WO2011016472A1 - Dérivés de pyridine et de pyrimidine ayant une activité inhibitrice de ttk - Google Patents

Dérivés de pyridine et de pyrimidine ayant une activité inhibitrice de ttk Download PDF

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WO2011016472A1
WO2011016472A1 PCT/JP2010/063153 JP2010063153W WO2011016472A1 WO 2011016472 A1 WO2011016472 A1 WO 2011016472A1 JP 2010063153 W JP2010063153 W JP 2010063153W WO 2011016472 A1 WO2011016472 A1 WO 2011016472A1
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substituted
unsubstituted
formula
alkyl
hydrogen
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Japanese (ja)
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兼一 日下部
奈緒子 山口
恭典 三岡
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オンコセラピー・サイエンス株式会社
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention relates to pyridine and pyrimidine derivatives having an inhibitory / suppressing action on TTK (TTK protein kinase) activity.
  • the present invention relates to a medicament comprising this pyridine and pyrimidine derivative.
  • Protein kinases are enzymes that add (phosphorylate) phosphate groups to other protein molecules. Protein kinases have an activity of transferring a phosphate group from ATP to a hydroxyl group at an amino acid residue in a protein molecule to covalently bond it. Many protein kinases react with hydroxyl groups of serine and threonine in protein molecules (serine / threonine kinase), react with hydroxyl groups of tyrosine (tyrosine kinase), react with all three types (dual specificity) Kinase). The activity of protein kinases is precisely regulated, and protein kinases themselves may be regulated by phosphorylation. These modulations are caused by binding of other activating (or suppressing) proteins and low molecular weight compounds, localization changes in cells, and the like. Kinase dysfunction often causes illness.
  • TTK protein kinase is a bispecific kinase that phosphorylates serine, threonine and tyrosine residues in a protein serving as a substrate (see, for example, Non-Patent Document 1).
  • Kinase domains required for expressing kinase activity are known (see, for example, Non-Patent Documents 1 and 2).
  • Mad1 for example, see Non-Patent Document 3
  • Spcl10p Nuflp
  • CHK2 for example, Non-Patent Document 5
  • Borealin for example, Non-Patent Document 6
  • Mad1 for example, see Non-Patent Document 3
  • Spcl10p Nuflp
  • CHK2 for example, Non-Patent Document 5
  • Borealin for example, Non-Patent Document 6
  • TTK expression correlates with cell proliferation and plays a role in cell cycle control.
  • Patent Document 1 describes that TTK is expressed in malignant ovarian cancer and a screening method including a step of measuring the expression level of TTK.
  • Patent Document 2 discloses an application relating to a method for identifying cancer cells by detecting TTK activity and a method for identifying a drug that suppresses tumor growth, and TTK using tau, cdc25, and their partial peptides as a substrate as a screening method. An activity measurement method is described.
  • Patent Document 3 describes a method for measuring TTK activity using a partial peptide of p38MAPK as a substrate as a method for cleaning TTK activity. Examples of the TTK inhibitor include those described in Patent Documents 4 and 5.
  • pyridine and pyrimidine derivatives include those described in Patent Documents 6 to 59 and Non-Patent Documents 7 to 20, but none are known as TTK inhibitors, and Patent Document 60 discloses TTK inhibitory activity. Is not described.
  • An object of the present invention is to provide an effective inhibitor of TTK protein kinase, and thus to provide an effective medicine.
  • the Applicant has discovered a novel series of compounds with specific properties that inhibit the action of TTK kinase and are particularly useful in formulating pharmaceuticals for treating the above diseases. Therefore, the present compounds are useful in diseases that are considered effective by inhibiting the action of TTK kinase.
  • the present invention provides the following items.
  • X is ⁇ C (R 4 ) — or ⁇ N—
  • A is a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring (provided that a substituted or unsubstituted aromatic ring Except for pyrazole or fused pyrazole.)
  • R 1 is hydrogen, substituted or unsubstituted alkyl, a group represented by the formula: —NR 1A R 1A ′ or a group represented by the formula: —OR 1B ;
  • R 1A is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or un
  • R 1A ′′ and R 2A ′′ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted An acyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl, wherein R a and R b are each independently hydrogen or substituted or unsubstituted alkyl, and n is 0-3 Which may be an integer).
  • R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or halogen;
  • R 4 is hydrogen or halogen;
  • R 5A and R 5B are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Carbamoyl, a group represented
  • X is ⁇ C (R 4 ) —
  • A is substituted or unsubstituted piperidine, substituted or unsubstituted thiophene, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted fused pyrimidine, substituted or unsubstituted
  • R 2 is cyano
  • R 1 is of the formula: —NR 1A R 1A ′
  • R 1B is methyl
  • R 2 is cyano
  • R 3 is hydrogen
  • R 1 is a group represented by the formula: —NR 1A R 1A ′ (where R 1A ′ is substituted or unsubstituted alkyl, substituted or unsubstituted Piperidinyl and substituted or unsubstituted cyclopropyl) and a group represented by the formula: —OR 1B (where R 1B is substituted or unsubstituted alkyl), (Viii) When X is ⁇ N—, A is a substituted or unsubstituted aromatic hydrocarbon ring or a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyridine).
  • R 2 is cyano
  • R 3 is hydrogen
  • R 5A is not substituted sulfinyl, substituted or unsubstituted carbamoyl, carboxy, substituted or unsubstituted morpholinyl and substituted sulfonyl.
  • R 1 is a group represented by the formula: —NR 1A R 1A ′ or a group represented by the formula: —OR 1B (wherein R 1A , R 1A ′ and R 1B are as defined in item (1A)) Yes, R 2 is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted
  • the compound according to item (1A) its pharmaceutically acceptable salt, or a solvate thereof, which is carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino or carboxy.
  • (3A) The compound according to item (1A) or (2A), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein A is a substituted or unsubstituted aromatic hydrocarbon ring.
  • R 2 is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted
  • R 1 has the formula: -NHR 1A 'in a group represented by or formula group (wherein, R 1A represented by -OR 1B' and R 1B item (1A) and synonymous) is, items (1A ) To (8A) and (8′A), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 1 is a group represented by the formula: —NHR 1A ′ , and R 1A ′ is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted saturated heterocyclyl.
  • R 1 has the formula: a group represented by -OR 1B, R 1B is a substituted or unsubstituted cycloalkyl, item (1A) ⁇ (8A), (8'A), and (9A) Or a pharmaceutically acceptable salt or solvate thereof.
  • R 1A ′′ and R 2A ′′ are each independently substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl, n is an integer of 0 to 2, R a and R b are the same as defined in item (1A)), A is a substituted or unsubstituted aromatic hydrocarbon ring; R 3 is hydrogen, the compound according to any one of items (1A) to (5A), (8A), (8′A), and (12A) to (15A), a pharmaceutically acceptable salt thereof, or Their solvates.
  • a pharmaceutical comprising the compound according to any one of items (1A) to (8A), (8'A), (9A) to (16A), a pharmaceutically acceptable salt thereof or a solvate thereof Composition.
  • X is ⁇ C (R 4 ) —
  • A is a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring (provided that a substituted or unsubstituted pyrazole or condensed pyrazole And substituted or unsubstituted thiophene), a substituted or unsubstituted non-aromatic hydrocarbon ring or a substituted or unsubstituted non-aromatic heterocyclic ring
  • R 1 is hydrogen, substituted or unsubstituted alkyl, a group represented by the formula: —NR 1A R 1A ′ or a group represented by the formula: —OR 1B ;
  • R 1A is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl
  • R 1A ′′ and R 2A ′′ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted Or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl, R a and R b are each independently hydrogen or substituted or unsubstituted alkyl; n is an integer of 0 to 3.
  • R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or halogen;
  • R 4 is hydrogen or halogen;
  • R 5A and R 5B are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Carbamoyl, a group represented
  • a method for preventing or treating cancer comprising:
  • N- A represents a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyrazole or fused pyrazole), a substituted or unsubstituted non-aromatic hydrocarbon ring.
  • R 1 is hydrogen, substituted or unsubstituted alkyl, a group represented by the formula: —NR 1A R 1A ′ or a group represented by the formula: —OR 1B ;
  • R 1A is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl or substituted or Unsubstituted saturated heterocyclyl
  • R 1A ′ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl,
  • R 1A ′′ and R 2A ′′ each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl
  • R a and R b are each independently hydrogen or substituted or unsubstituted alkyl
  • n is an integer of 0 to 3.
  • R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or halogen;
  • R 4 is hydrogen or halogen;
  • R 5A and R 5B are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted carbamoyl, a group represented
  • X is ⁇ C (R 4 ) —
  • A is substituted or unsubstituted piperidine, substituted or unsubstituted thiophene, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted fused pyrimidine, substituted or unsubstituted
  • R 2 is cyano
  • R 1 is of the formula: —NR 1A R 1A ′
  • R 1B is methyl
  • R 2 is cyano
  • R 3 is hydrogen
  • R 1 is a group represented by the formula: —NR 1A R 1A ′ (where R 1A ′ is substituted or unsubstituted alkyl, substituted or unsubstituted Piperidinyl and substituted or unsubstituted cyclopropyl) and a group represented by the formula: —OR 1B (where R 1B is substituted or unsubstituted alkyl), (Viii) When X is ⁇ N—, A is a substituted or unsubstituted aromatic hydrocarbon ring or a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyridine).
  • R 2 is cyano
  • R 3 is hydrogen
  • R 5A is not substituted sulfinyl, substituted or unsubstituted carbamoyl, carboxy, substituted or unsubstituted morpholinyl and substituted sulfonyl.
  • R 1 is a group represented by the formula: —NR 1A R 1A ′ or a group represented by the formula: —OR 1B (where R 1A , R 1A ′ and R 1B are as defined in item (1B)) Yes, R 2 is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl , A substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino or carboxy, a pharmaceutically acceptable salt thereof or a solvent thereof Japanese products.
  • R 2 is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbamoyl, substituted or unsubstituted
  • a pharmaceutically acceptable salt thereof or a solvate thereof which is acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino or carboxy.
  • R 1 is a group represented by the formula: —NHR 1A ′ , and R 1A ′ is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted saturated heterocyclyl.
  • R 1 has the formula: a group represented by -OR 1B, R 1B is a substituted or unsubstituted cycloalkyl A compound according to any of items (1B) ⁇ (10B), a pharmaceutically Acceptable salts or solvates thereof.
  • R 1A ′′ and R 2A ′′ are each independently substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl, n is an integer of 0 to 2, and R a and R b are the same as defined in item (1B)), A is a substituted or unsubstituted aromatic hydrocarbon ring, The compound according to any one of items (1B) to (15B), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 3 is hydrogen.
  • a pharmaceutical composition comprising the compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 1 is hydrogen, substituted or unsubstituted alkyl, a group represented by the formula: —NR 1A R 1A ′ or a group represented by the formula: —OR 1B ;
  • R 1A is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acy
  • R 1A ′′ and R 2A ′′ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted Or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl, R a and R b are each independently hydrogen or substituted or unsubstituted alkyl; n is an integer of 0 to 3.
  • R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or halogen;
  • R 4 is hydrogen or halogen;
  • R 5A and R 5B are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Carbamoyl, a group represented
  • (22B) A method for preventing or treating cancer, comprising administering the compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • TTK inhibitor containing the compound according to any one of items ((1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • An anticancer agent comprising the compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a therapeutic agent for immune system diseases comprising the compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (30B) A method, system, apparatus, kit, etc. for producing the compound according to any one of items (1B) to (16B), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the present invention provides an effective inhibitor of TTK protein kinase, and thus provides an effective medicament for diseases, disorders or conditions related to TTK such as cancer.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • alkyl includes a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • alkyl having 1 to 6 or 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, n-hexyl, isohexyl can be mentioned.
  • alkenyl includes straight-chain or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds to the above “alkyl”.
  • alkynyl includes linear or branched alkynyl having 2 to 8 carbon atoms having one or more triple bonds in the above “alkyl”, and includes, for example, ethynyl, Examples include propynyl and butynyl. Furthermore, it may have one or more double bonds.
  • cycloalkyl includes a cyclic saturated hydrocarbon group having 3 to 15 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclic hydrocarbon. Group, spiro hydrocarbon group and the like. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a bridged cyclic hydrocarbon group.
  • the “bridged cyclic hydrocarbon group” refers to hydrogen from an aliphatic ring having 5 to 12 carbon atoms in which two or more rings share two or more atoms. Includes groups that can be removed. Specifically, bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl, tricyclo [2.2. 1.0] heptyl, bicyclo [3.3.1] nonane, 1-adamantyl, 2-adamantyl and the like.
  • the “spiro hydrocarbon group” includes a group formed by removing one hydrogen from a ring in which two hydrocarbon rings are configured to share one carbon atom.
  • Specific examples include spiro [3.4] octyl.
  • cycloalkenyl includes a cyclic unsaturated aliphatic hydrocarbon group having 3 to 7 carbon atoms, and examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. Cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl. Cycloalkenyl also includes bridged cyclic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring.
  • aryl includes a monocyclic or condensed aromatic hydrocarbon ring. This may be condensed with the above “cycloalkyl” at all possible positions. Whether aryl is a single ring or a fused ring, it can be attached at all possible positions. Examples include phenyl, 1-naphthyl, 2-naphthyl, anthryl, tetrahydronaphthyl and the like. Examples include phenyl, 1-naphthyl and 2-naphthyl. An example is phenyl.
  • the “aromatic hydrocarbon ring” includes an aromatic 5- to 8-membered ring containing only a carbon atom in the ring or a ring in which two or more of them are condensed.
  • the monocyclic aromatic hydrocarbon ring includes a ring derived from a 6-membered aromatic hydrocarbon ring and optionally having a bond at any substitutable position.
  • the condensed aromatic hydrocarbon ring has a bond at any substitutable position where the 6-membered aromatic hydrocarbon ring is condensed with 1 to 4 6-membered aromatic hydrocarbon rings.
  • a 6-membered aromatic hydrocarbon ring is mentioned.
  • aromatic hydrocarbon ring examples include a benzene ring, a naphthalene ring, an anthracene ring, and a tetrahydronaphthalene ring.
  • a benzene ring and a naphthalene ring are mentioned.
  • non-aromatic hydrocarbon ring includes a non-aromatic 3- to 8-membered ring containing only a carbon atom in the ring or a ring in which two or more of them are condensed.
  • the monocyclic non-aromatic hydrocarbon ring includes a group derived from a 3- to 8-membered non-aromatic hydrocarbon ring and optionally having a bond at any substitutable position.
  • a fused non-aromatic hydrocarbon ring is any substitutable position where a 5- to 8-membered non-aromatic hydrocarbon ring is fused with 1 to 4 5- to 8-membered non-aromatic hydrocarbon rings Includes a group which may have a bond.
  • non-aromatic hydrocarbon ring examples include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, a cyclopropene ring, a cyclobutene ring, a cyclopentene ring, a cyclohexene ring, and a cycloheptene ring.
  • examples thereof include a cyclopentane ring, a cyclohexane ring, a cyclopentene ring, and a cyclohexene ring.
  • heteroaryl includes an optionally selected 5- to 8-membered aromatic hydrocarbon ring containing at least one oxygen atom, sulfur atom, and / or nitrogen atom in the ring. This may be condensed with the above “cycloalkyl”, the above “aryl”, the following “heterocyclyl”, or other heteroaryl at all possible positions. Whether the heteroaryl is a single ring or a fused ring, it can be attached at all possible positions.
  • pyrrolyl eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl
  • furyl eg, 2-furyl, 3-furyl
  • thienyl eg, 2-thienyl, 3-thienyl
  • imidazolyl eg, 2 -Imidazolyl, 4-imidazolyl
  • pyrazolyl eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl
  • isothiazolyl eg 3-isothiazolyl
  • isoxazolyl eg 3-isoxazolyl
  • oxazolyl eg 2-oxazolyl
  • 4-oxazolyl 5-oxazolyl
  • thiazolyl eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl
  • pyridyl eg 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyrazinyl eg
  • heterocyclyl may contain 1 to 4 oxygen atoms, sulfur atoms, and / or nitrogen atoms in the ring, and has a bond at any substitutable position.
  • Non-aromatic heterocycles which may be optionally included.
  • such a non-aromatic heterocyclic ring may be further bridged with an alkyl chain having 1 to 4 carbon atoms, such as a non-aromatic heterocyclic ring (including a 5- to 6-membered ring) or an aromatic hydrocarbon ring ( For example, a benzene ring) may be condensed. If it is non-aromatic, it may be saturated or unsaturated. For example, a 5- to 8-membered ring.
  • pyrrolinyl eg, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl
  • pyrrolidinyl eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl
  • pyrrolidinone imidazolinyl (eg, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), imidazolidinyl (eg 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl), imidazolidinone, pyrazolinyl (eg 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl), pyrazolidinyl (eg 1-pyrazolidinyl) , 3-pyrazolidinyl, 4-pyrazolidinyl), piperidinone, piperidino, piperidinyl (eg 2-piperidinyl, 3-piperid
  • saturated heterocyclyl is a ring having no unsaturated bond (double bond) in the above-mentioned “heterocyclyl”, and has a bond at any substitutable position.
  • the non-aromatic heterocyclic ring which may have is included. Further, such a non-aromatic heterocyclic ring may be further bridged with an alkyl chain having 1 to 4 carbon atoms, such as a non-aromatic heterocyclic ring (including 5- to 6-membered ring) or a non-aromatic hydrocarbon ring. May be condensed. For example, a 5- to 8-membered ring.
  • pyrrolidinyl eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl
  • pyrrolidinone imidazolidinyl (eg, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl), imidazolidinone
  • pyrazolidinyl eg, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl
  • piperidinone piperidino, piperidinyl (eg 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (eg 1-piperazinyl, 2-piperazinyl), piperazinone, morpholinyl (eg 2 -Morpholinyl, 3-morpholinyl), morpholino, tetrahydropyranyl, tetrahydrofuranyl and the like.
  • imidazolidinyl eg
  • the “aromatic heterocycle” is an arbitrarily selected aromatic 5- to 8-membered ring containing at least one oxygen atom, sulfur atom and / or nitrogen atom in the ring, or 2 Includes rings fused at least.
  • Monocyclic aromatic heterocycles include rings derived from 5- to 8-membered aromatic hydrocarbon rings that may contain from 1 to 4 oxygen, sulfur and / or nitrogen atoms in the ring. .
  • the monocyclic aromatic heterocycle may have a bond at any substitutable position.
  • the condensed aromatic heterocyclic ring is a 5- to 8-membered aromatic hydrocarbon ring which may contain 1 to 4 oxygen atoms, sulfur atoms and / or nitrogen atoms in the ring.
  • the fused aromatic heterocyclic ring may have a bond at any substitutable position.
  • a 5- to 6-membered aromatic heterocyclic ring can be mentioned.
  • aromatic heterocycle examples include pyrrole ring, furan ring, thiophene ring, imidazole ring, pyrazole ring, isothiazole ring, isoxazole ring, oxazole ring, thiazole ring, pyridine ring, pyrazine ring, pyrimidine ring, pyridazine ring, tetrazole Ring, oxadiazole ring, thiadiazole ring, indolizine ring, isoindole ring, indole ring, indazole ring, purine ring, quinolidine ring, isoquinoline ring, quinoline ring, phthalazine ring, naphthyridine ring, quinazoline ring, cinnoline ring , Pteridine ring, carbazole ring, phenanthridine ring, acridine ring, dibenzofuran ring,
  • non-aromatic heterocycle is a non-aromatic 5- to 8-membered ring containing at least one oxygen atom, sulfur atom and / or nitrogen atom in the ring, Includes two or more condensed rings.
  • Examples thereof include a dihydropyran ring, a tetrahydropyran ring, a dihydrofuran ring, and a tetrahydrofuran ring.
  • acyl refers to formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted Including substituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl.
  • fused pyrazole means that pyrazole, pyrimidine, and pyridine are the above “cycloalkyl”, the above “aryl”, the above “heterocyclyl”, or Includes fused rings fused at all possible positions with the “heteroaryl”.
  • the condensed pyrazole include 4,6-dihydro-1H-thieno [3,4-c] pyrazole.
  • the condensed pyrimidine include 6,7,8,9-tetrahydro-5H-pyrimido [4,5-d] azepine.
  • the condensed pyridine include pyrido [3,2-b] pyrazine, 1,8-naphthyridine, quinoline and the like.
  • alkoxy means, for example, methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy
  • Examples include 2-pentyloxy, 3-pentyloxy, n-hexyloxy, isohexyloxy, 2-hexyloxy, 3-hexyloxy, n-heptyloxy, n-octyloxy and the like.
  • An example is C1-C6 alkoxy.
  • Another example is C1-C4 alkoxy.
  • a carbon number when a carbon number is specified, it means “alkoxy” having a carbon number within the range.
  • substituted or unsubstituted alkyl substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted cycloalkenyl” ”,“ Substituted or unsubstituted aryl ”,“ substituted or unsubstituted heteroaryl ”,“ substituted or unsubstituted heterocyclyl ”,“ substituted or unsubstituted saturated heterocyclyl ”“ substituted or unsubstituted alkoxy ” , "Substituted or unsubstituted acyl", “substituted or unsubstituted alkoxycarbonyl", “substituted or unsubstituted piperidine”, “substituted or unsubstituted thioph
  • alkyl eg: CF 3, CH 2 CF 3 , CH 2 CCl 3
  • nitro, nitroso, cyano alkyl (e.g. methyl, ethyl, isopropyl, tert- butyl), alkenyl (e.g.
  • alkynyl Example: ethynyl
  • cycloalkyl eg, cyclohexyl, cyclopropyl, adamantyl
  • cycloalkylalkyl eg, cyclohexylmethyl, adamantylmethyl
  • cycloalkenyl eg, cyclopropenyl
  • aryl eg, phenyl, naphthyl
  • aryl Alkyl eg benzyl, phenethyl
  • heteroaryl eg: pyrazolyl, pyridyl, furyl
  • heteroarylalkyl eg: pyridylmethyl
  • heterocyclyl eg: piperidyl, tetrahydropyranyl
  • heterocyclylalkyl eg : Morpho Rumechiru
  • alkoxy e.g.
  • alkylamino eg: methylamino, ethylamino, dimethylamino
  • acylamino eg, : Acetylamino, benzoylamino
  • arylalkylamino eg, benzylamino, tritylamino
  • hydroxyamino alkylaminoalkyl (eg, diethylaminomethyl), sulfamoyl, oxo, carb
  • substituents of “substituted or unsubstituted amino”, “substituted amino” and “substituted or unsubstituted carbamoyl” include alkyl, alkenyl, aryl, heteroaryl, alkylcarbonyl, arylcarbonyl, heteroaryl.
  • alkyl part of “substituted or unsubstituted alkoxy” and “halogenated alkyl” means the above “alkyl”.
  • alkoxy moiety of “substituted or unsubstituted alkoxy”, “substituted or unsubstituted alkoxycarbonyl”, and “halogenated alkoxy” means the above “alkoxy”.
  • Pharmacologically acceptable salts of the compound of the present invention include the following salts.
  • Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt Aliphatic amine salts such as triethanolamine salt, procaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt; aralkylamine salts such as N, N-dibenzylethylenediamine salt and venetamine salt; pyridine salt, picoline salt, quinoline salt, Heterocyclic aromatic amine salts such as isoquinoline salt; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium Quaternary ammonium salts such as um salt, methyl trioctyl ammonium
  • the acid salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogencarbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate, ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate; Examples include acidic amino acids such as aspartate and glutamate.
  • the solvate means a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof, and examples thereof include alcohol (eg, ethanol) solvate and hydrate.
  • examples of the hydrate include monohydrate, dihydrate and the like.
  • one or more hydrogen, carbon or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon or other atoms.
  • the compound of formula (I) includes all radiolabels of the compound of formula (I). Such “radiolabeled”, “radiolabeled” and the like of the compounds of formula (I) are each encompassed by the present invention and are useful as research and / or diagnostic tools in metabolic pharmacokinetic studies and binding assays. . It is also useful as a pharmaceutical product.
  • Examples of isotopes that can be incorporated into the compound of formula (I) of the present invention include 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, and 35 S, respectively.
  • 18 F, and 36 Cl include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine.
  • the radiolabeled compound of the present invention can be prepared by methods well known in the art.
  • a tritium labeled compound of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) by, for example, catalytic dehalogenation reaction using tritium.
  • This method involves reacting a compound of formula (I) with a suitably halogen-substituted precursor and tritium gas in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base. May be.
  • a suitable catalyst for example Pd / C
  • 14 C-labeled compounds can be prepared by using raw materials having 14 C carbon.
  • Preferred embodiments of the present invention are exemplified as (A1) to (A12), (B1) to (B6), (C1) to (C13), and (D1) to (D6) below. Unless otherwise specified, each symbol has the same meaning as described above.
  • X includes ⁇ C (R 4 ) — or ⁇ N—.
  • X includes ⁇ C (R 4 ) —.
  • A includes a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring (however, a substituted or unsubstituted pyrazole or condensed pyrazole (for example, 4,6-dihydro-1H-thieno [3 , 4-c] pyrazole.), Substituted or unsubstituted non-aromatic hydrocarbon rings or substituted or unsubstituted non-aromatic heterocycles.
  • A includes a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyrazole or fused pyrazole and substituted or unsubstituted thiophene), Examples thereof include a substituted or unsubstituted non-aromatic hydrocarbon ring or a substituted or unsubstituted non-aromatic heterocyclic ring.
  • A includes a substituted or unsubstituted aromatic hydrocarbon ring.
  • R 1 examples include hydrogen, substituted or unsubstituted alkyl, a group represented by the formula: —NR 1A R 1A ′ , or a group represented by the formula: —OR 1B .
  • R 1 includes a group represented by the formula: —NR 1A R 1A ′ or a group represented by the formula: —OR 1B .
  • R 1 includes a group represented by the formula: —NHR 1A ′ or a group represented by the formula: —OR 1B .
  • R 1 includes a group represented by the formula: —NHR 1A ′ .
  • R 1 includes a group represented by the formula: —OR 1B .
  • R 1A is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cyclo Examples include alkyl or substituted or unsubstituted saturated heterocyclyl.
  • R 1A ′ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl Or a substituted or unsubstituted saturated heterocyclyl is mentioned.
  • R 1B represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl Or a substituted or unsubstituted saturated heterocyclyl is mentioned.
  • R 1 includes a group represented by the formula: —NHR 1A ′ , where R 1A ′ is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted saturated heterocyclyl. Is mentioned.
  • R 1 includes a group represented by the formula: —OR 1B , and R 1B includes a substituted or unsubstituted cycloalkyl.
  • R 2 is cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Heterocyclyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino, halogen, carboxy or hydrogen.
  • R 2 includes cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Examples include substituted heterocyclyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino or carboxy.
  • R 2 includes cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbamoyl, substituted or unsubstituted Examples include substituted acyl, substituted or unsubstituted alkoxycarbonyl, substituted amino or carboxy.
  • R 2 include cyano
  • R 1A ′′ and R 2A ′′ each independently represent substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, Substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl.
  • R 1A ′′ and R 2A ′′ each independently include substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
  • R a and R b each independently include hydrogen or substituted or unsubstituted alkyl.
  • N is an integer from 0 to 3.
  • n is an integer from 0 to 2.
  • R 3 includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or halogen.
  • R 3 includes hydrogen
  • R 3 includes substituted or unsubstituted alkyl.
  • R 4 includes hydrogen or halogen.
  • R 4 includes hydrogen
  • R 5A and R 5B are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or Examples thereof include unsubstituted carbamoyl, a group represented by the formula: —SO 2 —R ′, a group represented by the formula: —SO—R ′, or a group represented by the formula: —SR ′.
  • R 5A includes substituted or unsubstituted heteroaryl or substituted or unsubstituted alkenyl.
  • R 5A includes substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl.
  • R 5B includes hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • R ′ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Substituted heterocyclyl is mentioned.
  • X C (R 4 )-and A is substituted or unsubstituted piperidine, substituted or unsubstituted thiophene, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted fused pyrimidine (for example, 6,7,8,9-tetrahydro-5H-pyrimido [4,5-d] azepine), substituted or unsubstituted fused pyridine (eg, pyrido [3,2-b] pyrazine, 1,8-naphthyridine, Quinoline) or substituted or unsubstituted tetrahydrofuran, R 2 is cyano.
  • R 1 is represented by the formula: —NR 1A R It is not a group represented by 1A ′ (where R 1A ′ is phenylethyl) and a group represented by the formula: —OR 1B (where R 1B is methyl).
  • R 1 is a group represented by the formula: —NR 1A R 1A ′ (Wherein R 1A ′ is substituted or unsubstituted alkyl) and is not a group represented by the formula: —OR 1B (where R 1B is substituted or unsubstituted alkyl).
  • X is ⁇ C (R 4 ) —
  • A is a substituted or unsubstituted aromatic hydrocarbon ring
  • R 2 is cyano
  • R 1 is represented by the formula: —NR 1A R 1A ′
  • R 1A ′ is substituted or unsubstituted alkyl, or a group represented by the formula: —OR 1B (where R 1B is methyl or ethyl), R 3 is hydrogen is there.
  • R 1 is a group represented by the formula: —NR 1A R 1A ′ (where R 1A ' Is not substituted or unsubstituted alkyl).
  • R 1 is a group represented by the formula: —NR 1A R 1A ′ (wherein R 1A ′ is a substituted or unsubstituted alkyl, substituted or non-substituted Substituted piperidinyl and substituted or unsubstituted cyclopropyl) and a group of formula: —OR 1B where R 1B is a substituted or unsubstituted alkyl.
  • A is a substituted or unsubstituted aromatic hydrocarbon ring or a substituted or unsubstituted aromatic heterocyclic ring (excluding substituted or unsubstituted pyridine).
  • R 2 is cyano
  • R 3 is hydrogen
  • R 5A is not substituted sulfinyl, substituted or unsubstituted carbamoyl, carboxy, substituted or unsubstituted morpholinyl and substituted sulfonyl.
  • the following embodiment may also be one embodiment.
  • X includes ⁇ C (R 4 ) — (where R 4 has the same meaning as the above item (1A) or (1B)).
  • R 1A ′′ and R 2A ′′ each independently include substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
  • N is an integer from 0 to 2.
  • A includes a substituted or unsubstituted aromatic hydrocarbon ring.
  • R 3 includes hydrogen
  • X CH- A is a substituted or unsubstituted aromatic hydrocarbon ring
  • R 1 is a group represented by the formula: —NHR 1A ′
  • R 1A ′ is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl
  • R 2 is cyano
  • R 3 is hydrogen
  • R 5A is substituted or unsubstituted heteroaryl or substituted or unsubstituted alkenyl
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • X CH- A is substituted or unsubstituted benzene
  • R 1 is a group represented by the formula: —NHR 1A ′
  • R 1A ′ is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl
  • R 2 is cyano
  • R 3 is hydrogen
  • R 5A is substituted or unsubstituted heteroaryl or substituted or unsubstituted alkenyl
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • X CH- A is substituted or unsubstituted benzene
  • R 1 is a group represented by the formula: —NHR 1A ′
  • R 1A ′ is substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl
  • R 2 is cyano
  • R 3 is hydrogen
  • R 5A is substituted or unsubstituted heteroaryl or substituted or unsubstituted alkenyl
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • X CH- A is substituted or unsubstituted benzene, R 1 is a group represented by the formula: —NHR 1A ′ ; R 1A ′ is a substituted or unsubstituted cycloalkyl, R 2 is cyano, R 3 is hydrogen; R 5A is substituted or unsubstituted heteroaryl or substituted or unsubstituted alkenyl, R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • X CH- A is substituted or unsubstituted benzene
  • R 1 is a group represented by the formula: —NHR 1A ′
  • R 1A ′ is a substituted or unsubstituted cycloalkyl
  • R 2 is cyano
  • R 3 is hydrogen
  • R 5A is a substituted or unsubstituted heteroaryl
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • X CH- A is substituted or unsubstituted benzene
  • R 1 is a group represented by the formula: —NHR 1A ′
  • R 1A ′ is a substituted or unsubstituted cycloalkyl
  • R 2 is cyano
  • R 3 is hydrogen
  • R 5A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • X CH- A is substituted or unsubstituted benzene
  • R 1 is a group represented by the formula: —NHR 1A ′
  • R 1A ′ is a substituted or unsubstituted cycloalkyl
  • R 2 is cyano
  • R 3 is hydrogen
  • R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl, imidazolyl substituted or unsubstituted imidazolyl substituted with C1-C6 alkyl, oxazolyl or unsubstituted oxazolyl substituted with C1-C6 alkyl, C1- Oxadiazolyl or unsubstituted oxadiazolyl substituted with C6 alkyl or alkenyl or unsubstituted alkenyl substituted with carbamoyl
  • R 5B is hydrogen, substituted or unsubstituted alkoxy
  • X CH- A is substituted or unsubstituted benzene, R 1 is a group represented by the formula: —NHR 1A ′ ; R 1A ′ is a substituted or unsubstituted cycloalkyl, R 2 is cyano, R 3 is hydrogen; R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl or unsubstituted alkenyl substituted with carbamoyl; R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • X CH- A is substituted or unsubstituted benzene, R 1 is a group represented by the formula: —NHR 1A ′ ; R 1A ′ is a substituted or unsubstituted cycloalkyl, R 2 is cyano, R 3 is hydrogen; R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl, R 5B is substituted or unsubstituted alkoxy.
  • X CH- A is substituted or unsubstituted benzene, R 1 is a group represented by the formula: —NHR 1A ′ ; R 1A ′ is a substituted or unsubstituted cycloalkyl, R 2 is cyano, R 3 is hydrogen; R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl, R 5B is alkoxy substituted with cyano or unsubstituted alkoxy.
  • A is an unsubstituted (excluding R 5A and R 5B ) aromatic hydrocarbon ring, an unsubstituted (except R 5A and R 5B ) aromatic heterocyclic ring, or unsubstituted non-aromatic hydrocarbon ring (excluding R 5A and R 5B), a non-aromatic heterocycle unsubstituted (except for R 5A and R 5B), benzene include unsubstituted (except for R 5A and R 5B) It is done.
  • X CH- A is substituted or unsubstituted pyridine;
  • R 1 is a group represented by the formula: —NHR 1A ′ ;
  • R 1A ′ is a substituted or unsubstituted cycloalkyl,
  • R 2 is cyano,
  • R 3 is hydrogen;
  • R 5A is a substituted or unsubstituted heteroaryl,
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • X CH- A is substituted or unsubstituted pyridine;
  • R 1 is a group represented by the formula: —NHR 1A ′ ;
  • R 1A ′ is a substituted or unsubstituted cycloalkyl,
  • R 2 is cyano,
  • R 3 is hydrogen;
  • R 5A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl,
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • X CH- A is substituted or unsubstituted pyridine;
  • R 1 is a group represented by the formula: —NHR 1A ′ ;
  • R 1A ′ is a substituted or unsubstituted cycloalkyl,
  • R 2 is cyano,
  • R 3 is hydrogen;
  • R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl, imidazolyl substituted or unsubstituted imidazolyl substituted with C1-C6 alkyl, oxazolyl or unsubstituted oxazolyl substituted with C1-C6 alkyl, C1- Oxadiazolyl or unsubstituted oxadiazolyl substituted with C6 alkyl or alkenyl or unsubstituted alkenyl substituted with carbamoyl,
  • R 5B is hydrogen, substituted or unsubstituted al
  • X CH- A is substituted or unsubstituted pyridine;
  • R 1 is a group represented by the formula: —NHR 1A ′ ;
  • R 1A ′ is a substituted or unsubstituted cycloalkyl,
  • R 2 is cyano,
  • R 3 is hydrogen;
  • R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • X CH- A is substituted or unsubstituted pyridine;
  • R 1 is a group represented by the formula: —NHR 1A ′ ;
  • R 1A ′ is a substituted or unsubstituted cycloalkyl,
  • R 2 is cyano,
  • R 3 is hydrogen;
  • R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
  • R 5B is substituted or unsubstituted alkoxy.
  • X CH- A is substituted or unsubstituted pyridine;
  • R 1 is a group represented by the formula: —NHR 1A ′ ;
  • R 1A ′ is a substituted or unsubstituted cycloalkyl,
  • R 2 is cyano,
  • R 3 is hydrogen;
  • R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl,
  • R 5B is alkoxy substituted with cyano or unsubstituted alkoxy.
  • examples of A include unsubstituted pyridine (excluding R 5A and R 5B ).
  • R 1A ′ is substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl;
  • R 3 is hydrogen or substituted or unsubstituted alkyl;
  • R 5A is a substituted or unsubstituted heteroaryl,
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • R 1A ′ is a substituted or unsubstituted cycloalkyl
  • R 3 is hydrogen or substituted or unsubstituted alkyl
  • R 5A is a substituted or unsubstituted heteroaryl
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • R 1A ′ is a substituted or unsubstituted cycloalkyl, R 3 is hydrogen; R 5A is a substituted or unsubstituted heteroaryl, R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • R 1A ′ is a substituted or unsubstituted cycloalkyl
  • R 3 is hydrogen
  • R 5A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • R 1A ′ is a substituted or unsubstituted cycloalkyl, R 3 is hydrogen; R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl, imidazolyl substituted or unsubstituted imidazolyl substituted with C1-C6 alkyl, oxazolyl or unsubstituted oxazolyl substituted with C1-C6 alkyl, C1- Oxadiazolyl or unsubstituted oxadiazolyl substituted with C6 alkyl or alkenyl or unsubstituted alkenyl substituted with carbamoyl, R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • R 1A ′ is a substituted or unsubstituted cycloalkyl, R 3 is hydrogen; R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl, R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • R 1A ′ is a substituted or unsubstituted cycloalkyl, R 3 is hydrogen; R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl, R 5B is substituted or unsubstituted alkoxy.
  • R 1A ′ is a substituted or unsubstituted cycloalkyl, R 3 is hydrogen; R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl, R 5B is alkoxy substituted with cyano or unsubstituted alkoxy.
  • R 1A ′ is a substituted or unsubstituted cycloalkyl
  • R 3 is substituted or unsubstituted alkyl
  • R 5A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • R 1A ′ is a substituted or unsubstituted cycloalkyl
  • R 3 is substituted or unsubstituted alkyl
  • R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl, imidazolyl substituted or unsubstituted imidazolyl substituted with C1-C6 alkyl, oxazolyl or unsubstituted oxazolyl substituted with C1-C6 alkyl, C1- Oxadiazolyl or unsubstituted oxadiazolyl substituted with C6 alkyl or alkenyl or unsubstituted alkenyl substituted with carbamoyl
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • R 1A ′ is a substituted or unsubstituted cycloalkyl
  • R 3 is substituted or unsubstituted alkyl
  • R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl.
  • R 1A ′ is a substituted or unsubstituted cycloalkyl
  • R 3 is substituted or unsubstituted alkyl
  • R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl
  • R 5B is substituted or unsubstituted alkoxy.
  • R 1A ′ is a substituted or unsubstituted cycloalkyl
  • R 3 is substituted or unsubstituted alkyl
  • R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl
  • R 5B is alkoxy substituted with cyano or unsubstituted alkoxy.
  • R 5A is a substituted or unsubstituted heteroaryl
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino or substituted or unsubstituted alkyl
  • R a and R b are each independently hydrogen
  • n is an integer from 0 to 3
  • R 1A ′′ and R 2A ′′ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl.
  • R 5A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted oxadiazolyl, or substituted or unsubstituted alkenyl
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino or substituted or unsubstituted alkyl
  • R a and R b are each independently hydrogen
  • n is an integer from 0 to 3
  • R 1A ′′ and R 2A ′′ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl.
  • R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl, imidazolyl substituted or unsubstituted imidazolyl substituted with C1-C6 alkyl, oxazolyl or unsubstituted oxazolyl substituted with C1-C6 alkyl, C1- Oxadiazolyl or unsubstituted oxadiazolyl substituted with C6 alkyl or alkenyl or unsubstituted alkenyl substituted with carbamoyl, R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino or substituted or unsubstituted alkyl; R a and R b are each independently hydrogen, n is an integer from 0 to 3, R 1A ′′ and R 2A ′′ are each independently substituted or unsubstituted alkyl, substituted or un
  • R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl
  • R 5B is hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino or substituted or unsubstituted alkyl
  • R a and R b are each independently hydrogen
  • n is an integer from 0 to 3
  • R 1A ′′ and R 2A ′′ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl.
  • R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl, R 5B is substituted or unsubstituted alkoxy; R a and R b are each independently hydrogen, n is an integer from 0 to 3, R 1A ′′ and R 2A ′′ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl.
  • R 5A is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C6 alkyl or alkenyl substituted with carbamoyl or unsubstituted alkenyl
  • R 5B is alkoxy substituted with cyano or unsubstituted alkoxy
  • R a and R b are each independently hydrogen
  • n is an integer from 0 to 3
  • R 1A ′′ and R 2A ′′ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted saturated heterocyclyl.
  • the present invention provides a medicament comprising a compound according to any of the above, a pharmaceutically acceptable salt or solvate thereof, or a prodrug (eg, ester, amide) thereof.
  • a composition is provided.
  • prodrug and “prodrug compound” have a group that can be chemically or metabolically decomposed, and are pharmaceutically active by hydrolysis, solvolysis, or decomposition under physiological conditions.
  • Various forms of prodrugs are known in the art.
  • Prodrugs of compounds of formula (I) are prepared by modifying functional groups present in compounds of formula (I) by a modification method such that the parent compound is released upon cleavage in vivo.
  • a prodrug is a compound of formula (I) wherein the hydroxy, sulfhydryl or amino group in the compound of formula (I) is linked to a group that regenerates the free hydroxy, amino, or sulfhydryl group, respectively, when cleaved in vivo.
  • Examples of prodrugs include, but are not limited to, esters of hydroxy functional groups (eg, acetate, formate, and benzoate derivatives), carbamates (eg, N, N-dimethylaminocarbonyl) in compounds of formula (I) Etc.
  • esters of hydroxy functional groups eg, acetate, formate, and benzoate derivatives
  • carbamates eg, N, N-dimethylaminocarbonyl
  • prodrug group is an in vivo cleavable ester group of a pharmaceutically acceptable ester that is cleaved in the human or animal body to yield the parent acid.
  • a prodrug group, together with the carboxy group to which it is attached can be combined with a C 1-6 alkyl ester or C 1-6 cycloalkyl ester, such as methyl, ethyl, propyl, isopropyl, n-butyl or Esters of cyclopentyl; C 1-6 alkoxymethyl esters, such as methoxymethyl esters; C 1-6 alkanoyloxymethyl esters, such as pivaloyloxymethyl esters; phthalidyl esters; C 3-8 cycloalkoxycarbonyloxy C 1 -6 alkyl esters such as 1-cyclohexylcarbonyloxyethyl ester; 1,3-dioxolan-2-ylmethyl ester such as 5-methyl-1,3-
  • the prodrug is an ester with a C 1-4 alkyl group such as isopropyl or cyclopentyl, or an ester selected from an optionally substituted heterocyclic group such as N-methyltetrahydropyridyl. Can be mentioned.
  • composition of the present invention containing any of the specific compounds listed above is also characterized by being a TTK inhibitor. Accordingly, any pharmaceutical composition that exhibits a medicinal effect by being administered to a patient in need of inhibition of TTK is provided.
  • the present invention provides a medicament for the treatment or prevention of cancer or immune disease comprising any of the specific compounds listed above.
  • the raw material compounds are commercially available compounds, those described in Patent Documents 4 to 60 and Non-Patent Documents 7 to 20, and those described in this specification as well as other references cited in this specification. In addition to those described in (1), other known compounds can be used.
  • Some of the compounds of the present invention may have tautomers, positional isomers and optical isomers, but the present invention includes all possible isomers and mixtures thereof, including these. To do.
  • the compound of the present invention when obtaining a salt of the compound of the present invention, if the compound of the present invention is obtained in the form of a salt, it can be purified as it is, and if it is obtained in a free form, it can be dissolved in an appropriate organic solvent. Alternatively, it may be suspended and an acid or base is added to form a salt by a conventional method.
  • the compounds of the present invention and pharmaceutically acceptable salts thereof may exist in the form of adducts (hydrates or solvates) with water or various solvents, and these adducts are also included in the present invention. Is included.
  • prodrugs are converted and activated in the body, and are also referred to as “prodrugs” in the present specification.
  • prodrugs are understood to include, for example, the above salts and solvates, as well as esters (eg, alkyl esters), amides, and the like.
  • the present invention also relates to a system, apparatus and kit for producing the compound of the present invention. It is understood that the constituent requirements of such a system, apparatus, and kit can use those known in the art and can be appropriately designed by those skilled in the art.
  • each symbol has the same meaning as the above item (1A) or (1B), and X represents a leaving group (halogen, OTf, etc.).
  • X represents a leaving group (halogen, OTf, etc.).
  • Tf represents a trifluoromethanesulfonyl group.
  • the compound represented by the formula (1-2) can be produced by reacting the compound represented by the formula (1-1) with the compound represented by the formula (1-5).
  • an organic base such as DIEA, NMP, DMF, ether solvents (eg, THF, dioxane, etc.), and alcohol solvents (eg, ethanol, propanol, etc.) should be performed at a temperature of 80 ° C. or higher.
  • an organic base such as DIEA, NMP, DMF, ether solvents (eg, THF, dioxane, etc.), and alcohol solvents (eg, ethanol, propanol, etc.) should be performed at a temperature of 80 ° C. or higher.
  • the corresponding compound represented by the formula (1-2) can be produced.
  • this reaction involves palladium catalysts (eg Pd (OAc) 2 , Pd 2 (dba) 3 etc.), phosphine-based ligands (eg BINAP, Xantphos etc.) and bases (eg cesium carbonate, potassium carbonate etc.) )
  • palladium catalysts eg Pd (OAc) 2 , Pd 2 (dba) 3 etc.
  • phosphine-based ligands eg BINAP, Xantphos etc.
  • bases eg cesium carbonate, potassium carbonate etc.
  • the compound represented by the formula (1-3) can be produced by reacting the compound represented by the formula (1-2) with the compound represented by the formula (NHR 1A R 1A ′ ). That is, it corresponds to the formula (1-2) by carrying out a compound represented by the formula (NHR 1A R 1A ′ ) of 2 equivalents or more in a solvent such as NMP and DMF at a temperature of 100 ° C. or higher.
  • a compound represented by the formula (1-3) can be produced.
  • the temperature can be raised to about 250 ° C. using a microwave reaction apparatus.
  • the compound represented by the formula (1-4) can be produced by reacting the compound represented by the formula (1-2) and the formula (R 1B OH).
  • the compound represented by the formula (R 1B OH) is carried out in the presence of sodium hydride in a solvent such as NMP and DMF at a temperature of 80 ° C. or higher.
  • a compound represented by the formula (1-4) can be produced.
  • the temperature can be raised to about 250 ° C. using a microwave reaction apparatus.
  • the compound represented by the formula (1-2) is synonymous with the compound shown in Scheme 1, and can be produced by the method shown in Scheme 1, but a known compound may be used or from a known compound A compound derived by a conventional method may be used.
  • the compound represented by the formula (2-1) can be produced by a Suzuki coupling reaction between the compound represented by the formula (1-2) and the formula (2-3). That is, in the presence of a palladium catalyst (eg, Pd (PPh 3 ) 4 , Pd 2 (dba) 3 ) and a base (eg, sodium carbonate, potassium carbonate), NMP, DMF, an ether solvent (eg, THF, dioxane) Etc.) and an alcohol solvent (eg, ethanol, propanol, etc.) at a temperature of 50 ° C. or higher, the corresponding compound represented by the formula (2-1) can be produced.
  • a palladium catalyst eg, Pd (PPh 3 ) 4 , Pd 2 (dba) 3
  • a base eg, sodium carbonate, potassium carbonate
  • NMP eg, sodium carbonate, potassium carbonate
  • NMP e.g, NMP, DMF, an ether solvent (eg, THF, di
  • the compound represented by the formula (2-2) can be produced by a hydrogenation reaction to an olefin.
  • a hydrogenation reaction to an olefin.
  • ether solvents eg, THF, dioxane, etc.
  • alcohol solvents eg, ethanol, propanol, etc.
  • This reaction is not limited to these conditions, and a known method can be applied.
  • each symbol has the same meaning as the above item (1A) or (1B), and X represents a leaving group (halogen, OTf, etc.).
  • X represents a leaving group (halogen, OTf, etc.).
  • Tf represents a trifluoromethanesulfonyl group.
  • the compound represented by the formula (3-1) can be produced from the compound represented by the formula (1-2).
  • a palladium catalyst eg, Pd (PPh 3 ) 4
  • each symbol has the same meaning as the above item (1A) or (1B), and X represents a leaving group (halogen, OTf, etc.).
  • X represents a leaving group (halogen, OTf, etc.).
  • Tf represents a trifluoromethanesulfonyl group.
  • a known compound may be used, or a compound derived from a known compound by a conventional method may be used.
  • the compound represented by the formula (4-2) can be produced by reacting the compound represented by the formula (4-1) with the compound represented by the formula (NHR 1A R 1A ′ ). That is, when the compound represented by the formula (NHR 1A R 1A ′ ) of 2 equivalents or more with respect to the formula (4-1) is carried out in a solvent such as NMP and DMF at room temperature, the corresponding formula (4- The compound shown in 2) can be produced. When the reaction proceeds slowly or does not proceed, the temperature can be raised to about 100 ° C.
  • the compound represented by the formula (4-3) can be produced by reacting the compound represented by the formula (4-1) and the formula (R 1B OH).
  • the compound represented by the formula (R 1B OH) is carried out in the presence of sodium hydride in a solvent such as NMP and DMF at a temperature of 80 ° C. or higher.
  • a compound represented by the formula (4-3) can be produced.
  • the temperature can be raised to about 100 ° C.
  • the compound represented by formula (4-4) or formula (4-5) is obtained by reacting the compound represented by formula (4-2) or formula (4-3) with the compound represented by formula (1-5).
  • a compound represented by the formula (4-4) or the formula (4-5) can be produced by carrying out the reaction at a temperature of 80 ° C. or higher in a solvent such as dioxane and toluene.
  • each symbol has the same meaning as the above item (1A) or (1B), and X represents a leaving group (halogen, OTf, etc.).
  • X represents a leaving group (halogen, OTf, etc.).
  • Tf represents a trifluoromethanesulfonyl group.
  • the compound represented by formula (5-4) can be produced from the compound represented by formula (5-1) in three steps.
  • X 1 shown in Scheme 5 is a halogen atom or an OTf group, preferably a fluorine or chlorine atom.
  • X 2 is a halogen atom or an OTf group, preferably a bromine or iodine atom.
  • X is as defined above.
  • the compound represented by the formula (5-1) or the formula (R 2 -X) a known compound may be used, or a compound derived from a known compound by a conventional method may be used.
  • the compound represented by the formula (R 1 -H) is synonymous with the compound represented by the formula (NHR 1A R 1A ′ ) or the formula (R 1B OH) described above.
  • the compound represented by the formula (5-2) can be produced by reacting the compound represented by the formula (5-1) and the formula (R 1 -H). This reaction can be carried out under the same conditions as in the production method of formula (1-3) or formula (1-4).
  • the compound represented by the formula (5-3) can be produced by a Suzuki coupling reaction between the compound represented by the formula (5-2) and the compound represented by the formula (R 2 -X). That is, in the presence of a palladium catalyst (eg, Pd (PPh 3 ) 4 , Pd 2 (dba) 3 ) and a base (eg, sodium carbonate, potassium carbonate), NMP, DMF, an ether solvent (eg, THF, dioxane) Etc.) and an alcohol solvent (eg, ethanol, propanol, etc.) at a temperature of 50 ° C. or higher, the corresponding compound represented by the formula (5-3) can be produced.
  • a palladium catalyst eg, Pd (PPh 3 ) 4 , Pd 2 (dba) 3
  • a base eg, sodium carbonate, potassium carbonate
  • NMP e.g, sodium carbonate, potassium carbonate
  • DMF eg, NMP, DMF, an ether solvent
  • the compound represented by the formula (5-4) can be produced by reacting with the compound represented by the formula (1-5). This reaction can be carried out under the same conditions as in the production method of formula (1-2).
  • R represents a lower (eg, C1-C6) alkyl group
  • X represents a leaving group (halogen, OTf, etc.).
  • Tf represents a trifluoromethanesulfonyl group.
  • the compound represented by formula (6-6) can be produced from the compounds represented by formula (6-1) and formula (6-2) in four steps.
  • the compound represented by the formula (6-1) or the formula (6-2) a known compound may be used, or a compound derived from a known compound by a conventional method may be used.
  • the compounds represented by the formula (1-5) and the formula (R 1 -H) are synonymous with the compounds described above.
  • the compound represented by the formula (6-3) can be produced by reacting the compound represented by the formula (6-1) or a salt thereof with the compound represented by the formula (6-2). That is, in the presence of a base (eg, potassium hydroxide aqueous solution) in an ether solvent (eg, THF, dioxane, etc.) or an alcohol solvent (eg, ethanol, etc.) at 0 ° C. to room temperature, A corresponding compound represented by the formula (6-3) can be produced.
  • a base eg, potassium hydroxide aqueous solution
  • an ether solvent eg, THF, dioxane, etc.
  • an alcohol solvent eg, ethanol, etc.
  • the compound represented by the formula (6-4) can be produced by reacting the compound represented by the formula (6-3) with the compound represented by the formula (1-5). In other words, in the presence of acetic acid, the reaction is carried out at a temperature of 80 ° C. or higher in an ether solvent (eg, dioxane, diglyme, etc.) and an alcohol solvent (eg, t-butanol, ethanol, propanol, etc.).
  • an ether solvent eg, dioxane, diglyme, etc.
  • an alcohol solvent eg, t-butanol, ethanol, propanol, etc.
  • the compound represented by the formula (6-5) can be produced by heating and refluxing the formula (6-4) in phosphorus oxychloride.
  • the compound represented by the formula (6-6) can be produced by reacting the compound represented by the formula (6-5) with the compound represented by the formula (R 1 -H). This reaction can be carried out under the same conditions as in the production method of formula (1-3) or formula (1-4).
  • R represents a phenyl group, lower (eg, C1-C6) alkyl, and X represents a leaving group (halogen, OTf, etc.).
  • Tf represents a trifluoromethanesulfonyl group.
  • the compound represented by the formula (7-2) can be produced by reacting the compound represented by the formula (7-1) with the compound represented by the formula (NH 2 R 1A ′′ ).
  • the compound represented by the formula (7-2) is produced by carrying out the compound represented by the formula (NH 2 R 1A ′′ ) of 2 equivalents or more in a solvent such as NMP and DMF at a temperature of 150 ° C. or higher. can do. If the reaction proceeds slowly or does not proceed, the temperature can be raised to about 250 ° C. using a microwave reaction apparatus.
  • the compound represented by the formula (ClC ( ⁇ O) OR) is preferably phenyl chloroformate, and the compound represented by the formula (XC ( ⁇ O) X) is preferably carbonyldiimidazole or triphosgene.
  • This reaction is carried out in the presence of a base (eg, sodium bicarbonate water, triethylamine, etc.) in a solvent such as ethyl acetate, THF, or acetonitrile at a temperature of about room temperature to about 100 ° C. to give the corresponding formula (7-3).
  • a base eg, sodium bicarbonate water, triethylamine, etc.
  • a solvent such as ethyl acetate, THF, or acetonitrile
  • the compound represented by the formula (7-4) can be produced by reacting the compound represented by the formula (7-3) with the compound represented by the formula (R 2A ′′ -X). That is, in the presence of sodium hydride, DMF, NMP, Alternatively, the corresponding compound represented by the formula (7-4) can be produced by carrying out the reaction at room temperature in an ether solvent (eg, dioxane, diglyme, etc.).
  • an ether solvent eg, dioxane, diglyme, etc.
  • the compound represented by the formula (7-5) can be produced by reacting with the compound represented by the formula (1-5). This reaction can be carried out under the same conditions as in the production method of formula (1-2).
  • each symbol has the same meaning as the above item (1A) or (1B), and X represents a leaving group (halogen, OTf, etc.), where “Tf” represents a trifluoromethanesulfonyl group.
  • the compound represented by 5A- B (OR) 2 means a corresponding boronic acid or boronic ester.
  • the compound represented by the formula (8-5) can be produced from the compound represented by the formula (8-1) in four steps.
  • R 5A -B (OR) 2 (boronic acid or boronic ester) or the formula (R 5B ′ -X)
  • a known compound may be used.
  • a compound derived from a compound by a conventional method may be used.
  • PG described above represents a hydroxyl-protecting group, and examples thereof include ether-based protecting groups such as a methyl group and a methoxymethyl (MOM) group, and Si-based protecting groups such as a t-butyldimethylsilyl (TBS) group.
  • ether-based protecting groups such as a methyl group and a methoxymethyl (MOM) group
  • Si-based protecting groups such as a t-butyldimethylsilyl (TBS) group.
  • TBS t-butyldimethylsilyl
  • the compound represented by the formula (8-2) can be produced by deprotecting the formula (8-1) by a conventional method.
  • the compound represented by the formula (8-3) can be produced by reacting the compound represented by the formula (7-3) with the compound represented by the formula (R 5B ′ -X). That is, in the presence of a base (eg, potassium carbonate, sodium hydride, etc.) in DMF, NMP, or an ether solvent (eg, THF, dioxane, diglyme, etc.) at room temperature, the corresponding formula (8 -3) can be produced.
  • a base eg, potassium carbonate, sodium hydride, etc.
  • NMP eg, NMP, or an ether solvent (eg, THF, dioxane, diglyme, etc.) at room temperature
  • an ether solvent eg, THF, dioxane, diglyme, etc.
  • the compound represented by the formula (8-4) can be produced by a Suzuki coupling reaction between the compound represented by the formula (8-3) and the compound represented by the formula (R 5A -B (OR) 2 ). That is, in the presence of a palladium catalyst (eg, Pd (PPh 3 ) 4 , Pd 2 (dba) 3 ) and a base (eg, sodium carbonate, potassium carbonate), NMP, DMF, an ether solvent (eg, THF, dioxane) Etc.) and an alcohol solvent (eg, ethanol, propanol, etc.) at a temperature of 50 ° C. or higher, the corresponding compound represented by the formula (5-3) can be produced.
  • This reaction is not limited to these conditions, and a known method can be applied.
  • the compound represented by the formula (8-5) can be produced by a reduction reaction of a nitro group.
  • This reaction can be carried out by a known method. For example, in the presence of palladium carbon, NMP, DMF, ethyl acetate, an ether solvent (eg, THF, dioxane, etc.), an alcohol solvent (eg, ethanol, propanol, etc.), or By carrying out under a hydrogen atmosphere in these mixed solvents, the corresponding compound represented by the formula (2-2) can be produced.
  • This reaction is not limited to these conditions, and a known method can be applied.
  • each symbol has the same meaning as the above item (1A) or (1B), and X represents a leaving group (halogen, OTf, etc.), where “Tf” represents a trifluoromethanesulfonyl group.
  • the compound represented by the formula (9-3) can be produced from the compound represented by the formula (9-1) in two steps.
  • the compound represented by the formula (9-2) can be produced by reacting with a compound represented by the formula (R 5A -B (OR) 2 ). This reaction can be carried out under the same conditions as in the production method of formula (8-4).
  • the compound represented by the formula (9-3) can be produced by a reduction reaction of a nitro group. This reaction can be carried out under the same conditions as in the production method of formula (8-5).
  • each symbol has the same meaning as the above item (1A) or (1B), and Alk represents lower (for example, C1-C6) alkyl.
  • R 2 ′ is suitably used as a substituent such as hydrogen or alkyl. And two R 2 ′s may be combined to form a ring.
  • the compound represented by formula (10-3) can be produced from the compound represented by formula (10-1) in two steps.
  • the compound represented by the formula (10-2) can be produced by hydrolyzing the compound represented by the formula (10-1).
  • the reaction solvent is ether solvent such as dioxane, THF and DME, alcohol solvent such as ethanol and methanol, solvent such as DMF, DMA, DMSO and NMP and water are mixed and water is used as the base. Lithium hydroxide or the like can be used.
  • the reaction temperature is preferably room temperature, but may be further increased when the reaction proceeds slowly.
  • the compound represented by the formula (10-3) can be synthesized by condensing the compound represented by the formula (10-2) with a compound represented by the formula NH (R 2 ′ ) 2 .
  • the reaction solvent DMF, NMP, DMA, dimethyl sulfoxide, dichloromethane, tetrahydrofuran, dioxane, acetonitrile and the like can be used.
  • condensing agent examples include DCC (dicyclohexylcarbodiimide), BOP (benzotriazol-1-yloxy-trisdimethylaminophosphate), PyBOP (hexafluorophosphate (benzotriazol-1-yloxy) tripyrrolidinophosphonium), PyBrop (hexafluoro).
  • Bromotrispyrrolidinophosphonium phosphate HATU, DPPA, WSC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride), DMT-MM (4- (4,6-dimethoxy-1,3, 5-triazin-2-yl) -4-methylmorpholinium chloride) and the like can be used.
  • These reagents can be used in combination with, for example, HOSu (1-hydroxysuccinimide), HOBt (1-hydroxybenzotriazole), HOAt (1-hydroxy-7-azabenzotriazole) and the like. In some cases, it is preferably carried out in the presence of an organic amine such as triethylamine or DIEA.
  • the reaction temperature and reaction time are not particularly limited, but the reaction is usually carried out at room temperature, and when the reaction proceeds slowly, the reaction may be promoted by heating.
  • each symbol has the same meaning as the item (1A) or (1B), and examples of R 2 ′′ include hydrogen, alkyl, and the like, which are appropriate as substituents.
  • the compound represented by the formula (11-3) can be produced from the compound represented by the formula (11-1) in two steps.
  • the compound represented by the formula (11-2) can be produced by reducing the compound represented by the formula (11-1).
  • the reaction solvent an ether solvent such as dioxane, THF and DME, an alcohol solvent such as ethanol and methanol, a solvent such as DMF, DMA, DMSO and NMP and water are mixed and used.
  • the reducing agent for example, hydrogen and palladium carbon can be used.
  • the reaction temperature is preferably room temperature, but if the reaction proceeds slowly, the temperature may be further increased.
  • the compound represented by the formula (11-3) is obtained by converting the compound represented by the formula (11-2) into a carboxylic acid represented by the formula R 2 ′′ C ( ⁇ O) OH or a corresponding acid chloride, and an acid anhydride. It can synthesize
  • carboxylic acid When carboxylic acid is used, it can be carried out under the same conditions as in the production method of formula (10-3). Moreover, what is necessary is just to implement according to a conventional method about reaction with an acid chloride and an acid anhydride.
  • the production of the present invention can be carried out by appropriately modifying, combining, or adding known techniques to the above preferred embodiments.
  • the compound of the present invention can be protected using a protecting group.
  • a protecting group typically, halogen (I, Br, Cl, F, etc.), lower (here, typically, C1-C6 is shown, but not limited thereto) alkoxy, lower alkylthio, lower alkylsulfonyloxy, aryl Represents sulfonyloxy and the like.
  • An appropriate substituent can be protected by a method known in the art. Examples of such protecting groups include protection described in Protective Groups in Organic Synthesis, TWGreen, John Wiley & Sons Inc. (1981), such as ethoxycarbonyl, t-butoxycarbonyl, acetyl, and benzyl. You can raise a group.
  • Methods for introducing and removing protecting groups are those commonly used in organic synthetic chemistry [for example, see Protective Groups in Organic Synthesis, written by TWGreene, John Wiley & Sons Inc. (1981)], or the like. It can obtain according to.
  • the functional group contained in each substituent can be converted by a known method [for example, Comprehensive Organic Transformations, RCLarock (1989), etc.], and the compound of the present invention. Some of these can lead to further novel derivatives as synthetic intermediates.
  • the intermediates and target compounds in the above production methods are isolated and purified by purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. can do.
  • the intermediate can be subjected to the next reaction without any particular purification.
  • TTK protein kinase is an enzyme described and defined in Patent Document 3, for example, an amino acid sequence registered as Genbank NM — 003318, or a deletion or addition of one or several amino acids in the amino acid sequence. And a polypeptide containing an amino acid sequence which is inserted or substituted and has kinase activity.
  • a preferable amino acid sequence any of those listed in Patent Document 3 can be adopted.
  • activity of TTK protein kinase” and “TTK activity” mean phosphorylation of threonine and / or serine and / or tyrosine.
  • TTK activity can be measured using the measurement method used in the screening method of Patent Document 3. Whether or not the polypeptide has kinase activity is determined by, for example, contacting the polypeptide, a substrate for measuring TTK activity, and a phosphate group donor, measuring TTK activity, and TTK activity of wild-type TTK protein kinase under the same conditions. Can be examined by comparing with.
  • a known substrate for measuring TTK activity and a phosphate donor can be used. Further, the novel substrate for measuring TTK activity described in the present invention may be used.
  • the TTK protein kinase only needs to be a polypeptide having TTK protein kinase activity, that is, one or several amino acids are deleted or added in the amino acid sequence described in Patent Document 3 known as a kinase activity domain. Any polypeptide that contains an amino acid sequence that may be inserted or substituted and that has kinase activity may be used. The total length of the polypeptide, addition of a modifying group, alteration of amino acid residues, and the like are appropriately selected as necessary, and are not limited to the sequences described herein.
  • TTK TTK protein kinase
  • hMPS1 human monopolar spindle 1
  • PYT Phosphotyrosine-picked threonine kinase
  • MPS1L1 Monopolar spindle 1-like 1
  • the compound obtained by the screening method of the present invention or a salt thereof can exert a therapeutic or preventive action against a disease that develops in association with an increase in TTK activity.
  • a candidate compound for a therapeutic or prophylactic agent effective for cancer, immune disease, etc. that develops due to an increase in TTK activity can be screened.
  • cancer examples include various malignant neoplasms such as solid cancer, hemangioma, hemangioendothelioma, sarcoma, Kaposi sarcoma and hematopoietic tumor, and include colon cancer and liver cancer, and further metastasis of these cancers. Is also included.
  • the present invention has succeeded in the discovery of a novel series of compounds having specific properties that inhibit the action of TTK kinases and make them particularly useful in formulating pharmaceuticals for treating the above diseases.
  • the compounds are particularly useful in the treatment of proliferative diseases such as cancers where TTK kinase, which develops as either a solid tumor or a hematological tumor, is known to be active, in particular colorectal cancer, It is useful in diseases such as breast cancer, lung cancer, prostate cancer, pancreatic cancer or bladder cancer and kidney cancer as well as leukemia and lymphoma.
  • proliferative diseases such as cancers where TTK kinase, which develops as either a solid tumor or a hematological tumor, is known to be active, in particular colorectal cancer
  • diseases such as breast cancer, lung cancer, prostate cancer, pancreatic cancer or bladder cancer and kidney cancer as well as leukemia and lymphoma.
  • immune diseases include atopy, asthma, rheumatism, collagen disease, allergies and the like.
  • the compound of the present invention or a salt thereof provides a pharmaceutical composition for use in the treatment or prevention of diseases related to TTK protein kinase, for example, cancer or immune disease involving TTK protein kinase.
  • the above-mentioned pharmaceutical composition is characterized by containing the compound of the present invention or a salt thereof as an active ingredient. Therefore, the pharmaceutical composition exhibits an excellent effect of being able to act on the disease that develops in connection with TTK protein kinase through suppression of the activity of the enzyme.
  • the pharmaceutical composition of the present invention has an excellent effect that it can act on cancers, immune diseases, etc., particularly cancers, immune diseases, etc. that develop in relation to TTK activity, through suppression of the enzyme activity. Demonstrate.
  • conventional cancer therapy for example, radiation therapy, chemotherapy, in particular, prior to or prior to the application of a DNA degrading agent for presensitizing tumor cells. But you can use it.
  • the content of the compound or a salt thereof in the pharmaceutical composition can be adjusted as appropriate depending on the disease to be treated, the age, weight, etc. of the patient, and may be a therapeutically effective amount.
  • a compound for example, 0.0001 to 1000 mg, preferably 0.001 to 100 mg.
  • a polypeptide or a derivative thereof for example, 0.0001 to 1000 mg, preferably 0.001 to 100 mg, a nucleic acid or a derivative thereof.
  • the pharmaceutical composition may further contain various auxiliaries that can stably hold the compound or a salt thereof.
  • auxiliaries that can stably hold the compound or a salt thereof.
  • pharmaceutically acceptable auxiliaries, excipients, binders, and stabilizers that exhibit the property of inhibiting the active ingredient from degrading before reaching the site where the active ingredient is to be delivered.
  • the dosage form of the pharmaceutical composition is appropriately selected according to the type of active ingredient; individual, organ, local site, tissue to be administered; age, weight, etc. of the individual to be administered.
  • Examples of the administration form include subcutaneous injection, intramuscular injection, intravenous injection, and local administration.
  • the dosage of the above pharmaceutical composition is also appropriately selected according to the type of active ingredient; individual, organ, local site, tissue to be administered; age, weight, etc. of the individual to be administered.
  • the administration is not particularly limited, but when the active ingredient is a low molecular compound or a high molecular compound, the amount of the active ingredient is, for example, 0.0001 to 1000 mg / kg body weight, preferably 0.001 to 100 mg.
  • / Kg body weight in the case of a polypeptide or a derivative thereof, for example, 0.0001 to 1000 mg / kg body weight, preferably 0.001 to 100 mg / kg body weight, in the case of a nucleic acid or a derivative thereof, for example, 0.00001 to 100 mg / kg Administration may be performed a plurality of times per day, for example, 1 to 3 times, so as to obtain a single dose of kg body weight, preferably 0.0001 to 10 mg / kg body weight.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually preferable to provide it as various pharmaceutical preparations. In addition, these pharmaceutical preparations are used for animals and humans.
  • the administration route is preferably the most effective one for treatment, and can be oral or parenteral such as rectal, buccal, subcutaneous, intramuscular, intravenous and the like.
  • Administration forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, and injections.
  • Liquid preparations such as emulsions and syrups suitable for oral administration include water, sugars such as sucrose, sorbit, fructose, glycols such as polyethylene glycol, propylene glycol, oils such as sesame oil, olive oil, soybean oil And preservatives such as p-hydroxybenzoates, and flavors such as strawberry flavor and peppermint.
  • excipients such as lactose, glucose, sucrose and mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl It can be produced using a binder such as alcohol, hydroxypropylcellulose, gelatin, a surfactant such as fatty acid ester, and a plasticizer such as glycerin.
  • Formulations suitable for parenteral administration preferably comprise sterile aqueous preparations containing the active compound that is isotonic with the blood of the recipient.
  • a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of salt water and a glucose solution.
  • Topical formulations are prepared by dissolving or suspending the active compound in one or more media such as mineral oil, petroleum, polyhydric alcohol and the like or other bases used in topical pharmaceutical formulations.
  • media such as mineral oil, petroleum, polyhydric alcohol and the like or other bases used in topical pharmaceutical formulations.
  • Preparations for enteral administration are prepared using conventional carriers such as cacao butter, hydrogenated fat, hydrogenated fatty carboxylic acid and the like and provided as suppositories.
  • glycols, oils, flavors, preservatives (including antioxidants), excipients, disintegrants, lubricants, binders, surface active agents exemplified in oral preparations are used in parenteral preparations.
  • One or more auxiliary components selected from agents, plasticizers and the like can also be added.
  • the effective dose and frequency of administration of the compound of the present invention or a pharmaceutically acceptable salt thereof vary depending on the administration form, patient age, body weight, nature or severity of symptoms to be treated, etc.
  • the daily dose is 0.01 to 1000 mg / person, preferably 5 to 500 mg / person, and the administration frequency is preferably once a day or divided.
  • the compound of the present invention preferably has the inhibitory activity of the test substance on the basis of the fluorescence value when the TTK IC 50 in the case of screening for a compound having a TTK kinase activity inhibitory action using the p38MAPK peptide is no test substance.
  • the present invention also relates to a system, device, and kit for producing the pharmaceutical composition of the present invention. It is understood that the constituent requirements of such a system, apparatus, and kit can use those known in the art and can be appropriately designed by those skilled in the art.
  • the present invention also relates to a system, apparatus, and kit using the compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof. It is understood that the constituent requirements of such a system, apparatus, and kit can use those known in the art and can be appropriately designed by those skilled in the art.
  • the compound of the present invention is a compound having utility as a medicine.
  • it is a compound with high metabolic stability, low induction of drug metabolizing enzymes, small inhibition of drug metabolizing enzymes that metabolize other drugs, and high oral absorbability
  • a point, a point with a small clearance, or a point with a sufficiently long half-life for exhibiting a medicinal effect is included.
  • LC / MS analysis used a Waters system (ZQ2000 mass detector; 1525 HPLC pump; 2996 photodiode array detector; 2777 autosampler).
  • a reverse phase C18 column Waters, X-Bridge C18, 4.6 ⁇ 50 mm, 5 ⁇ M
  • water / acetonitrile (0.1% formic acid) was used as an elution solvent.
  • Elution conditions were 10-100% acetonitrile (3 minutes linear gradient) and 100% acetonitrile (1 minute) at a flow rate of 3 mL / min.
  • the described LC / MS t R indicates the retention time (minute) of the target compound in LC / MS analysis, and UV at 254 nm was used for peak detection.
  • Reverse phase preparative liquid chromatography was performed using a Waters system (ZQ 2000 mass detector; 2525 HPLC pump; 2996 photodiode array detector; 2777 autosampler).
  • a reverse phase C18 column (Waters, X-Bridge, 19 ⁇ 50 mm, 5 ⁇ M) was used, and water / acetonitrile (0.1% formic acid) was used as an elution solvent.
  • Elution conditions were 10-100% acetonitrile (5 minutes linear gradient) and 100% acetonitrile (2 minutes) at a flow rate of 25 mL / min.
  • Silica gel chromatography used a system of Yamazen (YFLC-Wprep2XY), Moritex (Purif- ⁇ 2), or Isco (Combi Flash Companion).
  • the column was a Yamazen Hi-Flash column (S to 5 L), and the elution solvent was hexane / ethyl acetate or chloroform / methanol.
  • the microwave reactor used was Biotage initiator 8 or initiator 60.
  • reaction stop solution composition: 25 mM Tris-HCl, pH 7.5, 100 mM EDTA, 0.01% (v / v) TritonX-100, 0.1% (w / v ) BSA 50 ⁇ L was added and mixed.
  • Example 1 Methyl-2- (cyclohexylamino) -6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) nicotinate
  • Step 1 Methyl-6-chloro-2- (cyclohexylamino) nicotinate Methyl-6-chloro-2- (cyclohexylamino) nicotinate (5.65 g, 27.4 mmol) in NMP (20 mL) was added to cyclohexylamine (5.71 g , 6.59 mL, 57.6 mmol) and stirred at room temperature for 5 hours. After water and ethyl acetate were added to the reaction solution and separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate.
  • Step 2 Methyl 2- (cyclohexylamino) -6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) nicotinate Methyl 6-chloro-2- (cyclohexylamino) nicotinate ( 213 mg, 0.793 mmol), 3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) aniline (177 mg, 0.872 mmol), Xantphos (68.8 mg, 0.119 mmol), and cesium carbonate (387 mg) , 1.19 mmol) in dioxane (2.0 mL) was added Pd (OAc) 2 (17.8 mg, 0.079 mmol) and stirred for 8 hours under reflux.
  • Pd (OAc) 2 17.8 mg, 0.079 mmol
  • Step 1 6- (Cyclohexyloxy) -N- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -5-nitropyridin-2-amine cyclohexanol (778 mg, 7.77 mmol), and 2,6-Dichloro-3-nitropyridine (1.0 g, 5.18 mmol) was added to an NMP solution (7 mL) of 60% sodium hydride (249 mg, 6.22 mol), and the mixture was stirred at room temperature for 1 hour.
  • Step 3 N- (2- (cyclohexyloxy) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenylamino) pyridin-3-yl) acetamide 6- (cyclohexyl) -N 2- (4- (1-Methyl-1H-pyrazol-4-yl) phenyl) pyridine-2,5-diamine (35 mg, 0.096 mmol) and triethylamine (48.7 mg, 67 ⁇ L, 0.481 mmol) in THF (2.0 mL ) Acetic anhydride (19.7 mg, 18 ⁇ L, 0.193 mol) was added to the solution and stirred at room temperature for 1 hour.
  • Step 1 2,6-Dichloro-N-cyclopropylnicotinamide Implemented in the same manner as in Example 1-3 to obtain the title compound (265 mg, 1.15 mmol, 73%) as a white solid.
  • Step 2 6-chloro-2- (cyclohexyloxy) -N-cyclopropylnicotinamide 2 in NMP solution (2 mL) of cyclohexanol (195 mg, 1.95 mmol) and sodium hydride (51.9 mg, 1.30 mmol) , 6-Dichloro-N-cyclopropylnicotinamide (150 mg, 0.649 mmol) 60% was added and stirred at room temperature for 3 hours. After water and ethyl acetate were added to the reaction solution and separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate.
  • Step 3 2- (cyclohexyloxy) -N-cyclopropyl-6- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) nicotinamide
  • Example 1-1 Step 2
  • the title compound (51.1 mg, 0.111 mmol, 60%) was obtained as a beige amorphous substance.
  • Example 1-14 (2- (cyclohexylamino) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenylamino) pyridin-3-yl) ethanone
  • Step 1-1 2-Bromo-5-nitrophenol 1-Bromo-2-methoxy-4-nitrobenzene (5.0 g, 21.6 mmol) in dichloromethane (50 mL) was added to BBr 3 (1 M DCM solution, 32.3 mL). ) was added at 0 ° C. and stirred overnight. Water and ethyl acetate were added to the reaction solution and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure.
  • Step 1-2 2- (2-Bromo-5-nitrophenoxy) acetonitrile 2-Bromo-5-nitrophenol (5.64 g, 25.9 mmol), and potassium carbonate (10.7 g, 78.0 mmol) in acetonitrile (100 mL) Bromoacetonitrile (3.72 g, 2.16 mL, 31.0 mmol) was added to the solution, followed by stirring overnight at room temperature. Water and ethyl acetate were added to the reaction solution and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and then concentrated under reduced pressure.
  • Step 1-3 2- (2- (1-Methyl-1H-pyrazol-4-yl) -5-nitrophenoxy) acetonitrile 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1H-pyrazole (6.50 g, 31.2 mmol), 2- (2-bromo-5-nitrophenoxy) acetonitrile (6.69 g, 26.0 mmol), and PdCl 2 (dppf) To a solution of CH 2 Cl 2 (2.13 g, 2.61 mmol) in THF (80 mL) was added 2M aqueous sodium carbonate solution (26 mL), and the mixture was stirred for 8 hours under reflux with heating.
  • Step 1-4 2- (5-Amino-2- (1-methyl-1H-pyrazol-4-yl) phenoxy) acetonitrile Performed in the same manner as in Example 1-9 and Step 2, and the residue was medium pressure
  • the title compound (1.27 g, 5.54 mmol, 33%) was obtained by purification by silica gel chromatography (chloroform / ethyl acetate; 20-100% ethyl acetate gradient).
  • Step 2-1 6-chloro-N-cyclohexyl-3-iodopyridin-2-amine 2,6-dichloro-3-iodopyridine (6.85 g, 25.0 mmol) in NMP (100 mL) was added to cyclohexylamine ( 5.45 g, 6.29 mL, 55.0 mmol) was added, followed by stirring at 100 ° C. for 8 hours. Water and ethyl acetate were added to the reaction solution and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure.
  • Step 2-2 6-chloro-N-cyclohexyl-3- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine Performed in the same manner as in Step 1-3, and the title compound (3.14 g , 10.8 mmol, 78%) was obtained as a red oil.
  • Step 2-3 2- (5- (6- (cyclohexylamino) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-ylamino) -2- (1-methyl-1H-pyrazole -4-yl) phenoxy) acetonitrile
  • the title compound (71.9 mg, 0.149 mmol, 43%) was obtained in the same manner as in Example 1-1, Step 2.
  • Example 1-16 2- (5- (6- (cyclohexylamino) -5- (oxazol-5-yl) pyridin-2-ylamino) -2- (1-methyl-1H-pyrazol-4-yl) phenoxy) acetonitrile
  • Step 1 5- (2,6-dichloropyridin-3-yl) oxazole 2,6-dichloronicotinaldehyde (4.90 g, 27.8 mmol) and TosMIC (6.52 g, 33.4 mmol) in methanol (60 mL) solution After adding potassium carbonate (5.00 g, 36.2 mmol), the mixture was stirred for 2 hours with heating under reflux. Water and ethyl acetate were added to the reaction solution and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure.
  • Step 2 6-Chloro-N-cyclohexyl-3- (oxazol-5-yl) pyridin-2-amine 5- (2,6-dichloropyridin-3-yl) oxazole (430 mg, 2.0 mmol) NMP ( 2.0 mL) solution was added with cyclohexylamine (436 mg, 0.503 mL, 4.40 mmol), and then stirred at 150 ° C. for 10 hours under microwave irradiation. Water and ethyl acetate were added to the reaction solution and separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate.
  • Step 3 2- (5- (6- (Cyclohexylamino) -5- (oxazol-5-yl) pyridin-2-ylamino) -2- (1-methyl-1H-pyrazol-4-yl) phenoxy) acetonitrile
  • Example 1-1 was carried out in the same manner as in step 2, and the title compound (95 mg, 0.202 mmol, 45%) was obtained.
  • Step 1 6- (4-Bromo-3-methoxyphenylamino) -2-chloronicotinonitrile 2,6-dichloronicotinonitrile (9.15 g, 52.9 mmol) and DIEA (10.3 g, 13.9 mL, 79 mmol) 4-Bromo-3-methoxyaniline (12.8 g, 63.5 mmol) was added to an NMP (130 mL) solution, and the mixture was stirred at 100 ° C. for 10 hours. Water and ethyl acetate were added to the reaction solution and separated.
  • the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate.
  • the organic phase was filtered and then concentrated under reduced pressure.
  • a methanol / chloroform / hexane solution (40 mL / 60 mL / 480 mL) was added to the resulting residue to solidify, and the title compound (11.5 g, 34.1 mmol) was collected by filtration. , 64%) as a white solid.
  • Step 2 6- (4-Bromo-3-methoxyphenylamino) -2- (cyclohexylamino) nicotinonitrile 6- (4-Bromo-3-methoxyphenylamino) -2-chloronicotinonitrile (9.03 g, To a solution of 26.7 mmol) in NMP (90 mL) was added cyclohexylamine (15.3 mL, 15.3 mmol), followed by stirring at 150 ° C. for 5 hours. The reaction solution was returned to room temperature, poured into ice water, and the obtained solid was collected by filtration to give the title compound (9.74 g, 24.3 mmol, 91%) as a yellow solid.
  • Step 3 6- (4-Bromo-3-hydroxyphenylamino) -2- (cyclohexylamino) nicotinonitrile
  • Example 1-15 was carried out in the same manner as in Step 1-1, and the title compound (9.93 g, 25.6 mmol, 100%) as a brown solid.
  • Step 4 6- (4-Bromo-3- (cyanomethoxy) phenylamino) -2- (cyclohexylamino) nicotinonitrile
  • Example 1-15 was carried out in the same manner as in Step 1-2, and the title compound (7.10 g, 16.7 mmol, 70%) was obtained as a pale green solid.
  • Example 1-15 The method was carried out in the same manner as in Step 1-3 to obtain the title compound (1.89 g, 4.42 mmol, 45%) as a yellow solid.
  • MS (ESI) m / z 428 (M + H)
  • Step 1 (E) -methyl 3- (6-chloro-2- (cyclohexylamino) pyridin-3-yl) acrylate acrylamide (12.1 mg, 0.171 mmol), 6- (4-bromo-3- (cyanomethoxy) Phenylamino) -2- (cyclohexylamino) nicotinonitrile (48.7 mg, 0.114 mmol) and Pd [P (t-Bu) 3 ] 2 (5.84 mg, 0.011 mmol) in NMP (1.2 mL) solution in triethylamine (1.2 mL) 23.1 mg, 0.228 mmol) was added and stirred for 8 hours under microwave irradiation.
  • Step 2 (E) -3- (6-Chloro-2- (cyclohexylamino) pyridin-3-yl) acrylic acid
  • E -methyl 3- (6-chloro-2- (cyclohexylamino) pyridine-3- Yl) acrylate (767 mg, 2.60 mmol) in methanol / THF solution (4.0 mL / 4.0 mL) was added 4 mol / L sodium hydroxide aqueous solution (1.95 mL), and the mixture was stirred at room temperature for 4 hours. After acidifying with 2 mol / L hydrochloric acid aqueous solution, ethyl acetate was added and separated.
  • the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered, and then the reaction solution was concentrated to obtain the title compound (831 mg).
  • Step 3 (E) -3- (6-Chloro-2- (cyclohexylamino) pyridin-3-yl) -N-cyclopropylacrylamide Performed in the same manner as in Example 1-3, and the title compound (428 mg , 1.34 mmol, 52%).
  • Step 4 (E) -3- (6- (3- (cyanomethoxy) -4- (1-methyl-1H-pyrazol-4-yl) phenylamino) -2- (cyclohexylamino) pyridin-3-yl ) -N-cyclopropylacrylamide
  • the title compound (11.9 mg, 0.023 mmol, 7%) was obtained in the same manner as in Example 1-1 / Step 2.
  • Step 1 4-hydroxy-2- (methylthio) pyrimidine-5-carbonitrile
  • potassium hydroxide (2.33 g, 41.5 mmol) in methanol (15 mL)
  • S-methylisothiourea sulfate (6.80 g, 24.4 mmol)
  • the reaction solution was filtered to remove insoluble matters.
  • E -ethyl 2-cyano-3-ethoxyacrylate (8.27 g, 48.9 mmol) was added to the filtrate at 0 ° C., and the mixture was stirred at the same temperature for 1 hour.
  • the precipitated solid was collected by filtration and washed with methanol and ether cooled at 0 ° C. To the obtained solid was added 0.5 mol / L aqueous sodium hydroxide solution (48.9 mL, 24.3 mmol), and the mixture was stirred at 50 ° C. for 30 min. The reaction solution was filtered to remove insolubles, and then a 2N aqueous hydrochloric acid solution was added to the filtrate cooled to 0 ° C. to adjust the pH to about 1. The precipitated solid was collected by filtration to give the title compound (935 mg, 5.59 mmol, 23%) as a white solid. 1H-NMR (400 MHz, CD3OD) ⁇ 2.62 (s, 3H), 8.37 (s, 1H).
  • Step 2 4-hydroxy-2- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) pyrimidine-5-carbonitrile 4-hydroxy-2- (methylthio) pyrimidine-5 -Carbononitrile (56.2 mg, 0.336 mmol) and acetic acid (385 ⁇ L, 6.72 mmol) in t-butanol solution (1.7 mL) were mixed with 3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) aniline (89.0 mg, 0.437 mmol) was added, followed by stirring for 3 hours under microwave irradiation.
  • Step 3 4-chloro-2- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) pyrimidine-5-carbonitrile 4-hydroxy-2- (3-methoxy-4 A solution of-(1-methyl-1H-pyrazol-4-yl) phenylamino) pyrimidine-5-carbonitrile (54.3 mg, 0.168 mmol) in phosphorus oxychloride (1.0 mL) was stirred at 80 ° C. for 2 hours. The solvent was concentrated under reduced pressure, and the obtained residue was solidified with hexane / ethyl acetate to give the title compound (77.6 mg) as a yellow solid.
  • Step 4 4- (Cyclohexylamino) -2- (3-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) pyrimidine-5-carbonitrile 4-chloro-2- (3- Methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenylamino) pyrimidine-5-carbonitrile (63.6 mg, 0.187 mmol) and DIEA (130 ⁇ L, 0.747 mmol) in dioxane (2.0 mL) After adding cyclohexylamine (64 ⁇ L, 0.560 mmol), the mixture was stirred at 80 ° C. for 4 hours.
  • Step 1 6-Chloro-N 2 -cyclopentylpyridine-2,3-diamine 2,6-dichloropyridin-3-amine (1.63 g, 10 mmol) in NMP (10 mL) was added to cyclopentylamine (4.93 mL, 50 mmol) and then stirred at 200 ° C. for 10 hours under microwave irradiation. After water and ethyl acetate were added to the reaction solution and separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and then concentrated under reduced pressure.
  • Step 2 5-chloro-3-cyclopentyl-1H-imidazo [4,5-b] pyridin-2 (3H) -one 6-chloro-N 2 -cyclopentylpyridine-2,3-diamine (2.33 g, 11.0 mmol ), And sodium hydrogen carbonate (2.77 g, 33.0 mmol) in water / ethyl acetate (10 mL / 25 mL) was added dropwise phenylchloroformate (2.07 mL, 16.5 mmol) at 0 ° C, and 70 ° C for 2 hours. Stir. The reaction solution was returned to room temperature, the organic phase was separated and extracted, and the solvent was concentrated under reduced pressure.
  • Step 3 5-chloro-3-cyclopentyl-1-methyl-1H-imidazo [4,5-b] pyridin-2 (3H) -one 5-chloro-3-cyclopentyl-1H-imidazo [4,5-b ] Methyl iodide (0.304 mL, 4.86 mmol) was added to a DMF (5.0 mL) solution of pyridin-2 (3H) -one (770 mg, 3.24 mmol) and 60% sodium hydride (194 mg, 4.86 mmol). The solution was added dropwise at ° C and stirred at room temperature for 1 hour.
  • Step 4 2- (5- (3-Cyclopentyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridin-5-ylamino) -2- (1-methyl -1H-pyrazol-4-yl) phenoxy) acetonitrile
  • the title compound (85.9 mg, 0.194 mmol, 49%) was obtained in the same manner as in Example 1-1 / Step 2.
  • Example 1-84 2- (5- (3- (cyanomethoxy) -4- (1-methyl-1H-pyrazol-4-yl) phenylamino) -3-cyclopentyl-2-oxo-2,3-dihydro-1H-imidazo [ 4,5-b] pyridin-1-yl) acetonitrile
  • Example 1-86 4- (6- (3- (cyanomethoxy) -4- (1-methyl-1H-pyrazol-4-yl) phenylamino) -2- (cyclohexylamino) pyridin-3-yl) -N-cyclopropylbenzamide
  • CYP3A4 fluorescence MBI test is a test to examine the enhancement of CYP3A4 inhibition of a compound by metabolic reaction.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), pre- 62.5 pmol / mL during reaction, 6.25 pmol / mL during reaction (diluted 10 times); test drug concentration, 0.625, 1.25, 2.50, 5.00, 10.0, 20.0 ⁇ mol / L (6 points).
  • the control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration of the test drug solution was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model. The case where the difference in IC 50 value was 5 ⁇ M or more was designated as (+), and the case where it was 3 ⁇ M or less was designated as ( ⁇ ).
  • Example 4 CYP Inhibition Test 7-ethoxyresorufin O-deethylation as a typical substrate metabolic reaction of human tumor CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), hydroxylation of terfenadine (CYP3A4) The degree to which the amount of each metabolite produced was inhibited by the test compound was evaluated.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6) ), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; test drug concentration, 1.0, 5.0, 10, 20 ⁇ mol / L ( 4 points).
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the supernatant of the supernatant was collected using a fluorescent multilabel counter with tolbutamide hydroxide (CYP2C9 metabolite) and mephenytoin 4 ′ hydroxide (CYP2C19 metabolite).
  • dextrorphan CYP2D6 metabolite
  • CYP3A4 metabolite terfenadine alcohol
  • the control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration of the test drug solution was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model.
  • Example 5 FAT test 20 ⁇ L of frozen Salmonella typhimurium TA98 strain, TA100 strain was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) for 10 hours at 37 ° C. Incubated before shaking.
  • TA98 strain culture solution was removed by a bacterial solution of 9mL centrifuged (2000 ⁇ g, 10 min), Micro F buffer 9mL (K 2 HPO 4: 3.5 g / L, KH2PO4: 1 g / L, ( NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L) : Micro F buffer solution containing 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, glucose: 8 mg / mL), and TA100 strain was added to 120 mL of Exposure medium to 3.16 mL bacterial solution to prepare a test bacterial solution .
  • Test substance DMSO solution (maximum dose 50 mg / mL to 8-fold dilution at 2-fold common ratio), DMSO as negative control, 50 ⁇ g / mL 4-nitroquinoline for TA98 strain under non-metabolic activation conditions as positive control -1-oxide DMSO solution, TA100 strain, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, metabolic activation conditions against TA98 strain 40 ⁇ g / mL 2-aminoanthracene DMSO solution and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for TA100 strain, respectively, and 588 ⁇ L test bacterial solution (498 ⁇ L test bacterial solution under metabolic activation conditions) And S9 mix 90 ⁇ L) were mixed, and cultured at 37 ° C.
  • Indicator Medium (MicroF buffer solution containing biotin: 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 ⁇ g / mL) 2300 50 ⁇ L each was mixed in ⁇ L, dispensed into 48 microwells / dose of the microplate, and statically cultured at 37 ° C. for 3 days.
  • Example 7 Metabolic stability test Using commercially available pooled human liver microsomes, the target compound was reacted for a certain period of time, and the residual ratio was calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism in the liver. .
  • hERG test For the purpose of risk assessment of ECG QT interval prolongation, HEK293 cells expressing human ether-a-go-go related gene (hERG) channel are used to play an important role in ventricular repolarization process
  • IKr delayed rectifier K + current
  • the absolute value of the maximum tail current was measured from the obtained IKr using analysis software (DataXpress ver. 1, Molecular Devices Corporation) based on the current value at the holding membrane potential. Furthermore, the inhibition rate with respect to the maximum tail current before application of the test substance was calculated, and compared with the medium application group (0.1% dimethyl sulfoxide solution), the influence of the test substance on IKr was evaluated.
  • Example 9 Formulation example 1 tablet
  • a tablet having the following composition is produced by a conventional method. 100 mg of the compound of the present invention Lactose 60mg Potato starch 30mg Polyvinyl alcohol 2mg Magnesium stearate 1mg Tar pigment Trace amount.
  • Example 10 Formulation example 2 powder
  • a powder having the following composition is produced by a conventional method. 150 mg of the compound of the present invention Lactose 280 mg.
  • Example 11 Formulation example 3 syrup
  • a syrup having the following composition is produced by a conventional method. 100 mg of the compound of the present invention Purified white sugar 40 g 40 mg ethyl p-hydroxybenzoate Propyl p-hydroxybenzoate 10mg Chocolate flavor 0.1cc Water is added to make a total amount of 100 cc.
  • the present invention provides a medicament for treating a TTK kinase-dependent disease, a compound used therefor, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the compound of the present invention exhibits an excellent TTK kinase inhibitory action as described in the above Examples.

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Abstract

Cette invention concerne un inhibiteur efficace de la protéine kinase TTK ; et un agent thérapeutique efficace. Spécifiquement, un composé et des modes de réalisation concernant ledit composé (par exemple, composition pharmaceutique, inhibiteur de TTK, et autres) sont décrits. De nouveaux composés sont découverts, chacun d'eux ayant la capacité d'inhiber l'activité de la kinase TTK et ayant des propriétés spécifiques particulièrement utiles pour la formulation d'un agent thérapeutique apte à traiter des maladies. Par conséquent, les composés selon l'invention sont utiles pour les maladies chez lesquelles l'inhibition de l'activité de la kinase TTK devrait être efficace.
PCT/JP2010/063153 2009-08-06 2010-08-04 Dérivés de pyridine et de pyrimidine ayant une activité inhibitrice de ttk WO2011016472A1 (fr)

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US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11672800B2 (en) 2017-04-21 2023-06-13 Epizyme, Inc. Combination therapies with EHMT2 inhibitors
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12065494B2 (en) 2021-04-12 2024-08-20 Incyte Corporation Combination therapy comprising an FGFR inhibitor and a Nectin-4 targeting agent
US12084453B2 (en) 2021-12-10 2024-09-10 Incyte Corporation Bicyclic amines as CDK12 inhibitors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105229002A (zh) * 2012-12-20 2016-01-06 拜耳医药股份有限公司 抑制bet蛋白的二氢吡啶并吡嗪酮
US20160176867A1 (en) * 2013-07-09 2016-06-23 Bayer Pharma Aktiengesellschaft Modified bet-protein-inhibiting dihydroquinoxalinones and dihydropyridopyrazinones

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06508621A (ja) * 1991-06-12 1994-09-29 イー・アイ・デユポン・ドウ・ヌムール・アンド・カンパニー 置換されたピリジン除草剤
JP2001517699A (ja) * 1997-09-26 2001-10-09 アスタ メディカ アクチエンゲゼルシャフト セリン／トレオニンプロテインキナーゼ作用の変性のためのアザベンズイミダゾールを基礎とする化合物
JP2002309115A (ja) * 2001-04-09 2002-10-23 Fuji Photo Film Co Ltd アゾ化合物、着色組成物、インク組成物、及びインクジェット記録方法
JP2004533458A (ja) * 2001-05-30 2004-11-04 アストラゼネカ アクチボラグ サイクリン依存性キナーゼ阻害剤としての２−アニリノ−ピリミジン誘導体
JP2007505127A (ja) * 2003-09-11 2007-03-08 ケミア，インコーポレイテッド サイトカイン阻害剤
JP2008523033A (ja) * 2004-12-08 2008-07-03 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ２，４（４，６）ピリミジン誘導体
JP2008534689A (ja) * 2005-04-05 2008-08-28 ファーマコペイア， インコーポレイテッド 免疫抑制のためのプリン及びイミダゾピリジン誘導体
WO2008128231A1 (fr) * 2007-04-16 2008-10-23 Hutchison Medipharma Enterprises Limited Dérivés de pyrimidine
JP2008544972A (ja) * 2005-07-01 2008-12-11 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング オーロラ阻害剤としての２，４−ジアミノ−ピリミジン
JP2009513703A (ja) * 2005-11-01 2009-04-02 ターゲジェン インコーポレーティッド キナーゼのビ−アリールメタ−ピリミジン阻害剤
WO2010007756A1 (fr) * 2008-07-14 2010-01-21 塩野義製薬株式会社 Dérivé de pyridine ayant une activité d'inhibition de la ttk

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06508621A (ja) * 1991-06-12 1994-09-29 イー・アイ・デユポン・ドウ・ヌムール・アンド・カンパニー 置換されたピリジン除草剤
JP2001517699A (ja) * 1997-09-26 2001-10-09 アスタ メディカ アクチエンゲゼルシャフト セリン／トレオニンプロテインキナーゼ作用の変性のためのアザベンズイミダゾールを基礎とする化合物
JP2002309115A (ja) * 2001-04-09 2002-10-23 Fuji Photo Film Co Ltd アゾ化合物、着色組成物、インク組成物、及びインクジェット記録方法
JP2004533458A (ja) * 2001-05-30 2004-11-04 アストラゼネカ アクチボラグ サイクリン依存性キナーゼ阻害剤としての２−アニリノ−ピリミジン誘導体
JP2007505127A (ja) * 2003-09-11 2007-03-08 ケミア，インコーポレイテッド サイトカイン阻害剤
JP2008523033A (ja) * 2004-12-08 2008-07-03 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ２，４（４，６）ピリミジン誘導体
JP2008534689A (ja) * 2005-04-05 2008-08-28 ファーマコペイア， インコーポレイテッド 免疫抑制のためのプリン及びイミダゾピリジン誘導体
JP2008544972A (ja) * 2005-07-01 2008-12-11 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング オーロラ阻害剤としての２，４−ジアミノ−ピリミジン
JP2009513703A (ja) * 2005-11-01 2009-04-02 ターゲジェン インコーポレーティッド キナーゼのビ−アリールメタ−ピリミジン阻害剤
WO2008128231A1 (fr) * 2007-04-16 2008-10-23 Hutchison Medipharma Enterprises Limited Dérivés de pyrimidine
WO2010007756A1 (fr) * 2008-07-14 2010-01-21 塩野義製薬株式会社 Dérivé de pyridine ayant une activité d'inhibition de la ttk

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KATAYAMA, N. ET AL.: "Identification of a key element for hydrogen-bonding patterns between protein kinases and their inhibitors", PROTEINS: STRUCTURE, FUNCTION, AND BIOINFORMATICS, vol. 73, 2008, pages 795 - 801 *
LUDOVICI, D.W. ET AL.: "Evolution of anti-HIV drug candidates. Part 3: diarylpyrimidine (DAPY) analogues", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 11, 2001, pages 2235 - 2239, XP002329859, DOI: doi:10.1016/S0960-894X(01)00412-7 *
THAKUR, A. ET AL.: "SAR and QSAR studies: Modelling of new DAPY derivatives", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 43, 2008, pages 471 - 477, XP022511498, DOI: doi:10.1016/j.ejmech.2007.04.005 *

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* Cited by examiner, † Cited by third party
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US9701643B2 (en) 2011-04-22 2017-07-11 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US10040770B2 (en) 2011-04-22 2018-08-07 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US11325890B2 (en) 2011-04-22 2022-05-10 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US10919865B2 (en) 2011-04-22 2021-02-16 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US9351974B2 (en) 2011-11-10 2016-05-31 OSI Pharmaceuticals, LLC Substituted pteridinones for the treatment of cancer
JP2014533737A (ja) * 2011-11-29 2014-12-15 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ パーキンソン病の処置のためのキナーゼｌｒｒｋ２モジュレーターとしての２−（フェニル又はピリド−３−イル）アミノピリミジン誘導体
US20130158057A1 (en) * 2011-11-29 2013-06-20 Genentech, Inc. Aminopyrimidine derivatives as lrrk2 modulators
US8791130B2 (en) * 2011-11-29 2014-07-29 Genentech, Inc. Aminopyrimidine derivatives as LRRK2 modulators
US9611267B2 (en) 2012-06-13 2017-04-04 Incyte Holdings Corporation Substituted tricyclic compounds as FGFR inhibitors
US11840534B2 (en) 2012-06-13 2023-12-12 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
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US9814713B2 (en) 2014-01-30 2017-11-14 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
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WO2016166255A1 (fr) * 2015-04-17 2016-10-20 Netherlands Translational Research Center B.V. Biomarqueurs pronostiques pour chimiothérapie basée sur un inhibiteur de ttk
US11208696B2 (en) 2015-04-17 2021-12-28 Netherlands Translational Research Center B.V. Prognostic biomarkers for TTK inhibitor chemotherapy
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US12054784B2 (en) 2015-04-17 2024-08-06 Netherlands Translational Research Center B.V. Prognostic biomarkers for TTK inhibitor chemotherapy
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