -1- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl ⁇ -3- (trifluoromethyl) azetidine- 3-ol hydrochloride
  • 3- (trifluoromethyl) azetidin-3-ol hydrochloride was used instead of 3-hydroxyazetidine hydrochloride, and 1,4-dioxane was used as the solvent.
  • Example 207 (S) -4- (3,3-difluoroazetidin-1-yl) -N 2- [1- (4-fluorophenyl) ethyl] -N 6- (pyrazin-2-yl) pyridine- 2,6-diamine hydrochloride
  • 3,3-difluoroazetidine hydrochloride was used instead of 3-hydroxyazetidine hydrochloride, and 1,4-dioxane was used as the solvent.
  • Step 2 (S) -2-Chloro-6- [1- (4-fluorophenyl) ethylamino] t-butyl 4-pyrocarbamate
  • t-butyl pyridin-4-ylcarbamate To 10 ml of degassed 1,4-dioxane, 2,6-dichloro 390 mg of t-butyl pyridin-4-ylcarbamate, 220 ⁇ l of (S)-( ⁇ )-1- (4-fluorophenyl) ethylamine, 243 mg of bis [2- (diphenylphosphino) phenyl] ether, 199 mg of sodium t-butoxide And 67 mg of palladium acetate were sequentially added, followed by stirring at 100 ° C.
  • Step 3 (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-ylcarbamate t-butyl carbamate
  • Step 4 (S) —N 2- [1- (4-Fluorophenyl) ethyl] -N 6- (pyrazin-2-yl) pyridine-2,4,6-triamine
  • S -2- [1- ( 2-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-ylcarbamate t-butyl (210 mg) was dissolved in methylene chloride (3 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 5 hours. did. The reaction solution was poured into an ice-cooled saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
  • Step 5 (S) —N- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl ⁇ acetamide
  • S —N 2 — [1- 50 mg of (4-fluorophenyl) ethyl] -N 6- (pyrazin-2-yl) pyridine-2,4,6-triamine is dissolved in 1 ml of methylene chloride, 43 ⁇ l of triethylamine, 22 ⁇ l of acetic anhydride and 1 mg of 4-dimethylaminopyridine And stirred at room temperature overnight.
  • reaction solution was diluted with water and extracted with ethyl acetate.
  • organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 32 mg of the title compound as a yellow powder.
  • Step 2 1-Benzhydryl-3-cyclopropyl-3-methoxyazetidine 334 mg of 1-benzhydryl-3-cyclopropylazetidin-3-ol was dissolved in N, N-dimethylformamide and 60% hydrogenated under ice water cooling. Sodium (72 mg) was added, and the mixture was stirred at room temperature for 30 minutes.
  • Step 3 (S) -4- (3-Cyclopropyl-3-methoxyazetidin-1-yl) -N 2- [1- (4-fluorophenyl) ethyl] -N 6- (pyrazin-2-yl) Pyridine-2,6-diamine hydrochloride
  • 1-Benzhydryl-3-cyclopropyl-3-methoxyazetidine (275 mg) was dissolved in 15 ml of methanol, 0.70 ml of 2N hydrochloric acid and 150 mg of 20% palladium hydroxide were added, and 3.5 kgf / cm 2 And stirred at room temperature overnight. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain 146 mg of white powder.
  • reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 631 mg of the title compound.
  • the extract was washed successively with water and saturated brine, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, 221 mg of a brown solid was obtained. This was dissolved in 10 ml of methylene chloride, 270 ⁇ l of triethylamine, 251 mg of methanesulfonic anhydride and 1 mg of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate.
  • Step 3 (S) -6-Chloro-N- [1- (4-fluorophenyl) ethyl] -4- [1- (methylsulfonyl) -1,2,3,6-tetrahydropyridin-4-yl] pyridine -2-Amine
  • 225 mg of 2,6-dichloro-4- [1- (methylsulfonyl) -1,2,3,6-tetrahydropyridin-4-yl] pyridine To 5 ml of degassed tetrahydrofuran, 225 mg of 2,6-dichloro-4- [1- (methylsulfonyl) -1,2,3,6-tetrahydropyridin-4-yl] pyridine, (S)-( ⁇ )-1 -(4-Fluorophenyl) ethylamine 104 ⁇ l, ( ⁇ ) -2,2′-bis (diphenylphosphino) -1,1′-bina
  • Step 4 (S) —N 2- [1- (4-Fluorophenyl) ethyl] -4- [1- (methylsulfonyl) -1,2,3,6-tetrahydropyridin-4-yl] -N 6 — (Pyrazin-2-yl) pyridine-2,6-diamine
  • (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -4- [1- (methyl (Sulfonyl) -1,2,3,6-tetrahydropyridin-4-yl] pyridin-2-amine 115 mg, 2-aminopyrazine 40 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 53 mg Sodium t-butoxide (40 mg) and tris (dibenzylideneacetone
  • Step 5 (S) —N 2- [1- (4-Fluorophenyl) ethyl] -4- [1- (methanesulfonyl) piperidin-4-yl] -N 6- (pyrazin-2-yl) pyridine-2 , 6-Diamine (S) -N 2- [1- (4-Fluorophenyl) ethyl] -4- [1- (methylsulfonyl) -1,2,3,6-tetrahydropyridin-4-yl] -N 6- (pyrazine -2-yl) pyridin-2,6-diamine (88 mg) was dissolved in methanol (5 ml), ammonium formate (599 mg) and 20% palladium hydroxide (18 mg) were added, and the mixture was refluxed for 3 hours.
  • the mixture was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride solution, water and saturated brine, and dried over magnesium sulfate. After removing the solvent under reduced pressure, 148 mg was obtained as a yellow oil. This was dissolved in 3 ml of acetonitrile, 209 mg of iodine and 451 mg of diammonium cerium (IV) nitrate were added under ice water cooling, and the mixture was stirred at room temperature for 5 hours. To this was added 6 ml of 5% aqueous sodium hydrogen sulfite solution, and the mixture was stirred at room temperature for 10 minutes.
  • the mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 167 mg of the title compound as a pale yellow oil.
  • Step 2 (S) -4- (1-Cyclopropyl-1H-pyrazol-4-yl) -N 2- [1- (4-fluorophenyl) ethyl] -N 6- (pyrazin-2-yl) pyridine- 2,6-diamine
  • 1-cyclopropyl-4-iodo-1H-pyrazole instead of 4-iodo-1-isopropyl-1H-pyrazole
  • Example 221 (S) -N 2 - [ 1- (4- fluorophenyl) ethyl] -6- [3- (methylamino) azetidin-1-yl] -N 4 - (pyrazin-2-yl) pyrimidine - 2,4-Diamine
  • the 2M-methylamine / tetrahydrofuran solution was used in place of the 2M-dimethylamine / tetrahydrofuran solution to give the title compound as a white powder.
  • Example 226 4- ⁇ 2-[(1S) -1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ -1 ⁇ 6 , 4-thiomorpholine-1 , 1-dione ⁇ br/> step 1 4- ⁇ 6-chloro -2 - [(1S) -1- ( 4- fluorophenyl) ethylamino] pyrimidin-4-yl ⁇ llambda 6, 4-thiomorpholine - 1,1-dione In the same manner as in Example 1, step 1, after reaction using thiomorpholine-1,1-dioxide instead of piperazin-2-one, the product was purified by silica gel column chromatography.
  • Step 2 (S) -1- (1- ⁇ 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl ⁇ azetidin-3-yl) urea (S) -1- (1- ⁇ 6-chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidine- (S) -1- (1- ⁇ 6-chloro-2- [1-fluorophenyl) ethylamino] pyrimidine- 4-yl ⁇ azetidin-3-yl) urea 73 mg, 2-aminopyrazine 25 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 38 mg, sodium t-butoxide 29 mg and tris (dibenzylideneacetone) ) 18 mg of dipall
  • reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 31 mg of the title compound as a brown powder.
  • test substance was dissolved in dimethyl sulfoxide (DMSO) at 10 mM, and further diluted with DMSO to a concentration 100 times the measured concentration (10, 1 ⁇ M). Further, the test substance solution was diluted 25 times with assay buffer. As a negative control, a solution obtained by diluting DMSO 25 times with assay buffer was used. (20 mM HEPES (pH 7.5), 0.01 (v / v)% Triton X-100, 2 mM dithiothreitol) was used as the assay buffer. 2. Measurement of ROS tyrosine kinase activity
  • an off-chip mobility shift assay (MSA) method was used for the measurement of the activity.
  • 5 ⁇ L of a test substance solution having a concentration 4 times the final concentration prepared in the assay buffer, 5 ⁇ L of a substrate / ATP / metal solution (200 ⁇ M ATP 20 mM MgCl 2 4000 nM peptide substrate) having a concentration 4 times the final concentration dissolved in the assay buffer, and the assay buffer 10 ⁇ L of the ROS tyrosine kinase solution having a concentration twice the final concentration dissolved in the solution was mixed in the well of a polypropylene 384-well plate and reacted at room temperature for 1 hour (n 2). Wells without kinase were used as background wells.
  • Termination Buffer Quality of Life Science
  • the fluorescence intensity of the substrate peptide and phosphopeptide quantified by the above system is expressed as the peak height of the waveform data.
  • the inhibition rate (%) of the kinase was calculated using the height of the substrate peptide peak (S) and the height of the phosphorylated peptide peak (P) using [(1 ⁇ ⁇ [P / (P + S)] of the drug-containing well.
  • Table 13 shows the inhibition rate (% inh) of the example compounds against Ros kinase at 100 nM and 10 nM.
  • Formulation Example 1 Tablet (internal tablet) Prescription 1 tablet 80mg The compound of the present invention of Example 1 5.0 mg Corn starch 46.6mg Crystalline cellulose 24.0mg Methylcellulose 4.0mg Magnesium stearate 0.4mg This proportion of the mixed powder is formed into tablets by a conventional method.
  • Formulation Example 2 Tablet (internal tablet) Prescription 1 tablet 80mg The compound of the present invention of Example 2 5.0 mg Corn starch 46.6mg Crystalline cellulose 24.0mg Methylcellulose 4.0mg Magnesium stearate 0.4mg This proportion of the mixed powder is formed into tablets by a conventional method.
  • a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is, for example, It can be used as a preventive or therapeutic agent for chronic myelomonocytic leukemia, glioma, meningioma, non-small cell lung cancer.

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Abstract

L'invention concerne un inhibiteur de ROS de tyrosine kinase contenant comme principe actif le composé de formule générale [1], dans laquelle soit (I) soit (II) s'applique, ou un sel pharmaceutiquement acceptable de celui-ci. (I) X représente CH ou N, R1 représente un halogène, R2 représente un halogène, H, cyano, un groupe représenté par la formule [9], un hétéroaryle facultativement substitué, etc., R3 représente H ou un hydroxy, R4 représente H ou un alkyle et R5 représente H ou un alkyle. (II) X représente -CRA, RA représente -CORB, RB représente un amino facultativement substitué, un alcoxy ou un groupe amino cyclique saturé, R1 représente un halogène, R2 représente H, R3 représente H ou un hydroxy, R4 représente H ou un alkyle et R5 représente H ou un alkyle.
PCT/JP2011/065492 2010-07-07 2011-07-06 Inhibiteur de ros de tyrosine kinase WO2012005299A1 (fr)

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WO2013183578A1 (fr) 2012-06-04 2013-12-12 第一三共株式会社 DÉRIVÉ D'IMIDAZO[1,2-b]PYRIDAZINE COMME INHIBITEUR DE KINASE
JP5668756B2 (ja) * 2010-08-11 2015-02-12 日本新薬株式会社 悪性リンパ腫治療剤
CN107216312A (zh) * 2016-03-22 2017-09-29 上海海和药物研究开发有限公司 一种具有突变型idh抑制活性的化合物、其制备方法及用途
CN111132971A (zh) * 2017-09-28 2020-05-08 日本新药株式会社 晶体
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation

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JP5668756B2 (ja) * 2010-08-11 2015-02-12 日本新薬株式会社 悪性リンパ腫治療剤
US9580413B2 (en) 2012-05-30 2017-02-28 Nippon Shinyaku Co., Ltd. Substituted pyrrolidines as ROS tyrosine kinase inhibitors
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CN104470918A (zh) * 2012-05-30 2015-03-25 日本新药株式会社 芳香族杂环衍生物及医药
AU2013268400B2 (en) * 2012-05-30 2017-07-13 Nippon Shinyaku Co., Ltd. Aromatic heterocyclic derivative and pharmaceutical
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US9751887B2 (en) 2012-06-04 2017-09-05 Daiichi Sankyo Company, Limited Imidazo[1,2-b]pyridazine derivatives as kinase inhibitors
US9187489B2 (en) 2012-06-04 2015-11-17 Daiichi Sankyo Company, Limited Imidazo[1,2-b]pyridazine derivatives as kinase inhibitors
WO2013183578A1 (fr) 2012-06-04 2013-12-12 第一三共株式会社 DÉRIVÉ D'IMIDAZO[1,2-b]PYRIDAZINE COMME INHIBITEUR DE KINASE
CN107216312A (zh) * 2016-03-22 2017-09-29 上海海和药物研究开发有限公司 一种具有突变型idh抑制活性的化合物、其制备方法及用途
CN107216312B (zh) * 2016-03-22 2023-08-01 上海海和药物研究开发股份有限公司 一种具有突变型idh抑制活性的化合物、其制备方法及用途
CN111132971A (zh) * 2017-09-28 2020-05-08 日本新药株式会社 晶体
US11680055B2 (en) 2017-09-28 2023-06-20 Nippon Shinyaku Co., Ltd. Crystals
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation

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