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  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4

Definitions

• the present invention relates to a bicyclic pyrimidine compound having Axl inhibitory activity or a salt thereof.
• Axl is a receptor tyrosine kinase belonging to the Tyro3-Axl-Mer (TAM) receptor tyrosine kinase family with a growth arrest specific gene 6 (Gas6) protein as a ligand, and was initially identified as a transforming gene in chronic myeloid leukemia (Non-Patent Document 1).
• the Gas6 / Axl signaling system regulates various cellular responses such as cell survival, cell division, autophagy, cell migration, angiogenesis, platelet aggregation, NK cell differentiation, etc.
• Non-patent document 2 primary colon cancer (non-patent document 3), stomach cancer (non-patent document 4), esophageal cancer (non-patent document 5), melanoma (non-patent document 6),
• Many overexpressions in cancer tissues such as ovarian cancer (Non-patent document 7), kidney cancer (Non-patent document 8), endometrial cancer (Non-patent document 9), thyroid cancer (Non-patent document 10) have been reported. . It has also been shown that the presence of Axl is greatly related to lymph node status and stage in lung cancer and ER expression in breast cancer (Non-Patent Document 11).
• Axl is immune (non-patent document 12), platelet function (non-patent document 13), spermatogenesis (non-patent document 14), vascular calcification (non-patent document 15), thrombin-induced vascular smooth muscle cells (VSMC). It has also been shown to have a role in proliferation (Non-Patent Document 16) and various kidney diseases such as acute and chronic glomerulonephritis, diabetic nephropathy and chronic allograft rejection (Non-Patent Document 17).
• Inhibitors include but are not limited to cancer (including solid tumors such as carcinomas, sarcomas and leukemias and lymphoid malignancies), as well as vascular diseases (including thrombosis, atherosclerosis and restenosis). ), Kidney disease (including but not limited to acute and chronic glomerulonephritis, diabetic nephropathy and transplant rejection), and disordered angiogenesis are critical Expected to be beneficial in the treatment of a number of diseases, including but not limited to diabetic retinopathy, retinopathy, psoriasis, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangiomas Has been.
• cancer including solid tumors such as carcinomas, sarcomas and leukemias and lymphoid malignancies
• vascular diseases including thrombosis, atherosclerosis and restenosis.
• Kidney disease including but not limited to acute and chronic glomerulonephritis,
• Examples of compounds that inhibit Axl include compounds having a sulfonamide structure (Patent Document 3), compounds having a pyrrolopyrimidine structure (Patent Documents 4 and 5), compounds having a pyridine and pyrazine structure (Patent Document 6), and pyrazine.
• a compound having a structure (Patent Document 7), a compound having a pyrazinylbenzimidazole structure (Patent Document 8), a compound having an indolinone structure (Patent Document 9), a compound having a triazolopyridine and a triazolopyrimidine structure (Patent Document) 10), a compound having an imidazole structure (Patent Document 11), a compound having a triazole structure (Patent Document 12, Patent Document 13, Patent Document 14, Patent Document 15, Patent Document 16, Patent Document 17, Patent Document 20, Patent Document) 24, Patent Document 25, Patent Document 26, Patent Document 27, Patent 28), compounds having a pyrimidinediamine structure (Patent Document 18), compounds having a pyrimidine structure (Patent Document 19, Non-Patent Document 18, Non-Patent Document 22), compounds having a quinolinyloxyphenylsulfonamide structure (Patent Document 19) 21), compounds having a quinoline structure (Patent Document 22, Patent Document 30, Non-Patent Document 21),
• the present invention provides a novel Axl inhibitory compound.
• the present invention also provides a therapeutic agent for a disease caused by hyperfunction of Axl, a therapeutic agent for a disease associated with hyperfunction of Axl, and / or treatment of a disease associated with hyperfunction of Axl, comprising an Axl inhibitory compound.
• An agent such as an anticancer agent is provided.
• the present inventors have found that a compound having a structure represented by the following general formula (1) or a salt thereof has strong Axl inhibitory activity, and completed the present invention. That is, the present invention relates to the following [1] to [25].
• A represents a phenylene group or a 6-membered heteroarylene group, and the relative configuration of the amino group and nitrogen-containing heterocycle bonded to A is a para configuration;
• W represents a carbon atom or a nitrogen atom (provided that when W is a nitrogen atom, R 4 does not exist);
• X represents CH or a nitrogen atom,
• Y represents a carbon atom or a nitrogen atom (provided that when Y is a nitrogen atom, R 6 does not exist);
• R 1 is a cycloalkyl group optionally having one or more substituents selected from group 1, an aryl group optionally having one or more substituents selected from group 1, group 1 represents a heteroaryl group optionally having one or more substituents selected from 1;
• R 2 is a C 1 -C 6 alkyl group optionally having one or more substituents selected from Group 2, —OR C (where R C is a C 1 -C 6 alkoxy group, A C 1 -C 6
• R 7 represents a hydrogen atom or a C 1 to C 6 alkyl group optionally having one or more substituents selected from Group 2.
• Group 1 a C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, C 1 -C 6 alkoxy group, oxo group, hydroxyl group and halogen atom which may have one or more substituents selected from a halogen atom and a hydroxyl group.
• Group 2 A halogen atom, An oxo group, -NR A R B , -CONR A R B (wherein R A and R B each independently have one or more substituents selected from a halogen atom, a C 1 -C 6 alkoxy group and a hydroxyl group) or show was good C 1 ⁇ C 6 alkyl group optionally or a hydrogen atom, together with the nitrogen atom to replace them together is R a and R B, a halogen atom, C 1 ⁇ C 6 alkyl groups, C A 1 to C 6 alkoxy group and a 3- to 7-membered heterocycloalkyl group which may have one or more substituents selected from a hydroxyl group may be formed).
• R C is, C 1 ⁇ C 6 alkoxy group, one or a plurality of which may have a substituent C 1 ⁇ C 6 alkyl group selected from a halogen atom and a hydroxyl group
• a halogen atom shows a C 1 ⁇ C 6 alkyl group and one or a plurality of substituents may be 3-7 membered heterocycloalkyl group selected from a hydroxyl group or a hydrogen atom.
• One or more selected from a C 1 to C 6 alkyl group, a C 1 to C 6 alkoxy group, an oxo group and a halogen atom which may have one or more substituents selected from a halogen atom and a hydroxyl group
• An aryl group which may have a substituent, One or more selected from a C 1 to C 6 alkyl group, a C 1 to C 6 alkoxy group, an oxo group, a hydroxyl group and a halogen
• R C may have one or more substituents selected from a C 1 -C 6 alkoxy group, a halogen atom, a 3- to 7-membered heterocycloalkyl group, and a hydroxyl group.
• a disease caused by increased Axl kinase function, a disease associated with increased Axl kinase function, and / or Axl kinase, comprising the compound or salt thereof according to any one of [1] to [7] as an active ingredient A medicament for the treatment of diseases associated with hyperfunction.
• a medicament for the treatment of a hyperproliferative disease comprising the compound according to any one of [1] to [7] or a salt thereof as an active ingredient.
• a medicament for treating cancer comprising the compound according to any one of [1] to [7] or a salt thereof as an active ingredient.
• a medicament for preventing cancer metastasis comprising the compound or salt thereof according to any one of [1] to [7] as an active ingredient.
• a medicament for releasing drug resistance comprising the compound or salt thereof according to any one of [1] to [7] as an active ingredient.
• Cancer is breast cancer, colon cancer, prostate cancer, lung cancer, stomach cancer, ovarian cancer, endometrial cancer, renal cancer, hepatocellular carcinoma, thyroid cancer, uterine cancer, esophageal cancer, squamous cell carcinoma, leukemia, osteosarcoma [12] or [13], wherein the medicament is selected from melanoma, glioblastoma, and neuroblastoma.
• a pharmaceutical composition comprising the compound according to any one of [1] to [7] or a salt thereof, and a pharmaceutically acceptable carrier.
• a method for treating a hyperproliferative disease comprising using the compound according to any one of [1] to [7] or a salt thereof.
• a method for treating cancer comprising using the compound according to any one of [1] to [7] or a salt thereof.
• [20] A method for preventing cancer metastasis, comprising using the compound or salt thereof according to any one of [1] to [7].
• [21] A method for releasing drug resistance, comprising using the compound or salt thereof according to any one of [1] to [7].
• Cancer is breast cancer, colon cancer, prostate cancer, lung cancer, stomach cancer, ovarian cancer, endometrial cancer, renal cancer, hepatocellular carcinoma, thyroid cancer, uterine cancer, esophageal cancer, squamous cell carcinoma, leukemia, osteosarcoma [19] or [20], wherein the method is selected from melanoma, glioblastoma and neuroblastoma.
• the present invention provides a novel bicyclic pyrimidine derivative represented by the above formula (1) having Axl inhibitory activity.
• novel compounds are useful as therapeutic agents, for example, anticancer agents, for diseases caused by increased Axl function, diseases associated with increased Axl function, and / or diseases associated with increased Axl function.
• Axl refers to a protein encoded by the Axl gene.
• Axl includes an Axl protein encoded by a full-length Axl gene or an Axl protein encoded by an Axl gene mutant (including a deletion mutant, a substitution mutant, or an additional mutant).
• Axl includes homologs derived from various animal species.
• Axl inhibitor refers to an inhibitor of the function of Axl as a tyrosine kinase.
• tumor and “cancer” are used interchangeably.
• a tumor, a malignant tumor, a cancer, a malignant neoplasm, a carcinoma, a sarcoma, etc. may be collectively referred to as “tumor” or “cancer”.
• “C 1 ⁇ C 6” means a linear or branched alkyl group having 1 to 6 carbon atoms.
• C 1 ⁇ C 6 Examples of the “alkyl group” include methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group and the like.
• alkoxy group means an alkoxy group having a linear or branched alkyl group having 1 to 6 carbon atoms.
• C 1 ⁇ C 6 Examples of the “alkoxy group” include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group.
• Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
• oxo group means a group represented by “ ⁇ O” unless otherwise specified.
• cycloalkyl group means a cyclic alkyl group having 3 to 8 carbon atoms unless otherwise specified, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
• heterocycloalkyl group means a monovalent saturated heterocyclic group, and includes a saturated heterocyclic group having a nitrogen atom in the ring, a saturated heterocyclic group having an oxygen atom in the ring, and the like, for example, pyrrolidine, And monovalent groups derived from imidazoline, piperidine, piperazine, azetidine, morpholine, dioxane, oxetane, tetrahydropyran, and quinuclidine.
• Examples of the “cycloalkenyl group” include those having an unsaturated bond such as one or more double bonds in the above “cycloalkyl group”, and examples thereof include a cyclopentenyl group and a cyclohexenyl group.
• Examples of the “heterocycloalkenyl group” include those having an unsaturated bond such as one or more double bonds in the above “heterocycloalkyl group”, and examples thereof include a tetrahydropyridyl group and a dihydropyranyl group. .
• aryl group means a monovalent substituent derived from an aromatic hydrocarbon, and examples of the aryl group include a phenyl group, an indenyl group, a naphthyl group, a fluorenyl group, an anthranyl group, and a phenanthrenyl group. .
• Heteroaryl group '' means a monovalent aromatic heterocyclic group, pyrrolyl group, pyrazolyl group, triazolyl group, oxazolyl group, oxadiazolyl group, thiophenyl group, thiazolyl group, thiadiazolyl group, pyridinyl group, pyrimidyl group, Examples include a pyridazyl group, a pyrazinyl group, a benzimidazolyl group, a benzotriazolyl group, a benzofuranyl group, a benzothiophenyl group, a quinolyl group, a carbazolyl group, and a dibenzofuranyl group.
• heteroarylene group means a divalent aromatic heterocyclic group, and examples thereof include a divalent group derived from pyridine, pyrimidine, pyrazine, pyridazine, triazine and the like.
• A represents a phenylene group or a 6-membered heteroarylene group.
• the relative arrangement of the amino group bonded to ring A and the nitrogen-containing heterocycle is a para arrangement.
• A is preferably a group containing a nitrogen atom, particularly preferably a group derived from pyridine.
• the position of elements other than carbon in the ring of A is not particularly limited.
• A is more preferably a phenylene group.
• W represents a carbon atom or a nitrogen atom (provided that when W is a nitrogen atom, R 4 Does not exist. ), More preferably a carbon atom.
• X represents CH or a nitrogen atom, and more preferably a nitrogen atom.
• Y represents a carbon atom or a nitrogen atom (provided that when Y is a nitrogen atom, R 6 Does not exist. ), More preferably a nitrogen atom.
• R 1 Is a cycloalkyl group optionally having one or more substituents selected from Group 1 above, an aryl group optionally having one or more substituents selected from Group 1 above, 1 represents a heteroaryl group optionally having one or more substituents selected from Group 1.
• R may optionally have one or more substituents selected from the above group 1” 1
• the “cycloalkyl group” is preferably a cyclopentyl group or a cyclohexyl group, where R 1 Is preferably an unsubstituted cyclohexyl group.
• the “aryl group” is preferably a phenyl group.
• the substituent of the phenyl group it may have 1 to 3 substituents selected from fluorine atom, chlorine atom and hydroxyl group.
• R 1 Is a “heteroaryl group” in which it is a “heteroaryl group optionally having one or more substituents selected from group 1” above, a heteroaryl group containing a nitrogen atom is preferred, and pyridinyl Group, pyrimidinyl group, pyridazinyl group or pyrazinyl group is more preferable, and pyridyl group is particularly preferable.
• the substituent for the heteroaryl group may have 1 to 3 substituents selected from a fluorine atom, a chlorine atom and a hydroxyl group.
• One to three groups selected from an alkoxy group, a hydroxyl group, a fluorine atom or a chlorine atom are preferred.
• R 1 As an unsubstituted phenyl group, 1 to 3 halogen atoms may be substituted.
• 1 ⁇ C 6 A phenyl group substituted with 1 to 3 groups selected from an alkyl group and a halogen atom, an unsubstituted pyridinyl group, and 1 to 3 halogen atoms optionally substituted with C 1 ⁇ C 6 More preferred is a pyridinyl group substituted with 1 to 3 groups selected from an alkyl group and a halogen atom.
• R 2 May have one or more substituents selected from Group 2 above 1 ⁇ C 6 Alkyl group, -OR C (Where R C Is C 1 ⁇ C 6 C which may have one or more substituents selected from an alkoxy group, a halogen atom and a hydroxyl group 1 ⁇ C 6 An alkyl group or a hydrogen atom is shown. ), Optionally having one or more substituents selected from group 2 above 1 ⁇ C 6 Alkylthio group, -NR A R B (Where R A And R B Are independently C 1 ⁇ C 6 Represents an alkyl group, or a hydrogen atom, or R A And R B Together with the nitrogen atom with which they are substituted may form a 3-7 membered heterocycloalkyl group.
• a cycloalkyl group or a hydrogen atom which may have one or more substituents selected from the above group 1.
• alkyl group a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group is preferable.
• R 2 "C optionally having one or more substituents selected from group 2 above” 1 ⁇ C 6 C in the case of “alkyl group” 1 ⁇ C 6
• the halogen atom as a substituent of the alkyl group is preferably a fluorine atom, a chlorine atom or a bromine atom, and more preferably a fluorine atom.
• C 1 ⁇ C 6 A plurality of the same or different halogen atoms may be substituted on the alkyl group, and the number of substitution is preferably 1 to 3 in the case of substitution.
• R 2 Is "-OR C (Where R C Is C 1 ⁇ C 6 C which may have one or more substituents selected from an alkoxy group, a halogen atom and a hydroxyl group 1 ⁇ C 6 An alkyl group or a hydrogen atom is shown. ) "If R C The preferred range of C is C 1 ⁇ C 6 Alkoxy group and halogen atom may be substituted C 1 ⁇ C 6 An alkyl group is preferred, R C Is C 1 ⁇ C 3 Alkoxy group and fluorine atom may be substituted C 1 ⁇ C 3 More preferably, it is an alkyl group.
• a preferred range in the case of “alkylthio group” is an unsubstituted C 1 ⁇ C 6 C substituted with an alkyl group 1 ⁇ C 6
• Alkylthio groups are preferred and unsubstituted C 1 ⁇ C 6
• An alkylthio group is more preferred.
• R A And R B Each independently represents an unsubstituted C 1 ⁇ C 6 An alkyl group or a hydrogen atom, or R A And R B Together with the nitrogen atom with which they are substituted, a halogen atom, C 1 ⁇ C 6 Alkyl group, C 1 ⁇ C 6 It is preferable to form a 3- to 6-membered heterocycloalkyl group which may have one or more substituents selected from an alkoxy group and a hydroxyl group, wherein “3- to 6-membered heterocycloalkyl group” "Is preferably a pyrrolidinyl group or an azetidinyl group.
• R 2 Is a “cycloalkyl group” in which it is a “cycloalkyl group optionally having one or more substituents selected from group 1” above, a 3- to 7-membered cycloalkyl group is preferred, A propyl group and a cyclobutyl group are more preferable.
• R 3 Is a substituent on A (wherein n represents an integer of 0 to 4 and n is 2 or more, R 3 May be the same as or different from each other. ), C optionally having one or more substituents selected from group 2 1 ⁇ C 6 C may have one or more substituents selected from an alkyl group, a halogen atom and a hydroxyl group 1 ⁇ C 6 C which may have one or more substituents selected from an alkoxy group, a halogen atom and a hydroxyl group 1 ⁇ C 6 An alkylthio group, a halogen atom or a hydroxyl group is shown.
• the preferred range in the case of “alkyl group” is the above R 2 "C optionally having one or more substituents selected from group 2 above” 1 ⁇ C 6 Synonymous with “alkyl group” but R 3 "C optionally having one or more substituents selected from group 2 above” 1 ⁇ C 6
• an “alkyl group” it may be substituted with 1 to 3 fluorine atoms, chlorine atoms, bromine atoms or hydroxyl groups.
• 1 ⁇ C 6 It is preferably an alkyl group, and unsubstituted C 1 ⁇ C 6 More preferably, it is an alkyl group.
• R 3 Is "C optionally having one or more substituents selected from a halogen atom and a hydroxyl group” 1 ⁇ C 6
• C may be substituted with 1 to 3 fluorine atoms, chlorine atoms, bromine atoms or hydroxyl groups.
• 1 ⁇ C 3 It is preferably an alkoxy group, and unsubstituted C 1 ⁇ C 3 More preferably, it is an alkoxy group.
• R 3 Is "C optionally having one or more substituents selected from a halogen atom and a hydroxyl group" 1 ⁇ C 6
• an alkylthio group it may be substituted with 1 to 3 fluorine atoms, chlorine atoms, bromine atoms or hydroxyl groups.
• 1 ⁇ C 3 It is preferably an alkylthio group, and unsubstituted C 1 ⁇ C 3 More preferably, it is an alkylthio group.
• R 3 N is preferably 0 to 3, more preferably n is 0 or 1, and when n is 1 to 3, 3 Is a fluorine atom, a chlorine atom, a bromine atom, C 1 ⁇ C 6 Alkyl group or C 1 ⁇ C 6 More preferably, it is an alkoxy group.
• R 4 Is a substituent on W when W is a carbon atom, and may have one or more substituents selected from Group 2 above.
• C 1 ⁇ C 6 Alkyl group, C 1 ⁇ C 6 C may have one or more substituents selected from an alkoxy group, a cycloheteroalkyl group, a halogen atom and a hydroxyl group 1 ⁇ C 6
• a heterocycloalkyl group optionally having one or more substituents selected from group 3, a heterocycloalkenyl group optionally having one or more substituents selected from group 3 above,
• An aryl group optionally having one or more substituents selected from group 3 or a heteroaryl group optionally having one or more substituents selected from group 3; a cyano group; Indicates an atom or a hydrogen atom.
• the preferred range in the case of “alkyl group” is the above R 2 "C optionally having one or more substituents selected from group 2 above” 1 ⁇ C 6
• Synonymous with “alkyl group” but unsubstituted C 1 ⁇ C 6 Alkyl group, C substituted with 1 to 3 halogen atoms 1 ⁇ C 6 Alkyl groups are preferred and unsubstituted C 1 ⁇ C 6
• An alkyl group is more preferred.
• R 4 Is "C 1 ⁇ C 6 Optionally having one or more substituents selected from an alkoxy group, a heterocycloalkyl group, a halogen atom and a hydroxyl group 1 ⁇ C 6
• alkoxy group unsubstituted C 1 ⁇ C 6 C substituted with an alkoxy group or 1 to 3 halogen atoms 1 ⁇ C 6 Alkoxy groups are preferred and unsubstituted C 1 ⁇ C 6 An alkoxy group is more preferable.
• R 4 Is a “cycloalkyl group” in the case of “a cycloalkyl group optionally having one or more substituents selected from the group 3”, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. Group is preferred, R 4 Is a cyclopentenyl group or a cyclohexenyl group, preferably “cycloalkenyl group optionally having one or more substituents selected from group 3” above.
• R 4 Is a “heterocycloalkyl group” in the case of “heterocycloalkyl group optionally having one or more substituents selected from group 3” as azetidinyl group, pyrrolidinyl group, piperidinyl group, A piperazinyl group or a morpholinyl group is preferred, and R 4 Is a “heterocycloalkenyl group that may have one or more substituents selected from the above group 3”, the “heterocycloalkenyl group” includes a tetrahydropyridyl group or a dihydropyranyl group.
• R 4 Is a phenyl group as the aryl group, preferably an aryl group optionally having one or more substituents selected from Group 3 above, 4 Is a “heteroaryl group” in the case of “a heteroaryl group optionally having one or more substituents selected from the above group 3”, a pyridinyl group, pyrazinyl group, pyrimidinyl group, pyrazolyl group An imidazolyl group, a thiophenyl group, a thiazolyl group, an isothiazolyl group, a furanyl group, an oxazolyl group or a triazolyl group is preferred.
• the number of substituents substituted on the cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group is preferably 0 to 3.
• the substituent of these cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group may be “which may have one or more substituents selected from the above group 2.
• alkyl group 1 ⁇ C 6
• a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group is preferable.
• the substituent of the cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group may have “one or more substituents selected from the above group 2”.
• C 1 ⁇ C 6 A preferable range in the case of “alkyl group” includes a halogen atom, C 1 ⁇ C 6 Alkyl group, -NR A R B And -CONR A R B (Where R A And R B Each independently represents a halogen atom, C 1 ⁇ C 6 C which may have one or more substituents selected from an alkoxy group and a hydroxyl group 1 ⁇ C 6 Represents an alkyl group, or a hydrogen atom, or R A And R B Together with the nitrogen atom with which they are substituted, a halogen atom, C 1 ⁇ C 6 Alkyl group, C 1 ⁇ C 6 A 3- to 7-membered heterocycloalkyl group which may have one or a plurality of substituents selected from an alkoxy group and a hydroxyl group may be formed.
• R C Is C 1 ⁇ C 6 C which may have one or more substituents selected from an alkoxy group, a halogen atom and a hydroxyl group 1 ⁇ C 6 Alkyl group, halogen atom, C 1 ⁇ C 6 3 to 7-membered heterocycloalkyl group optionally having one or more substituents selected from an alkyl group and a hydroxyl group, or a hydrogen atom.
• R C which may be substituted with an optionally substituted heterocycloalkyl group 1 ⁇ C 6
• An alkyl group is preferred.
• the halogen atom as the substituent of the alkyl group is preferably a fluorine atom, a chlorine atom or a bromine atom, and C 1 ⁇ C 6
• a plurality of the same or different halogen atoms may be substituted on the alkyl group, and the number of substitution is preferably 1 to 3 in the case of substitution.
• C 1 ⁇ C 6 —NR as a substituent of an alkyl group A R B And -CONR A R B
• R A And R B Each independently represents a halogen atom, C 1 ⁇ C 6 C which may have one or more substituents selected from an alkoxy group and a hydroxyl group
• 1 ⁇ C 6 Represents an alkyl group, or a hydrogen atom, or R A And R B Together with the nitrogen atom with which they are substituted, a halogen atom, C 1 ⁇ C 6 Alkyl group, C 1 ⁇ C 6 A 3- to 7-membered heterocycloalkyl group which may have one or a plurality of substituents selected from an alkoxy group and a hydroxyl group may be formed.
• Particularly preferred are amino groups forming a substituted azetidinyl group, pyrrolidinyl group, piperidinyl group.
• C 1 ⁇ C 6 -OR as a substituent of an alkyl group C (Where R C May have one or more substituents selected from a halogen atom and a hydroxyl group. 1 ⁇ C 6 An alkyl group or a hydrogen atom is shown.
• Is R C Is C 1 ⁇ C 6 It is preferably an alkyl group or a hydrogen atom, and the number of substitutions for substitution is preferably 1 to 3.
• the heterocycloalkyl group which may have a substituent as a substituent of the alkyl group may have one or more substituents selected from a halogen atom and a hydroxyl group.
• C 1 ⁇ C 6 Alkyl group C 1 ⁇ C 6 It is preferably a 3- to 7-membered heterocycloalkyl group which may have one or more substituents selected from an alkoxy group, an oxo group, a hydroxyl group and a halogen atom, Unsubstituted or C 1 ⁇ C 6 A 3- to 7-membered heterocycloalkyl group substituted with an alkyl group is more preferred.
• the “3- to 7-membered heterocycloalkyl group” includes a tetrahydropyranyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, an imidazolidinyl group, and a pyrazolidinyl group.
• Group, piperidino group, morpholino group, dioxanyl group and oxetanyl group are preferable, and pyrrolidinyl group and dioxanyl group are more preferable.
• each heterocycloalkyl group 1 ⁇ C 6 The bonding position to the alkyl group is not limited, but in the case of a dioxanyl group, it is preferably bonded at the 2-position, and in the case of a pyrrolidinyl group, it is preferably bonded at the 2-position.
• the substituent of these cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group may be “which may have one or more substituents selected from the above group 2.
• acyl group is C 1 ⁇ C 6 Alkyl group, -OR C (Where R C Is C 1 ⁇ C 6 An alkyl group or a hydrogen atom is shown. C) optionally substituted with 1 ⁇ C 6 An acyl group is preferred. Hydroxyl group or C 1 ⁇ C 3 C in which the alkyl group may be substituted 1 ⁇ C 3 More preferably, it is an acyl group.
• the substituent of these cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group is “having one or more substituents selected from a halogen atom and a hydroxyl group.
• R A And R B Each independently represents an unsubstituted C 1 ⁇ C 6 An alkyl group or a hydrogen atom, or R A And R B Together with the nitrogen atom with which they are substituted, a halogen atom, C 1 ⁇ C 6 Alkyl group, C 1 ⁇ C 6 It is preferable to form a 3- to 6-membered heterocycloalkyl group which may have one or more substituents selected from an alkoxy group and a hydroxyl group, wherein “3- to 6-membered heterocycloalkyl group” "Is preferably a pyrrolidinyl group, a morpholino group, an azetidinyl group or a piperidinyl group.
• the substituent of these cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group is represented by "-OR C (Where R C Is C 1 ⁇ C 6 Optionally having one or more substituents selected from an alkoxy group, a halogen atom, a 3- to 7-membered heterocycloalkyl group and a hydroxyl group 1 ⁇ C 6 Alkyl group, halogen atom, C 1 ⁇ C 6 3 to 7-membered heterocycloalkyl group optionally having one or more substituents selected from an alkyl group and a hydroxyl group, or a hydrogen atom.
• An alkyl group or a hydrogen atom is preferred, and C 1 ⁇ C 6 C substituted with an alkoxy group or a 3-7 membered heterocycloalkyl group 1 ⁇ C 6
• An alkyl group is more preferred.
• the 3- to 7-membered heterocycloalkyl group is preferably a pyrrolidyl group, imidazolidinyl group, pyrazolidinyl group, piperidinyl group, piperazinyl group, tetrahydropyranyl group, dioxanyl group or tetrahydrofuranyl group.
• R C is particularly preferably a methyl group, an ethyl group, a methyl group substituted with a dioxanyl group, an ethyl group substituted with a dioxanyl group, a methyl group substituted with a methoxy group, or an ethyl group substituted with a methoxy group.
• the substituent of these cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, heterocycloalkenyl group, aryl group or heteroaryl group may have “one or more substituents selected from Group 1”.
• “heterocycloalkyl” C 1 ⁇ C 6 Alkyl group, C 1 ⁇ C 6
• An alkoxy group, an oxo group, a hydroxyl group or a heterocycloalkyl group optionally substituted with a halogen atom is preferred, and C 1 ⁇ C 6
• a heterocycloalkyl group substituted with an alkyl group, a halogen atom or an oxo group or an unsubstituted heterocycloalkyl group is more preferred.
• the nitrogen-containing heteroaryl group is preferably a pyridinyl group or a pyrazolyl group.
• R 5 May have one or more substituents selected from Group 1 above.
• R C Is C 1 ⁇ C 6 C which may have one or more substituents selected from an alkoxy group, a halogen atom and a hydroxyl group 1 ⁇ C 6 Alkyl group, halogen atom, C 1 ⁇ C 6 3 to 7-membered heterocycloalkyl group optionally having one or more substituents selected from an alkyl group and a hydroxyl group, or a hydrogen atom.
• R C Is C 1 ⁇ C 6 C which may have one or more substituents selected from an alkoxy group, a halogen atom and a hydroxyl group 1 ⁇ C 6 Alkyl group, halogen atom, C 1 ⁇ C 6 3 to 7-membered heterocycloalkyl group optionally having one or more substituents selected from an alkyl group and a hydroxyl group, or a hydrogen atom.
• Or a hydrogen atom Or a hydrogen atom.
• R 5 "C optionally having one or more substituents selected from the above group 1 1 ⁇ C 6 The preferred range in the case of “alkyl group” is the above R 2 "C optionally having one or more substituents selected from the above group 1" 1 ⁇ C 6 Synonymous with “alkyl group”, but unsubstituted C 1 ⁇ C 6 Alkyl group, C substituted with 1 to 3 halogen atoms 1 ⁇ C 6 Alkyl groups are preferred and unsubstituted C 1 ⁇ C 6 An alkyl group is more preferred.
• R 5 Is "-OR C (Where R C Is C 1 ⁇ C 6 C which may have one or more substituents selected from an alkoxy group, a halogen atom and a hydroxyl group 1 ⁇ C 6 Alkyl group, halogen atom, C 1 ⁇ C 6 3 to 7-membered heterocycloalkyl group optionally having one or more substituents selected from an alkyl group and a hydroxyl group, or a hydrogen atom.
• the compound represented by the general formula (1) of the present invention is preferably 1 compound selected from the following group.
• the compound represented by the formula (1) of the present invention may have stereoisomers or optical isomers derived from asymmetric carbon atoms.
• a pharmaceutically acceptable salt can be obtained as desired.
• examples of such salts include hydrohalates such as hydrochloride and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate; methanesulfonate and trifluoromethanesulfone.
• Lower alkane sulfonate such as acid salt and ethane sulfonate; aryl sulfonate such as benzene sulfonate and p-toluene sulfonate; formic acid, acetic acid, malic acid, fumarate, succinate, citric acid Organic acid salts such as acid salts, tartrate salts, oxalate salts, maleates; and amino acid salts such as ornithates, glutamates, aspartates; and the like. preferable.
• the compound represented by the general formula (1) of the present invention has an acidic group such as a carboxy group, it is generally possible to form a base addition salt.
• Examples of the pharmaceutically acceptable salt include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; dibenzylamine salt , Morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl And organic amine salts such as -N- (2-phenylethoxy) amine salt, piperazine salt, tetramethylammonium salt, and tris (hydroxymethyl) aminomethane salt.
• alkali metal salts such as sodium salt, potassium salt and lithium salt
• alkaline earth metal salts such as calcium salt and magnesium salt
• inorganic salts such as ammonium salt
• the compound represented by the general formula (1) or a salt thereof of the present invention may exist as a free form or a solvate. It may exist as a hydrate by absorbing moisture in the air.
• the solvate is not particularly limited as long as it is pharmaceutically acceptable, and specifically, a hydrate, an ethanolate, and the like are preferable.
• a nitrogen atom is present in the compound of the present invention represented by the general formula (1), it may be an N-oxide, and these solvates and N-oxides are also within the scope of the present invention. included.
• the compound represented by the general formula (1) of the present invention may be a geometric isomer such as a cis isomer or a trans isomer, a tautomer, an optical isomer such as a d isomer, or an l isomer depending on the type or combination of substituents.
• the compounds of the present invention include all isomers, stereoisomers, and any ratios of these isomers and stereoisomer mixtures, unless otherwise specified. It is.
• the compound represented by the general formula (1) of the present invention may contain an unnatural proportion of atomic isotopes at one or more of the constituent atoms.
• deuterium 2 H
• tritium 3 H
• iodine-125 125 I
• carbon-14 14 C
• These compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotopic variants of the compound represented by general formula (1) are included within the scope of the present invention, whether radioactive or not.
• the present invention also relates to a compound that is converted into the compound (1) which is an active ingredient of the pharmaceutical composition of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced,
• a compound that is converted to compound (1) by hydrolysis or the like, or a “pharmaceutically acceptable prodrug compound” that is converted to compound (1) by hydrolysis or the like by gastric acid or the like is also encompassed in the present invention. .
• the prodrug when an amino group is present in the compound (1), a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosanoylated, alanylated, pentylamino Carbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.
• the amino group is eicosanoylated, alanylated, pentylamino Carbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.
• the compound (1) has a hydroxyl group
• a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated for example, the hydroxyl group is acetylated, palmitoyl.
• Propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbo Le reduction has been a compound.), And the like.
• a carboxy group is present in compound (I), a compound in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylamino Methyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, amidation, or methylamidated compounds).
• Prodrugs of the compounds of the present invention can be produced from compound (1) by known methods.
• the prodrug of the compound of the present invention is a compound that changes to compound (1) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198.
• R, G 1 , G 2 Represents a corresponding suitable alkyl group.
• L 1 ⁇ L 4 Represents a leaving group such as a halogen atom.
• the compound 1a shown below can be produced by, for example, the following reaction formula. (1) Conversion from compound 2 to compound 4 Conversion from compound 2 to compound 4 is carried out by a coupling reaction using a known organic chemical technique between compound 2 and a compound having a partial structure containing A (for example, compound 3).
• reaction is carried out with respect to compound 2 in the presence of a suitable organic boronic acid, organic tin, organic zinc, or organic magnesium derivative (for example, compound 3) and a suitable transition metal catalyst (for example, a palladium compound) as necessary.
• a suitable organic boronic acid for example, organic tin, organic zinc, or organic magnesium derivative
• a suitable transition metal catalyst for example, a palladium compound
• a base or an inorganic base for example, sodium carbonate, potassium carbonate, tripotassium phosphate, diisopropylethylamine
• a ligand for example, triphenylphosphine
• a known reaction promoting additive for example, lithium chloride or copper iodide
• the solvent is a suitable solvent that does not adversely influence the reaction (for example, N, N-dimethylformamide, tetrahydrofuran, toluene, 1,4-dioxane, water, etc.) or a mixed solvent thereof, and the reaction
• the temperature is preferably from 0 ° C. to 300 ° C., more preferably from room temperature to 200 ° C. (the optimum temperature is from 80 ° C. to 100 ° C.).
• the above reaction can also be carried out by treatment in a sealed tube or under microwave irradiation.
• the organic boronic acid and the like and the base are preferably used in an excess molar equivalent of 1 to 1 with respect to the compound 2, the organic boronic acid and the like are preferably used in an amount of 1 to 1.5 molar equivalents, and the base is preferably used in an amount of 1 to 5 molar equivalents .
• the reaction time is preferably 1 minute to 60 hours, more preferably 5 minutes to 24 hours.
• N N-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate, (1-cyano-2-ethoxy-2-oxoethylideneaminooxy, preferably at 0 ° C. to 50 ° C.
• Dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), N, N, N ′, N′-tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU), etc.
• a condensing agent Carried out by reacting separately synthesized carboxylic acid compound 5.
• the condensing agent may be used in an excess molar equivalent, preferably 1 to 5 molar equivalents relative to compound 4.
• a base for example, triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc. may be added as necessary.
• the amount of the base a catalytic amount or an excess amount can be used.
• the reaction time is preferably 10 minutes to 72 hours, more preferably 30 minutes to 24 hours.
• a well-known reaction promotion additive (1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, etc.) as needed.
• an excess amount from a catalyst amount can be used.
• the reaction is performed from ⁇ 30 ° C.
• Carboxylic acid derived from carboxylic acid compound 5 in the presence of a suitable base for example, triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.
• a suitable base for example, triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, etc.
• a catalytic amount or an excess amount can be used.
• the reaction time is preferably 10 minutes to 72 hours, more preferably 30 minutes to 24 hours.
• the reaction can be carried out by reacting compound 4 with carboxylic acid compound 5 in an acidic solvent (for example, polyphosphoric acid or the like) from 0 ° C. to the boiling point of the solvent used for the reaction, preferably 10 ° C. to 120 ° C.
• the reaction time is preferably 10 minutes to 72 hours, more preferably 30 minutes to 24 hours.
• conversion from compound 6 to compound 1a involves conversion of compound 6 and R 4 It is carried out by a coupling reaction using a known organic chemical technique with a compound having a partial structure containing A general coupling reaction similar to the coupling reaction described in (1) can be applied.
• the reaction may be carried out for compound 6 in the presence of a suitable organoboronic acid, organotin, organozinc, or organomagnesium derivative (such as compound 7) and a suitable transition metal catalyst (such as a palladium compound) as necessary.
• a suitable organoboronic acid for example, sodium carbonate, potassium carbonate, tripotassium phosphate, diisopropylethylamine, etc.
• a ligand for example, triphenylphosphine
• a known reaction promoting additive for example, lithium chloride or copper iodide.
• the solvent is a suitable solvent that does not adversely influence the reaction (for example, N, N-dimethylformamide, tetrahydrofuran, toluene, 1,4-dioxane, water, etc.) or a mixed solvent thereof, and the reaction
• the temperature is preferably from 0 ° C to 300 ° C, more preferably from room temperature to 200 ° C (optimum temperature is from 80 ° C to 120 ° C).
• the above reaction can also be carried out by treatment in a sealed tube or under microwave irradiation.
• the organic boronic acid and the like and the base may be used in an amount of 1 to excess molar equivalents, preferably 1 to 5 molar equivalents, relative to compound 6.
• the reaction time is preferably 1 minute to 60 hours, more preferably 5 minutes to 24 hours.
• the compound 1a can also be obtained by reacting the compound 4 of [Production Method 1] with the order of the amidation reaction (2) and the coupling reaction (3) reversed.
• (1) Conversion from compound 4 to compound 8 Conversion from compound 4 to compound 8 can be carried out by a general coupling reaction similar to the method described in (1) of [Production Method 1] above.
• (2) Conversion from compound 8 to compound 1a The conversion from compound 8 and compound 5 to compound 1a can be carried out by the usual amidation reaction similar to the method described in the above [Production Method 1].
• a compound 9 having a partial structure containing A is synthesized in advance, and the compound 1a can also be obtained by a route via a coupling reaction between the compound 9 and the compound 2.
• (1) Conversion from compound 3 to compound 9 Conversion from compound 3 and compound 5 to compound 9 is carried out by subjecting compound 3 to an amidation reaction using a known organic chemical technique. Details of the reaction are the same as in Method (2) (ordinary amidation reaction) described in [Production Method 1].
• (2) Conversion from compound 9 to compound 6 Conversion from Compound 2 and Compound 9 to Compound 6 is performed by a coupling reaction using a known organic chemical reaction between Compound 2 and Compound 9 having a partial structure containing A.
• an organic or inorganic base for example, potassium acetate, sodium carbonate, or diisopropylethylamine
• a suitable diboronic acid ester for example, potassium acetate, sodium carbonate, or diisopropylethylamine
• a suitable transition metal catalyst for example, a palladium compound.
• Etc. a ligand (such as triphenylphosphine)
• a known reaction promoting additive such as lithium chloride or copper iodide.
• the solvent is a suitable solvent that does not adversely influence the reaction (for example, N, N-dimethylformamide, tetrahydrofuran, toluene, 1,4-dioxane, water, etc.) or a mixed solvent thereof, and the reaction
• the temperature is preferably from 0 ° C to 300 ° C, more preferably from room temperature to 200 ° C.
• the above reaction can also be carried out by treatment in a sealed tube or under microwave irradiation.
• the diboronic acid ester and the like and the base may be used in an amount of 1 to excess molar equivalents, preferably 1 to 5 molar equivalents, relative to compound 11.
• the reaction time is preferably 1 minute to 60 hours, more preferably 5 minutes to 24 hours.
• Conversion from compound 12 to compound 8 is performed by a coupling reaction of compound 12 and compound 13 using a known organic chemical technique.
• an appropriate transition metal catalyst such as a palladium compound
• an organic or inorganic base such as sodium carbonate, potassium carbonate, tripotassium phosphate, diisopropylethylamine, etc.
• a ligand for example, triphenylphosphine
• a known reaction promoting additive for example, lithium chloride or copper iodide
• the solvent is a suitable solvent that does not adversely influence the reaction (for example, N, N-dimethylformamide, tetrahydrofuran, toluene, 1,4-dioxane, water, etc.) or a mixed solvent thereof, and the reaction
• the temperature is preferably from 0 ° C. to 300 ° C., more preferably from room temperature to 200 ° C. (the optimum temperature is from 80 ° C. to 100 ° C.).
• the above reaction can also be carried out by treatment in a sealed tube or under microwave irradiation.
• the compound 13 and the base may be used in an amount of 1 to excess molar equivalents, preferably 1 to 5 molar equivalents, relative to the compound 12, respectively.
• reaction time is preferably 1 minute to 60 hours, more preferably 5 minutes to 24 hours.
• Compound 1a can also be produced via Compound 14 that can be synthesized from Compound 5 and Compound 13 and Compound 12 described above.
• compound 1b in which W is N or CH can be produced by the following [Production Method 7].
• Conversion from compound 15 to compound 16 can be carried out by the same procedure as in the general coupling reaction described in [Production Method 1].
• Conversion from compound 16 to compound 1b can be carried out by the same procedure as in the ordinary amidation reaction described in [Production Method 1].
• compound 1b can be produced even if the order of the reaction of [Production Method 7] is changed.
• [Production Method 8] The details of the reaction are the same as those described in [Production Method 7].
• [Production Method 9] Compound 5 can be produced using intermediate 18 that can be synthesized with reference to commercially available or reported reports.
• L 3 Represents a leaving group such as a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group.
• Conversion from compound 18 to compound 20 may be carried out by subjecting compound 18 to an alkylation reaction using a known organic chemical technique.
• a suitable solvent for example, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile
• a suitable solvent for example, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile
• a suitable solvent for example, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile
• a mixed solvent thereof for example, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile
• R 7 It is carried out by treatment with a compound 19 having a partial structure containing, for example, an alkyl halide compound or a methanesulfonyloxyalkyl compound, a trifluoromethanesulfonyloxyalkyl compound, a p-toluenesulfonyloxyalkyl compound, or the like.
• Compound 19 and the base may each be used in an amount of 1 to excess molar equivalents, preferably 1 to 5 molar equivalents, relative to Compound 18.
• the reaction time is preferably 1 minute to 72 hours, more preferably 5 minutes to 24 hours.
• Conversion from compound 20 to compound 5 The conversion from the compound 20 to the compound 5 may be performed by a normal hydrolysis reaction.
• the reaction temperature is 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C. in an appropriate solvent (for example, methanol, ethanol, propanol, or water) or a mixed solvent thereof that does not adversely influence the compound 20
• an appropriate solvent for example, methanol, ethanol, propanol, or water
• an appropriate acid for example, sulfuric acid, hydrochloric acid, etc.
• alkali for example, sodium hydroxide, potassium carbonate, etc.
• Suitable acids or alkalis use from 1 to excess molar equivalents relative to compound 20.
• the reaction time is preferably 1 minute to 72 hours, more preferably 5 minutes to 24 hours.
• the conversion from compound 20 to compound 5 is carried out in an appropriate solvent that does not adversely influence the reaction (for example, pyridine, quinoline, N, N-dimethylformamide, acetonitrile, etc.) or a mixed solvent thereof from 1 to an excess molar equivalent. It can also be performed by treating with lithium iodide.
• the reaction temperature is from room temperature to 300 ° C, preferably from room temperature to 150 ° C.
• the reaction time is preferably 1 minute to 72 hours, more preferably 1 hour to 48 hours.
• the compound 18a shown below among the compounds 18 in [Production Method 9] can be produced from an aminotriazole compound 21 and diethyl ethoxymethylenemalonate 22 which can be synthesized on the basis of commercially available or known or reported reports. Conversion of compound 21 to compound 18a is R 2 In the absence of a solvent or a suitable solvent that does not adversely influence the reaction (for example, ethanol, toluene, xylene, diphenyl ether, N, N-dimethylformamide, acetic acid, etc.) or a mixed solvent thereof, It is carried out by treatment with diethyl ethoxymethylenemalonate from °C to 300 °C, preferably from room temperature to 150 °C.
• Diethyl ethoxymethylenemalonate may be used in an amount of 1 to an excess molar equivalent relative to compound 21.
• the reaction time is preferably 1 minute to 72 hours, more preferably 5 minutes to 24 hours.
• Compound 21 in [Production Method 10] can be produced from commercially available carboxylic acid compound 23 and aminoguanidine 24 as shown below. Conversion of compound 23 to compound 21 is R 2 0 to 300 ° C., preferably 0 to 300 ° C. in the absence of a solvent or a suitable solvent that does not adversely influence the reaction (for example, toluene, xylene, bromobenzene, water, etc.) or a mixed solvent thereof. The treatment is carried out at room temperature to 200 ° C.
• Compound 23 may be used in an amount of 1 to excess molar equivalents relative to Compound 24.
• the reaction time is preferably 1 minute to 72 hours, more preferably 5 minutes to 24 hours.
• Compound 21 in [Production Method 10] can also be produced from commercially available carboxylic acid ester 25 and aminoguanidine 24 as shown below.
• Conversion of compound 25 to compound 21 is R 2
• a suitable solvent for example, methanol, ethanol, tetrahydrofuran, etc.
• the compound 25 having a partial structure containing is at 0 ° C. to 300 ° C., preferably at room temperature to 100 ° C. It is carried out by treatment with aminoguanidine 24 or a salt of aminoguanidine 24.
• the reaction can be carried out by adding a base (sodium methoxide, sodium ethoxide, potassium tert-butoxide, pyridine, etc.) as necessary.
• Aminoguanidine 24 or a salt thereof may be used in an amount of 1 to excess molar equivalents, preferably 1 to 5 molar equivalents, relative to compound 25.
• the reaction time is preferably 1 minute to 72 hours, more preferably 5 minutes to 24 hours.
• [Production method 13] OG in compound 21 in [Production Method 11] 1 The compound 21a having the formula: Helvetica Chimica Acta, 1983, 66, 1129; Heterocyclic Chem. , 1984, 21, 61, etc., can be produced from commercially available alcohol 26 and dimethyl cyanocarbonodithioimidate 27.
• Conversion of compound 26 to compound 21a is OG 1
• a suitable solvent for example, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, etc.
• a mixed solvent thereof that does not adversely affect the reaction of the compound 26 having a partial structure containing, a base (sodium hydride, In the presence of potassium tert-butoxide, etc.) at ⁇ 30 ° C. to 200 ° C., preferably 0 ° C.
• Compound 26 may be used in an amount of 1 to excess molar equivalents, preferably 1 to 5 molar equivalents, relative to Compound 27.
• the base may be used in an amount of 1 to excess molar equivalents, preferably 1 to 2 molar equivalents, relative to compound 27.
• Hydrazine may be used in an amount of 1 to excess molar equivalents, preferably 1 to 1.5 molar equivalents, relative to compound 27.
• the compound 7a shown below among the compounds 7 can manufacture more commercially available or well-known boronic acid ester 28.
• L 4 represents a leaving group such as a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group.
• Ar-H represents a phenyl group having a hydroxyl group or a pyrazolyl group in which one nitrogen atom of a pyrazole ring is substituted with a hydrogen atom.
• Conversion from compound 28 to compound 7a may be carried out by subjecting compound 28 to an alkylation reaction using a known organic chemical technique.
• an organic or inorganic base (potassium carbonate, cesium carbonate, potassium) in a suitable solvent (for example, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile) or a mixed solvent thereof that does not adversely influence the compound 28.
• tert-butoxide or triethylamine in the presence of -30 ° C to 300 ° C, preferably 0 ° C to 100 ° C. 2 It is carried out by treating with a compound 29 (for example, an alkyl halide compound or a methanesulfonyloxyalkyl compound, a trifluoromethanesulfonyloxyalkyl compound, a p-toluenesulfonyloxyalkyl compound, etc.) having a partial structure containing Compound 29 and the base may be used in an amount of 1 to excess molar equivalents, preferably 1 to 5 molar equivalents, relative to Compound 28, respectively.
• a compound 29 for example, an alkyl halide compound or a methanesulfonyloxyalkyl compound, a trifluoromethanesulfonyloxyalkyl compound, a p-toluenesulfonyloxyalkyl compound, etc
• the reaction time is preferably 1 minute to 72 hours, more preferably 5 minutes to 24 hours.
• Production raw materials 2, 10 or 15 are commercially available or can be synthesized according to known methods.
• Production raw materials 3 and 28 are commercially available or can be synthesized according to a method described in the literature (Bioorg. Med. Chem. Lett., 2007.17.5406-5409, etc.).
• Production raw materials 7, 18, and 21 are commercially available or publicly known, or can be synthesized according to the methods described in the examples.
• Production raw materials 13, 19, 23, 25, 26 and 29 are commercially available or can be synthesized according to known methods.
• Axl inhibitors are diseases caused by Axl kinase hyperfunction, diseases associated with Axl kinase hyperfunction, and / or Axl kinase. Useful for the treatment of diseases with hyperfunction.
• Diseases caused by increased Axl kinase function, diseases associated with increased Axl kinase function, diseases associated with increased Axl kinase function include diseases having tissues in which overexpression of Axl gene and / or protein is observed, Axl phosphorus Examples include diseases having tissues in which an increase in oxidative activity is observed. Examples of the above diseases include, for example, hyperproliferative diseases. Examples of hyperproliferative diseases include endometrial hyperplasia, thrombin-induced vascular smooth muscle cell (VSMC) proliferative benign tumor, malignant tumor (cancer). Include, but are not limited to, acute and chronic glomerulonephritis, diabetic nephropathy, and the like.
• VSMC thrombin-induced vascular smooth muscle cell
• Axl is immune (Non-patent document 12), platelet function (Non-patent document 13), spermatogenesis (Non-patent document 14), vascular calcification (Non-patent document 15), (Non-patent document 16) and various It has also been shown to have a role in kidney disease, chronic allograft rejection (Non-Patent Document 17) and Axl inhibitors include but are not limited to vascular diseases (including but not limited to thrombosis, atherosclerosis and restenosis).
• disorders in which disordered angiogenesis is critical including but not limited to diabetic retinopathy, retinopathy, psoriasis, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangioma).
• the compounds of the present invention inhibit Axl, they are useful for the treatment of the diseases described above. More preferably, the compounds of the invention are useful for the treatment of various cancers.
• cancer examples include breast cancer, colon cancer, prostate cancer, lung cancer, stomach cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, renal cancer, hepatocellular carcinoma, thyroid cancer, esophageal cancer, squamous cell carcinoma , Leukemia, osteosarcoma, melanoma, glioblastoma, neuroblastoma, ovarian cancer, head and neck cancer, testicular tumor, colon cancer, blood cancer, retinoblastoma, pancreatic cancer, etc. It is not limited to. Regarding the relationship between cancer and Axl, various reports have been made from the viewpoints of inhibition of growth, inhibition of metastasis / movement / invasion, and release of drug resistance.
• Axl inhibitors are useful for inhibiting cell growth in cancer.
• Axl has been reported to promote cell invasion (Tai et al., Oncogene 2008, 27, 4044). It has been reported that R-428, an Axl inhibitor, inhibited a diffusion model of metastatic breast cancer (Holland et al., Cancer Res 2010, 70, 1544). It has been reported that Axl antibody, Axl shRNA and Axl inhibitor NA80x1 inhibited breast cancer cell migration and invasion (Yi-Xiang et al., Cancer Res 2008, 68 1905). In addition, it has been reported that Axl is involved in metastasis and malignancy of prostate cancer, spleen cancer, metastatic ovarian cancer, thymic cancer and the like.
• Axl inhibitors are useful for cancer metastasis, cell migration, inhibition of invasion, treatment, prevention and the like.
• an Axl inhibitor has released imatinib resistance in gastric cancer (Mahadevan et al., Oncogene 2007, 26, 3909).
• Axl is shown to be induced in acute myeloid leukemia in resistance to chemotherapeutic agents such as doxorubicin, VP16, cisplatin (Hong et al., Cancer Letters 2008, 268, 314).
• Axl activation is seen in lapatinib resistance in HER-2 positive breast cancer cells (Liu et al., Cancer Res 2009, 69, 6871).
• Axl has been reported to be involved in the PLX4032 (vemurafenib) resistance mechanism (Johannessen et al., Nature 2010, 468, 968).
• Axl is involved in resistance to temozolomode, carboplatin, and vincristine (AK Keating et al., Mol Cancer Ther 2010, 9 (5), 1298). From these reports, it is clear that Axl inhibitors are useful for releasing drug resistance, for example, releasing resistance to various anticancer agents.
• Axl has been reported to be involved in renal fibrosis such as kidney fibrosis and diabetic nephropathy (Japanese translations of publication 2005-517412), and the Axl inhibitor is the above-mentioned renal disease and other idiopathic pulmonary fibrosis. It is clear that it is useful for the treatment of fibrotic diseases such as
• the Axl inhibitory activity of a compound can be measured by, for example, the method described in Test Examples of the present application, but is not limited thereto. Cell growth inhibitory activity can be examined using a growth inhibition test method commonly used by those skilled in the art. Cell growth inhibitory activity can be performed by comparing the extent of cell (eg, tumor cell) growth in the presence or absence of the test compound.
• the degree of proliferation can be examined, for example, using a test system that measures live cells.
• a test system that measures live cells.
• a method for measuring living cells for example, [ 3 H] -thymidine incorporation test, BrdU method, MTT assay and the like.
• the antitumor activity in vivo can be investigated using the antitumor test method normally used by those skilled in the art. For example, various tumor cells are transplanted into mice, rats, etc., and after the engraftment of the transplanted cells is confirmed, the compound of the present invention is administered orally, intravenously, etc. The in vivo antitumor activity of the present invention can be confirmed by comparing the tumor growth in and the compound administration group.
• the pharmaceutical composition of the present invention comprises the compound of the present invention and a pharmaceutically acceptable carrier, and is used as various injections such as intravenous injection, intramuscular injection, subcutaneous injection, or oral administration or transdermal administration. Administration can be by a variety of methods.
• a pharmaceutically acceptable carrier is a pharmaceutically acceptable material involved in transporting a compound of the present invention or a composition comprising a compound of the present invention from one organ or organ to another. (For example, excipient, diluent, additive, solvent, etc.).
• an appropriate preparation for example, oral preparation or injection
• the preparation can be prepared by various preparation preparations which are usually used.
• oral preparations include tablets, powders, granules, capsules, pills, troches, solutions, syrups, elixirs, emulsions, and oily or aqueous suspensions.
• oral administration it may be in the free form or in the salt form.
• Aqueous preparations can be prepared by forming an acid adduct with a pharmaceutically acceptable acid or by forming an alkali metal salt such as sodium.
• stabilizers, preservatives or solubilizers can be used in the preparation.
• a solution that may contain these adjuvants and the like may be stored in a container and then prepared as a solid preparation by lyophilization or the like. Moreover, the single dose may be stored in one container, and the multiple doses may be stored in one container.
• solid preparations include tablets, powders, granules, capsules, pills, or lozenges. These solid preparations may contain pharmaceutically acceptable additives together with the compound of the present invention. Examples of the additive include fillers, extenders, binders, disintegrants, dissolution accelerators, wetting agents, and lubricants, which are selected and mixed as necessary. And can be formulated. Examples of the liquid preparation include solutions, syrups, elixirs, emulsions, and suspensions.
• liquid formulations may contain pharmaceutically acceptable additives along with the compounds of the present invention.
• the additive include a suspending agent or an emulsifier, and these can be selected and mixed as necessary to prepare a formulation.
• the compounds of the present invention can be used for the treatment of cancer in mammals, particularly humans.
• the dose and administration interval can be appropriately selected according to the judgment of the doctor according to the location of the disease, the height, weight, sex, or medical history of the patient.
• the dosage range is about 0.01 mg / kg body weight to about 500 mg / kg body weight, preferably about 0.1 mg / kg body weight to about 100 mg / kg body weight per day. It is.
• the compound of the present invention may be used in combination with other antitumor agents.
• antitumor antibiotics for example, antitumor antibiotics, antitumor plant components, BRM (biological response control substances), hormones, vitamins, antitumor antibodies, molecular targeted drugs, other antitumor agents and the like can be mentioned.
• examples of the alkylating agent include an alkylating agent such as nitrogen mustard, nitrogen mustard N-oxide or chlorambutyl, an aziridine alkylating agent such as carbocon or thiotepa, dibromomannitol or dibromodarsi
• alkylating agent such as nitrogen mustard, nitrogen mustard N-oxide or chlorambutyl
• an aziridine alkylating agent such as carbocon or thiotepa, dibromomannitol or dibromodarsi
• examples thereof include epoxide-based alkylating agents such as Toll, carmustine, lomustine, semustine, nimustine hydrochloride, nitrosourea-based alkylating agents such as streptozocin, chlorozotocin or ranimustine, busulfan, improsulfan tosylate or dacarbazine.
• antimetabolites include, for example, purine antimetabolites such as 6-mercaptopurine, 6-thioguanine or thioinosine, and pyrimidine metabolism antagonists such as fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine or enocytabine And antifolate inhibitors such as methotrexate or trimethrexate.
• purine antimetabolites such as 6-mercaptopurine, 6-thioguanine or thioinosine
• pyrimidine metabolism antagonists such as fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine or enocytabine
• antifolate inhibitors such as methotrexate or trimethrexate.
• Antitumor antibiotics include, for example, anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4′-epidoxorubicin or epirubicin, chromomycin A3 Or actinomycin D etc. are mentioned.
• Examples of the antitumor plant component include vinca alkaloids such as vindesine, vincristine or vinblastine, taxanes such as paclitaxel and docetaxel, and epipodophyllotoxins such as etoposide or teniposide.
• BRM examples include tumor necrosis factor or indomethacin.
• the hormone include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, plasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, methenolone, phosfestol, ethinyl estradiol, chlormadinone or medroxyprogesterone.
• vitamins include vitamin C and vitamin A.
• Anti-tumor antibodies and molecular targeted drugs include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, imatinib mesylate, gefitinib, erlotinib, sunitinib, lapatinib, dalatinib, satinib
• antitumor agents include cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, acecraton, schizophyllan, picibanil, procarbazine, pipobroman, neocartinostatin, Examples include hydroxyurea, ubenimex, and krestin.
• the present invention also includes a method for preventing and / or treating cancer, which comprises administering the compound of the present invention or a salt thereof. Furthermore, the present invention includes the use of the compound of the present invention, a salt thereof or a solvate thereof for producing the medicament.
• the present invention will be specifically described with reference to the following examples. However, the present invention is not limited to these examples, and is not construed as being limited in any way.
• reagents, solvents and starting materials not particularly described are readily available from commercially available sources.
• the present invention will be specifically described with reference to the following examples. However, the present invention is not limited to these examples, and is not construed as being limited in any way.
• reagents, solvents and starting materials not specifically mentioned herein are known in the report or are readily available from commercial sources.
• Step 3 4- (4-Fluorobenzyl) -7-oxo-4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxylic acid
• Ethyl 7-oxo-4,7-dihydropyrazole [1,5-a] pyrimidine-6-carboxylate (100 mg) was suspended in DMF (2 ml), potassium carbonate (167 mg), 4-fluorobenzyl bromide (71 ⁇ l). Were sequentially added and stirred at 50 ° C. for 13 hours. Water was added to the reaction solution, followed by stirring at 80 ° C. for 9 hours.
• Step 4 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -4- (4-fluorobenzyl) -7-oxo -4,7-dihydropyrazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 139 mg
• Example 2 [Step 1] 4-Benzyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (75 mg) is suspended in DMF (1 ml), potassium carbonate (65 mg), benzyl Bromide (53 ⁇ l) was sequentially added and stirred at 50 ° C. for 14 hours. 1N Aqueous sodium hydroxide solution (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 4 hr.
• Step 2 N- ⁇ 4- [2-Amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -4-benzyl-7-oxo-4,7- Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• DMF 2 ml
• EDC ⁇ HCl 69 mg
• Example 3 [Step 1] 4- (4-Fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyridine-6-carboxylate (100 mg) was suspended in DMF (1 ml) and potassium carbonate (86 mg), 4 -Fluorobenzyl bromide (71 ⁇ l) was sequentially added and stirred at 50 ° C. for 10 hours.
• Step 2 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -4- (4-fluorobenzyl) -7-oxo -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 101 mg was added at room temperature. After stirring at 50 ° C.
• Example 4 [Step 1] 4-Benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid Ethyl 2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (100 mg) was suspended in DMF (1 ml) and potassium carbonate ( 81 mg) and benzyl bromide (64 ⁇ l) were sequentially added, and the mixture was stirred at 50 ° C. for 3 hours.
• Step 2 N- ⁇ 4- [2-Amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -4-benzyl-2-methyl-7-oxo- 4,7-Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 61 mg was added at room temperature. After stirring at 50 ° C.
• Example 5 [Step 1] 4- (4-Fluorobenzyl) -2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid Ethyl 2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (75 mg) was suspended in DMF (1 ml) and potassium carbonate ( 61 mg) and 4-fluorobenzyl bromide (50 ⁇ l) were sequentially added, and the mixture was stirred at 50 ° C. for 14 hours.
• Step 2 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -4- (4-fluorobenzyl) -2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 82 mg was added at room temperature. After stirring at 50 ° C.
• Example 6 Ethyl 2-ethyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate 5-ethyl-4H-1,2,4-triazol-3-amine (50 mg) and diethyl ethoxymethylenemalonate (90 ⁇ l) were added to acetic acid (1 ml), and the mixture was heated to reflux for 5 hours. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 72 mg of the title compound. MS (ESI) m / z: 237 (M + H) + .
• Step 2 2-Ethyl-4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid
• DMF dimethyl methacrylate
• 105 mg potassium carbonate
• 4-fluorobenzyl bromide 45 ⁇ l
• Example 7 Ethyl 7-oxo-2- (propan-2-yl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate 5-Isopropyl-4H-1,2,4-triazol-3-amine (50 mg) and diethyl ethoxymethylenemalonate (80 ⁇ l) were added to acetic acid (1 ml), and the mixture was heated to reflux for 19 hours. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 63 mg of the title compound. MS (ESI) m / z: 251 (M + H) + .
• Step 2 4- (4-Fluorobenzyl) -7-oxo-2- (propan-2-yl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6 -Carboxylic acid
• DMF dimethyl methacrylate
• 86 mg potassium carbonate
• 4-fluorobenzyl bromide 37 ⁇ l
• Example 8 [Step 1] Ethyl 2- (methoxymethyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate Aminoguanidine bicarbonate (1.0 g) and methoxyacetic acid (0.61 ml) were heated to reflux in bromobenzene (1 ml) for 3 days. Thereafter, the concentrated residue and diethyl ethoxymethylenemalonate (1.48 ml) were added to acetic acid (10 ml), and the mixture was heated to reflux for 19 hours.
• Step 3 N- ⁇ 4- [2-Amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -4-benzyl-2- (methoxymethyl) -7 -Oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 55 mg was added at room temperature. After stirring at 50 ° C.
• Example 9 [Step 1] 4- (4-Fluorobenzyl) -2- (methoxymethyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid
• the compound (50 mg) obtained in Step 1 of Example 8 was suspended in DMF (1 ml), potassium carbonate (36 mg) and 4-fluorobenzyl bromide (29 ⁇ l) were successively added, and the mixture was stirred at 50 ° C. for 5 hours.
• 1N aqueous sodium hydroxide solution (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 9 hours.
• Example 10 [Step 1] Ethyl [2-cyclopropyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate 5-cyclopropyl-4H-1,2,4-triazol-3-amine (50 mg) and diethyl ethoxymethylenemalonate (81 ⁇ l) were added to acetic acid (1 ml), and the mixture was heated to reflux for 5 hours. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 74 mg of the title compound. MS (ESI) m / z: 249 (M + H) + .
• Step 2 2-Cyclopropyl-4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid
• DMF dimethyl methoxylate
• potassium carbonate 103 mg
• 4-fluorobenzyl bromide 44 ⁇ l
• Example 11 Ethyl 2-cyclobutyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate 5-cyclobutyl-4H-1,2,4-triazol-3-amine (50 mg) and diethyl ethoxymethylenemalonate (73 ⁇ l) were added to acetic acid (1 ml), and the mixture was heated to reflux for 19 hours. Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 68 mg of the title compound. MS (ESI) m / z: 263 (M + H) + .
• Example 12 [Step 1] Ethyl 2- (methylsulfanyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate Hydrazine monohydrate (25 ⁇ l) was added to ethanol (1 ml) of dimethyl cyanocarbonodithioimidate (50 mg), and the mixture was heated to reflux for 2 hours. Diethyl ethoxymethylenemalonate (104 ⁇ l) and acetic acid (2 ml) were added to the residue obtained by removing the reaction solution under reduced pressure, and the mixture was refluxed for 13 hours.
• Step 2 4- (4-Fluorobenzyl) -2- (methylsulfanyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid
• DMF dimethylsulfanyl
• 4-fluorobenzyl bromide (16 ⁇ l) were sequentially added, and the mixture was stirred at 50 ° C. for 1.5 hours.
• Step 3 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -4- (4-fluorobenzyl) -2- ( Methylsulfanyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 22 mg
• Example 13 Ethyl 2- (dimethylamino) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate To a THF solution (1 ml) of dimethyl cyanocarbonodithioimidate (200 mg) was added 2N dimethylamine tetrahydrofuran solution, and the mixture was stirred at room temperature for 3 hours. Thereafter, ethanol (1 ml) and hydrazine monohydrate (100 ⁇ l) were added, and the mixture was heated to reflux for 5 hours.
• Step 2 2- (Dimethylamino) -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid
• DMF dimethylamino
• potassium carbonate 36 mg
• 4-fluorobenzyl bromide 29 ⁇ l
• a 1N aqueous sodium hydroxide solution (1 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 3 hours.
• Step 3 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -2- (dimethylamino) -4- (4- Fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 43 mg
• Example 14 [Step 1] 4- (2-Fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) suspended in DMF (1 ml), potassium carbonate (43 mg), 2 -Fluorobenzyl bromide (35 ⁇ l) was sequentially added and stirred at 50 ° C. for 8 and a half hours.
• Step 2 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -4- (2-fluorobenzyl) -7-oxo -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 69 mg was added at room temperature. After stirring at 50 ° C.
• Example 15 [Step 1] 4- (2-Methylbenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) suspended in DMF (1 ml), potassium carbonate (43 mg), 1 -(Bromomethyl) -2-methylbenzene (39 ⁇ l) was sequentially added, and the mixture was stirred at 50 ° C. for 8 and a half hours.
• Step 2 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -4- (2-methylbenzyl) -7-oxo -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 69 mg
• Example 16 [Step 1] 4- (2-Methoxybenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) suspended in DMF (1 ml), potassium carbonate (43 mg), 2 -Methoxybenzyl chloride (40 ⁇ l) was sequentially added and stirred at 50 ° C. for 8 and a half hours.
• Step 2 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -4- (2-methoxybenzyl) -7-oxo -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 69 mg was added at room temperature. After stirring at 50 ° C.
• Example 17 [Step 1] 4- (2,4-Difluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (75 mg) is suspended in DMF (1 ml), potassium carbonate (65 mg), 2 , 4-Difluorobenzyl bromide (56 ⁇ l) was sequentially added and stirred at 50 ° C. for 13 hours.
• Step 2 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -4- (2,4-difluorobenzyl) -7 -Oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 75 mg
• Example 18 [Step 1] Ethyl 7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) is suspended in DMF (1 ml), potassium carbonate (83 mg), 2 -(Bromomethyl) pyridine hydrobromide (73 mg) was sequentially added, and the mixture was stirred at 50 ° C. for 13 hours.
• Example 19 [Step 1] 4-[(6-Methylpyridin-2-yl) methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid ethyl Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (100 mg) suspended in DMF (1 ml), potassium carbonate (86 mg), 2 -(Bromomethyl) -6-methylpyridine (107 mg) was sequentially added, and the mixture was stirred at 70 ° C for 9 and a half hours.
• Step 2 4-[(6-Methylpyridin-2-yl) methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid
• Ethanol (1 ml) and 1N aqueous sodium hydroxide solution (0.5 ml) were added to the compound (75 mg) obtained in Step 1 above, and the mixture was stirred at room temperature for 2 hours.
• 1N Aqueous hydrochloric acid solution was added, and the solvent was evaporated under reduced pressure to give the title compound as a crude product.
• Step 3 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -4-[(6-methylpyridin-2-yl) ) Methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 69 mg
• Example 20 [Step 1] Ethyl 7-oxo-4- (1H-pyrazol-1-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) is suspended in DMF (1 ml), potassium carbonate (83 mg), 1 -(Chloromethyl) -1H-pyrazole hydrochloride (44 mg) was sequentially added and stirred at 50 ° C. for 14 hours.
• Step 2 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -7-oxo-4- (1H-pyrazole-1 -Ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• Lithium iodide 28 mg was added to a pyridine (1 ml) solution of the compound obtained in the above Step 1 (69 mg) and heated under reflux for 19 hours, and then the solvent was distilled off under reduced pressure.
• Example 21 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -1-benzyl-4-oxo-1,4-dihydropyrimido [ 1,2-a] benzimidazole-3-carboxamide
• Ethyl 4-oxo-1,4-dihydropyrimido [1,2-a] benzimidazole-3-carboxylate (30 mg) was suspended in DMF (1 ml), and potassium carbonate (21 mg) and benzyl bromide (17 ⁇ l) were suspended. Sequentially added and stirred at 80 ° C. for 15 hours.
• Ethanol (2 ml) and 1N aqueous sodium hydroxide solution (1 ml) were added to the reaction solution, and the mixture was stirred at 80 ° C. for 8 hours.
• 1N hydrochloric acid was added to the reaction solution and filtered.
• EDC ⁇ HCl 32 mg was added at room temperature to a DMF (1 ml) solution of the compound (30 mg) obtained in Step 2 of Example 1 and HOBt (15 mg). After stirring at 50 ° C. for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate.
• Example 22 [Step 1] 3- (4-Aminophenyl) -5- ⁇ 1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl ⁇ pyridin-2-amine
• Compound (1 g) obtained in Step 1 of Example 1 1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-4-pyrazole boronic acid pinacol ester (1.39 g), tetrakis ( Triphenylphosphine) palladium (0.23 g) and potassium carbonate (1.62 g) were suspended in dioxane (20 ml) and water (2 ml), and the mixture was heated to reflux at 100 ° C.
• Step 2 N- [4- (2-amino-5- ⁇ 1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl ⁇ pyridin-3-yl) Phenyl] -4-benzyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 83 mg
• Step 3 N- (4- ⁇ 2-amino-5- [1- (2-hydroxyethyl) -1H-pyrazol-4-yl] pyridin-3-yl ⁇ phenyl) -4-benzyl-7-oxo -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide 1N Hydrochloric acid (1 ml) was added to a THF (2 ml) solution of the compound (110 mg) obtained in Step 2 above at room temperature. After stirring at room temperature for 13 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate.
• Example 23 [Step 1] N- [4- (2-amino-5- ⁇ 1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl ⁇ pyridin-3-yl) Phenyl] -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide To a solution of the compound (70 mg) obtained in Step 1 of Example 3 and the compound (92 mg) obtained in Step 1 of Example 22 and HOBt (34 mg) in DMF (2 ml), EDC ⁇ HCl (70 mg) was added at room temperature. It was.
• Step 2 N- (4- ⁇ 2-amino-5- [1- (2-hydroxyethyl) -1H-pyrazol-4-yl] pyridin-3-yl ⁇ phenyl) -4- (4-fluorobenzyl ) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide 1N Hydrochloric acid (1 ml) was added to a THF (2 ml) solution of the compound obtained in Step 1 above (92 mg) at room temperature. After stirring at 50 ° C.
• Example 24 [Step 1] N- [4- (2-Amino-5-bromopyridin-3-yl) phenyl] -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] Triazolo [1,5-a] pyrimidine-6-carboxamide To a solution of the compound (0.90 g) obtained in Step 1 of Example 1 and the compound (0.97 g) obtained in Step 1 of Example 4 in DMF (50 ml), EDC.HCl (0.85 g) and HOBt (0 .68 g) was added and stirred at 50 ° C. for 1 hour.
• Example 26 [Step 1] N- [4- (2-amino-5- ⁇ 1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl ⁇ pyridin-3-yl) Phenyl] -4-benzyl-2- (methoxymethyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide To a solution of the compound obtained in Step 2 of Example 8 (60 mg) and the compound obtained in Step 1 of Example 22 (73 mg) and HOBt (27 mg) in DMF (2 ml), EDC ⁇ HCl (55 mg) was added at room temperature.
• Step 2 N- (4- ⁇ 2-amino-5- [1- (2-hydroxyethyl) -1H-pyrazol-4-yl] pyridin-3-yl ⁇ phenyl) -4-benzyl-2- ( Methoxymethyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide 1N Hydrochloric acid (1 ml) was added to a THF (2 ml) solution of the above compound (89 mg) obtained in the above Step 1 at room temperature.
• Example 27 [Step 1] 3- (4-Aminophenyl) -5- ⁇ 1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl ⁇ pyridin-2-amine 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (10 g) was added to a suspension of cesium carbonate (75.6 g) in dioxane (200 ml).
• Example 28 N- [4- (2-amino-5- ⁇ 1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl ⁇ pyridin-3-yl) phenyl] -4- (4-Fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide Ethyl 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (50 mg) was suspended in DMF (1 ml), and potassium carbonate (43 mg), 4 -Fluorobenzyl bromide (35 ⁇ l) was sequentially added and stirred at 50 ° C.
• Example 29 N- [4- (2-amino-5- ⁇ 1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl ⁇ pyridin-3-yl) phenyl] -4- Benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 48 mg
• HOBt 3.5 mg
• Example 31 Ethyl 2-methoxy-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate
• a methanol solution (10 ml) of dimethyl cyanocarbonodithioimidate (1.00 g) was added 28% sodium methoxide methanol solution (2.64 g) at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour.
• pyridine hydrochloride (1.74 g) was added and stirred at 0 ° C. for 1 hour.
• To the reaction solution was added hydrazine monohydrate (498 ⁇ l), and the mixture was heated to reflux for 6 hours.
• Step 3 N- [4- (2-amino-5- ⁇ 1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl ⁇ pyridin-3-yl) phenyl ] -4-Benzyl-2-methoxy-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• a 1N aqueous sodium hydroxide solution (0.21 ml) was added to an ethanol (1 ml) solution of the compound obtained in the above step 2 (57 mg) and the mixture was stirred at room temperature for 2 hours.
• Example 32 [Step 1] Ethyl 2-methoxy-7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate The compound (101 mg) obtained in Step 1 of Example 31 was suspended in DMF (1 ml), and potassium carbonate (146 mg), 2- (bromomethyl) pyridine hydrobromide (60 mg) were successively added at 50 ° C. Stir for 8 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate.
• Step 2 N- [4- (2-amino-5- ⁇ 1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl ⁇ pyridin-3-yl) phenyl ] -2-Methoxy-7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• 1N aqueous sodium hydroxide solution (0.15 ml) and stirred at room temperature for 2 hours, and then 1N aqueous hydrochloric acid solution was added, followed by extraction with dichloromethane.
• Step 2 Ethyl 4-benzyl-2-ethoxy-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate
• DMF 10 ml
• potassium carbonate 356 mg
• benzyl bromide 283 ⁇ l
• a saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate.
• Step 3 4-Benzyl-2-ethoxy-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid
• Ethanol (4 ml) and 1N aqueous sodium hydroxide solution (0.88 ml) were sequentially added to the compound obtained in Step 2 (200 mg), and the mixture was stirred at 50 ° C. for 3 hours.
• To the reaction solution was added 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 151 mg of the title compound.
• Example 34 Ethyl 2-ethoxy-7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate
• the compound (500 mg) obtained in Step 1 of Example 33 was suspended in DMF (10 ml), and potassium carbonate (685 mg), 2- (bromomethyl) pyridine hydrobromide (602 mg) were successively added at 50 ° C. Stir for 6 hours.
• a saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate.
• Step 2 N- [4- (2-amino-5- ⁇ 1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl ⁇ pyridin-3-yl) phenyl ] -2-Ethoxy-7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide 1N Aqueous sodium hydroxide solution (0.22 ml) was added to an ethanol (2 ml) solution of the compound obtained in step 1 above (75 mg) and stirred at room temperature for 3 hours, and then the solvent was distilled off under reduced pressure.
• Example 35 [Step 1] 1-[(2R) -1,4-dioxan-2-ylmethyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H -Pyrazole 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (200 mg) is dissolved in THF, and potassium tert-butoxide (150 mg) is added to room temperature. And stirred for 30 minutes.
• the obtained organic layer was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 275 mg of a crude product of the title compound as an oily substance.
• Step 2 N- [4- (2-amino-5- ⁇ 1-[(2R) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl ⁇ pyridin-3-yl) phenyl ] -4-Benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide Using the compound (200 mg) obtained in Step 1 of Example 24 and the compound (166 mg) obtained in Step 1 above, synthesis was performed in the same manner as in Step 2 of Example 24 to obtain 130 mg of the title compound as a solid.
• Example 36 [Step 1] 1- (2-Fluoroethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole Solution of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (300 mg) and 1-fluoro-2-iodoethane (350 mg) in dioxane (10 ml) Was added cesium carbonate (755 mg), and the mixture was stirred at room temperature for 22 hours. The insoluble material was removed by filtration, and the filtrate was evaporated under reduced pressure.
• Example 37 [Step 1] 1- (2-methoxyethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole Performed with 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (300 mg) and 1-bromo-2-methoxyethane (280 mg) Synthesis in the same manner as in Step 1 of Example 36 gave 320 mg of the title compound as a solid.
• Step 2 N- (4- ⁇ 2-amino-5- [1- (2-methoxyethyl) -1H-pyrazol-4-yl] pyridin-3-yl ⁇ phenyl) -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• synthesis was performed in the same manner as in Step 2 of Example 24 to obtain 40 mg of the title compound as a solid.
• Example 38 [Step 1] tert-butyl 4- ⁇ 4- [6-amino-5- (4- ⁇ [(4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidin-6-yl) carbonyl] amino ⁇ phenyl) pyridin-3-yl] -1H-pyrazol-1-yl ⁇ piperidine-1-carboxylate
• the compound (75 mg) obtained in Step 1 of Example 24 and tert-butyl 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole Synthesis was performed in the same manner as in Step 2 of Example 24 using [-1-yl] piperidine-1-carboxylate (59 mg) to obtain 133 mg of a crude product of the title compound as an oily substance.
• Example 39 [Step 1] tert-butyl 2-methyl-2- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl] propanoate Using 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (300 mg) and tert-butyl 2-bromoisobutyrate (517 mg), Synthesis was performed in the same manner as in Step 1 of Example 36 to obtain 178 mg of the title compound as a solid.
• Example 40 N- ⁇ 4- [2-amino-5- (1- ⁇ 2-[(3R) -3-hydroxypyrrolidin-1-yl] -1,1-dimethyl-2-oxoethyl ⁇ -1H-pyrazole-4- Yl) pyridin-3-yl] phenyl ⁇ -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• Step 3 of Example 39 a solution of the compound (60 mg) in DMF (2 ml) was added (R)-( ⁇ )-3-pyrrolidinol monohydrochloride (25 mg), EDC ⁇ HCl (29 mg), HOBt (20 mg), N-methylmorpholine (22 ⁇ l) was added and stirred overnight at room temperature.
• reaction solution was evaporated under reduced pressure, the residue was diluted with water, extracted with chloroform containing 10% methanol, and dried over anhydrous sodium sulfate.
• Step 2 N- ⁇ 4- [2-amino-5- (1- ⁇ [(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl ⁇ -1H-pyrazole-4- Yl) pyridin-3-yl] phenyl ⁇ -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide Using the compound obtained in Step 1 of Example 24 (200 mg) and the compound obtained in Step 1 above (139 mg), the compound was synthesized in the same manner as in Step 2 of Example 24 to obtain 130 mg of the title compound as a solid.
• Example 42 N- [4- (2-amino-5- ⁇ 1-[(2S) -2,3-dihydroxypropyl] -1H-pyrazol-4-yl ⁇ pyridin-3-yl) phenyl] -4-benzyl-2 -Methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• a 4N dioxane hydrochloride (1 ml) solution was added dropwise under ice cooling, followed by stirring at room temperature for 90 minutes.
• Step 2 N- ⁇ 4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl ⁇ -4- (4-fluorobenzyl) -7-oxo-4,7- Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 101 mg was added at room temperature. After stirring at 50 ° C.
• Example 44 N- ⁇ 4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl ⁇ -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2 , 4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 9 mg
• Example 46 [Step 1] 4-[(3-Fluoropyridin-2-yl) methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylic acid ethyl
• thionyl chloride 86 ⁇ l
• Example 47 [Step 1] 2-Methyl-4-[(6-methylpyridin-2-yl) methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine- 6-ethyl carboxylate 2-Methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate (500 mg) was suspended in DMF (10 ml) and 2- ( Bromomethyl) -6-methylpyridine (502 mg) and potassium carbonate (404 mg) were sequentially added, and the mixture was stirred at 70 ° C. for 3 hours.
• Step 2 N- ⁇ 4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl ⁇ -2-methyl-4-[(6-methylpyridin-2-yl) Methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide 1N
• Aqueous sodium hydroxide solution (0.23 ml) was added to a solution of the compound obtained in Step 1 (75 mg) in ethanol (1 ml), stirred at room temperature for 2 hours, and concentrated under reduced pressure.
• Step 2 N- ⁇ 4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl ⁇ -2-methyl-7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide 1N aqueous sodium hydroxide solution (0.24 ml) was added to an ethanol (1 ml) solution of the compound obtained in Step 1 (75 mg), and the mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure.
• Example 50 [Step 1] N- [4- (2-Amino-5-bromopyridin-3-yl) phenyl] -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4 ] Triazolo [1,5-a] pyrimidine-6-carboxamide To a solution of the compound (1.3 g) obtained in Step 1 of Example 3 and the compound (1 g) obtained in Step 1 of Example 1 in DMF (13 ml), EDC.HCl (871 mg) and HOBt (58 mg) were added. Stir at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
• Example 51 [Step 1] 3-Bromo-5- ⁇ 4-[(2R) -1,4-dioxan-2-ylmethoxy] -3-methoxyphenyl ⁇ pyridin-2-amine 2-Methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (10.2 g), (2R) -1,4-dioxan-2-ylmethyl Methane sulfonate (8.0 g) and potassium carbonate (11.2 g) were suspended in DMF (200 ml) and stirred at 90 ° C. for 16 hours. After standing to cool, insolubles were removed and the solvent was distilled off under reduced pressure.
• Step 3 3- (4-Aminophenyl) -5- ⁇ 4-[(2R) -1,4-dioxan-2-ylmethoxy] -3-methoxyphenyl ⁇ pyridin-2-amine
• Compound (2.05 g) obtained in Step 2 above 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.14 g), tetrakis (triphenyl) Phosphine) palladium (0.3 g) and potassium carbonate (2.15 g) were suspended in dioxane (30 ml) and water (6 ml), and the mixture was stirred at 100 ° C. for 2 hours.
• Step 4 N- [4- (2-Amino-5- ⁇ 4-[(2R) -1,4-dioxane-2-ylmethoxy] -3-methoxyphenyl ⁇ pyridin-3-yl) phenyl] -4 -(4-Fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide To a solution of the compound obtained in Step 3 (50 mg) and the compound obtained in Step 1 of Example 3 (37 mg) in DMF (1 ml), EDC ⁇ HCl (25 mg) and HOBt (2 mg) were added, and the mixture was allowed to stand at room temperature overnight Stir.
• Step 2 3- (4-Aminophenyl) -5- [3-methoxy-4- (2-pyrrolidin-1-ylethoxy) phenyl] pyridin-2-amine 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) was added to a solution of the compound obtained in Step 1 (375 mg) in dioxane (10 ml) and water (1 ml). Aniline (285 mg), tetrakis (triphenylphosphine) palladium (110 mg) and potassium carbonate (396 mg) were added at room temperature. The reaction mixture was stirred at 100 ° C. for 5 hours. The reaction mixture was returned to room temperature and extracted with chloroform.
• Step 3 N- ⁇ 4- [2-amino-5- [3-methoxy-4- (2-pyrrolidin-1-ylethoxy) phenyl] pyridin-3-yl] phenyl ⁇ -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 57 mg
• Example 54 N- ⁇ 4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl ⁇ -4-benzyl-2-ethoxy-7-oxo-4,7-dihydro [1,2 , 4] triazolo [1,5-a] pyrimidine-6-carboxamide
• a 1N aqueous sodium hydroxide solution (0.26 ml) was added to an ethanol (1 ml) solution of the compound (75 mg) obtained in Step 2 of Example 33, and the mixture was stirred at room temperature for 2 hours. Extracted and dried over sodium sulfate.
• pyridine hydrochloride (869 mg) was added and stirred at 0 ° C. for 1 hour.
• hydrazine monohydrate (249 ⁇ l)
• Diethyl ethoxymethylenemalonate (1.04 ml)
• acetic acid (2 ml) were added to the residue obtained by removing the reaction solution under reduced pressure, and the mixture was heated to reflux for 13 hours.
• Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 70 mg of the title compound.
• Step 2 Ethyl 4-benzyl-2- (2-methoxyethoxy) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate
• DMF dimethyl methoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxyethoxylate
• benzyl bromide 37 ⁇ l
• a saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate.
• Step 3 N- ⁇ 4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl ⁇ -4-benzyl-2- (2-methoxyethoxy) -7-oxo- 4,7-Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• ethanol 1 ml
• 1N aqueous sodium hydroxide solution 0.2 ml
• 1N aqueous hydrochloric acid solution was added, followed by extraction with dichloromethane. Dried over sodium sulfate.
• pyridine hydrochloride (869 mg) was added and stirred at 0 ° C. for 1 hour.
• hydrazine monohydrate (249 ⁇ l)
• Diethyl ethoxymethylenemalonate (1.04 ml)
• acetic acid (2 ml) were added to the residue obtained by removing the reaction solution under reduced pressure, and the mixture was heated to reflux for 13 hours.
• Diisopropyl ether was added to the reaction solution, followed by filtration and washing with diisopropyl ether to obtain 78 mg of the title compound.
• Step 2 Ethyl 4-benzyl-2- (2-fluoroethoxy) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate
• DMF dimethyl methoxyethyl
• potassium carbonate 52 mg
• benzyl bromide 41 ⁇ l
• a saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate.
• Example 57 Ethyl 2- (difluoromethyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate
• ethanol solution (10 ml) of ethyl difluoroacetate (2.00 g) and aminoguanidine sulfate hydrate (3.97 g) was added an ethanol solution of sodium ethoxide (20%, 11.0 g) at room temperature, and 8 ° C. at 8 ° C. Stir for hours. The reaction solution was brought to room temperature, filtered, and the filtrate was concentrated.
• Step 2 Ethyl 4-benzyl-2- (difluoromethyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate
• DMF difluoromethyl
• potassium carbonate 522 mg
• benzyl bromide 414 ⁇ l
• Saturated ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and dried over sodium sulfate.
• Step 3 N- ⁇ 4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] phenyl ⁇ -4-benzyl-2- (difluoromethyl) -7-oxo-4, 7-Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• a 1N aqueous sodium hydroxide solution (0.33 ml) was added to an ethanol (1 ml) solution of the compound obtained in step 2 above (75 mg), and the mixture was stirred at room temperature for 3 hours. Then, a 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with dichloromethane.
• Example 58 [Step 1] 3-Bromo-5-[(trimethylsilyl) ethynyl] pyridin-2-amine To a solution of 3-bromo-5-iodopydin-2-amine (2.56 g) in THF (35 ml), copper (I) iodide (0.31 g), trimethylsilylacetylene (0.93 g), bis (trimethylphosphine) palladium. (II) Dichloride (0.08 g) was added, and triethylamine (15 ml) was added continuously at room temperature, followed by stirring overnight. The reaction solution was diluted with ethyl acetate and washed with water.
• Step 2 3-Bromo-5-ethynylpyridin-2-amine Tetrabutylammonium fluoride (9.10 ml) was added to a THF (30 ml) solution of the compound obtained in Step 1 (2.44 g) in an ice-water bath and stirred at the same temperature for 30 minutes. The reaction solution was diluted with ethyl acetate and washed with water. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.79 g of the title compound as a solid. MS (ESI) m / z: 198 (M + H) + .
• Step 3 3-Bromo-5- ⁇ 1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-1,2,3-triazol-4-yl ⁇ pyridin-2-amine
• (2R) -1,4-dioxan-2-ylmethyl methanesulfonate 216 mg
• DMSO DMSO
• sodium azide 93 mg
• the compound obtained in Step 2 (217 mg) and copper (I) iodide (63 mg) were added to the reaction solution, and the mixture was stirred at 80 ° C. for 3 hours.
• Step 4 3- (4-aminophenyl) -5- ⁇ 1-[(2S) -1,4-dioxane-2-ylmethyl] -1H-1,2,3-triazol-4-yl ⁇ pyridine- 2-Amine
• a solution of the compound obtained in Step 3 (341 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (120 mg) in dioxane (10 ml) was added water ( 1 ml), potassium carbonate (230 mg), tetrakis (triphenylphosphine) palladium (60 mg) were added, and the mixture was stirred at 100 ° C. for 2.3 hours.
• Example 60 [Step 1] 5- (4-Aminophenyl) -2'-methyl-3,4'-bipyridin-6-amine The compound (2.0 g) obtained in Step 1 of Example 1 and 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (1. 66 g) was used as a starting material and the title compound (871 mg) was obtained as a solid by the same reaction as in Step 2 of Example 1.
• Example 61 N- ⁇ 4- [2-amino-5- (3,6-dihydro-2H-pyran-4-yl) pyridin-3-yl] phenyl ⁇ -4-benzyl-2-methyl-7-oxo-4, 7-Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide Compound (150 mg) obtained in Step 1 of Example 24 and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydro-2H-pyran Water (0.5 ml), cesium carbonate (120 mg) and tetrakis (triphenylphosphine) palladium (33 mg) were added to a solution of (62 mg) in ethylene glycol dimethyl ether (4 ml), and the mixture was stirred at 100 ° C.
• Example 62 [Step 1] tert-Butyl 6-amino-5-bromo-3 ', 6'-dihydro-3,4'-bipyridine-1' (2'H) -carboxylate 3-Bromo-5-iodopyridin-2-amine (460 mg) and tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6- Water (2 ml), potassium carbonate (280 mg), tetrakis (triphenylphosphine) palladium (180 mg) were added to a dioxane (8 ml) solution of dihydropyridine-1 (2H) -carboxylate (500 mg), and the mixture was stirred at 80 ° C.
• Step 2 tert-Butyl 6-amino-5- (4-aminophenyl) -3 ', 6'-dihydro-3,4'-bipyridine-1' (2'H) -carboxylate
• a solution of the compound obtained in Step 1 (485 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (600 mg) in dioxane (8 ml) was added water ( 2 ml), potassium carbonate (280 mg), tetrakis (triphenylphosphine) palladium (160 mg) were added, and the mixture was stirred at 100 ° C. for 7 hours. The mixture was allowed to cool and diluted with chloroform.
• Step 3 tert-butyl 6-amino-5- [4-( ⁇ [4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5- a] pyrimidin-6-yl] carbonyl ⁇ amino) phenyl] -3 ′, 6′-dihydro-3,4′-bipyridine-1 ′ (2′H) -carboxylate 1H-benzotriazol-1-yloxytri (1-pyrrolidinyl) phosphonium hexafluorophosphate (1 ml) in a DMF (1 ml) solution of the compound obtained in Step 2 above (100 mg) and the compound obtained in Step 1 of Example 3 (78 mg) 160 mg) and stirred at room temperature for 17 hours.
• Example 64 [Step 1] tert-butyl 6-amino-5- (4- ⁇ [(4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a ] Pyrimidin-6-yl) carbonyl] amino ⁇ phenyl) -3 ', 6'-dihydro-3,4'-bipyridine-1' (2'H) -carboxylate To a solution of the compound obtained in Step 2 of Example 62 (470 mg) and the compound obtained in Step 1 of Example 4 (420 mg) in DMF (10 ml), EDC ⁇ HCl (370 mg) and HOBt (260 mg) were added, and the mixture was brought to room temperature. And stirred overnight.
• Step 2 N- [4- (6-Amino-1 ′, 2 ′, 3 ′, 6′-tetrahydro-3,4′-bipyridin-5-yl) phenyl] -4-benzyl-2-methyl- 7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• dichloromethane 10 ml
• Example 65 N- [4- (6-Amino-1′-methyl-1 ′, 2 ′, 3 ′, 6′-tetrahydro-3,4′-bipyridin-5-yl) phenyl] -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• the compound (100 mg) obtained in Step 1 of Example 24 and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2,3 , 6-Tetrahydropyridine (51 mg) was synthesized in the same manner as in Step 2 of Example 24 to obtain 50 mg of the title compound as a solid.
• Example 66 N- [4- (1′-acetyl-6-amino-1 ′, 2 ′, 3 ′, 6′-tetrahydro-3,4′-bipyridin-5-yl) phenyl] -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• Acetic anhydride (27 ⁇ l) was added to a DMF (3 ml) solution of the hydrochloride of the compound obtained in Step 2 of Example 64 (150 mg), and the mixture was stirred at room temperature for 6 hours.
• Example 67 N- [4- (6-Amino-1′-glycoloyl-1 ′, 2 ′, 3 ′, 6′-tetrahydro-3,4′-bipyridin-5-yl) phenyl] -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC.HCl 32 mg
• HOBt 23 mg
• N-methylmorpholine 15 ⁇ l
• reaction solution was diluted with water, extracted with chloroform containing 10% methanol, and dried over sodium sulfate.
• NH silica gel column chromatography
• Example 68 N- [4- (6-Amino-1′-lactoyl-1 ′, 2 ′, 3 ′, 6′-tetrahydro-3,4′-bipyridin-5-yl) phenyl] -4-benzyl-2-methyl -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• the title compound (25 mg) was obtained as a solid by synthesis in the same manner as in Example 67 using hydrochloride (70 mg) and lactic acid (10 mg) of the compound obtained in Step 2 of Example 64.
• Example 69 [Step 1] tert-butyl 4- [6-amino-5- (4-aminophenyl) pyridin-3-yl] piperidine-1-carboxylate To a solution of the compound obtained in Step 2 of Example 62 (300 mg) in ethanol (10 ml) was added 10% palladium carbon (300 mg), and the mixture was stirred at room temperature for 4 days in a hydrogen atmosphere.
• Step 2 tert-butyl 4- [6-amino-5- (4- ⁇ [(4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1, 5-a] pyrimidin-6-yl) carbonyl] amino ⁇ phenyl) pyridin-3-yl] piperidine-1-carboxylate
• the compound obtained in Step 1 above (170 mg) and the compound obtained in Step 1 of Example 4 (125 mg) were synthesized in the same manner as in Step 1 of Example 64 to obtain 210 mg of the title compound as a solid.
• Step 3 N- [4- (2-Amino-5-piperidin-4-ylpyridin-3-yl) phenyl] -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2 , 4] triazolo [1,5-a] pyrimidine-6-carboxamide TFA (1 ml) was added to a dichloromethane (2 ml) solution of the compound (210 mg) obtained in the above Step 2 under ice cooling, and the mixture was stirred for 2 hours while gradually returning to room temperature.
• Step 4 N- ⁇ 4- [5- (1-acetylpiperidin-4-yl) -2-aminopyridin-3-yl] phenyl ⁇ -4-benzyl-2-methyl-7-oxo-4,7 -Dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide Using the compound (105 mg) obtained in Step 3 above, synthesis was performed in the same manner as in Example 63 to obtain 57 mg of the title compound as a solid.
• Example 70 N- [4- (6-Amino-2 ′, 2 ′, 6 ′, 6′-tetramethyl-1 ′, 2 ′, 3 ′, 6′-tetrahydro-3,4′-bipyridin-5-yl) Phenyl] -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide Compound (75 mg) obtained in Step 1 of Example 24 and 2,2,6,6-tetramethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) -1,2,3,6-Tetrahydropyridine (39 mg) was synthesized in the same manner as in Step 2 of Example 24 to obtain 25 mg of the title compound as a solid.
• Example 71 [Step 1] tert-butyl 3- [6-amino-5- (4- ⁇ [(4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1, 5-a] pyrimidin-6-yl) carbonyl] amino ⁇ phenyl) pyridin-3-yl] -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate Compound (150 mg) obtained in Step 1 of Example 24 and tert-butyl 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -8-azabicyclo [3.
• Step 2 N- ⁇ 4- [2-amino-5- (8-azabicyclo [3.2.1] oct-2-en-3-yl) pyridin-3-yl] phenyl ⁇ -4-benzyl- 2-Methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide TFA (500 ⁇ l) was added to a solution of the compound obtained in Step 1 (95 mg) in dichloromethane (2 ml) under ice-cooling and stirred while gradually returning to room temperature.
• Example 73 6-Amino-5-bromonicotinonitrile To a solution of 6-aminonicotinonitrile (5.0 g) in DMF (50 ml) was added N-bromosuccinimide (7.8 g) under ice cooling, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain 7.0 g of the title compound as a solid.
• Step 2 6-amino-5- (4-aminophenyl) nicotinonitrile Compound (1.0 g) obtained in the above step 1 and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.3 g) in dioxane (18 ml) ) Water (2 ml), potassium carbonate (1.1 g), tetrakis (triphenylphosphine) palladium (0.58 g) were added to the solution, and the mixture was stirred at 100 ° C. After allowing to cool, water was added to the reaction solution, and the mixture was extracted with chloroform containing 10% methanol and dried over sodium sulfate.
• Step 3 N- [4- (2-Amino-5-cyanopyridin-3-yl) phenyl] -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4 ]
• Triazolo [1,5-a] pyrimidine-6-carboxamide 1H-benzotriazol-1-yloxytri (1-pyrrolidinyl) phosphonium hexafluorophosphate (DMF) was added to the DMF (5 ml) solution of the compound obtained in Step 2 above (250 mg) and the compound obtained in Step 1 of Example 3 (340 mg). 680 mg) was added and stirred at room temperature for 17 hours.
• Example 74 Ethyl 2,3-dimethyl-5-oxo-5,8-dihydroimidazo [1,2-a] pyrimidine-6-carboxylate 2-Amino-4,5-dimethylimidazole (183 mg) and diethyl ethoxymethylenemalonate (331 ⁇ l) were added to acetic acid (2 ml), and the mixture was heated to reflux for 9 hours. Water was added to the reaction solution, followed by filtration and washing with water and hexane to obtain 84 mg of the title compound. MS (ESI) m / z: 236 (M + H) + .
• Step 2 8- (4-Fluorobenzyl) -2,3-dimethyl-5-oxo-5,8-dihydroimidazo [1,2-a] pyrimidine-6-carboxylic acid
• DMF dimethyl methoxysulfoxide
• 64 mg potassium carbonate
• 4-fluorobenzyl bromide 52 ⁇ l
• Ethanol 2 ml
• 1N aqueous sodium hydroxide solution (1 ml) were added to the reaction solution, and the mixture was stirred at 80 ° C. for 14 hours.
• Step 5 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -8- (4-fluorobenzyl) -2,3 -Dimethyl-5-oxo-5,8-dihydroimidazo [1,2-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 34 mg
• Example 75 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] -3-fluorophenyl ⁇ -4- (4-fluorobenzyl) -7-oxo -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 72 mg
• Example 76 [Step 1] Ethyl 7-oxo-2- (trifluoromethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxylate 3- (Trifluoromethyl) -1H-1,2,4-triazol-5-amine (1 g) and diethyl ethoxymethylenemalonate (1.33 ml) were added to acetic acid (10 ml), and the mixture was heated to reflux for 9 hours. Water was added to the reaction solution, followed by filtration and washing with water and hexane to obtain 635 mg of the title compound. MS (ESI) m / z: 277 (M + H) + .
• Step 2 4- (4-Fluorobenzyl) -7-oxo-2- (trifluoromethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carbon Ethyl acid
• DMF dimethyl methyl
• potassium carbonate 130 mg
• 4-fluorobenzyl bromide 107 ⁇ l
• Step 3 4- (4-Fluorobenzyl) -7-oxo-2- (trifluoromethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carvone acid
• the compound (110 mg) obtained in the above Step 2 was suspended in ethanol (2 ml) and water (1 ml), potassium carbonate (79 mg) was successively added, and the mixture was stirred at room temperature for 3 days. 1N Hydrochloric acid aqueous solution was added, filtered and washed with water to give 80 mg of the title compound.
• Step 4 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] -3-fluorophenyl ⁇ -4- (4-fluorobenzyl) -7-oxo-2- (trifluoromethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 65 mg
• Example 77 [Step 1] 3-Bromo-5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine 3-Bromo-5-iodopyridin-2-amine (500 mg), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (348 mg), tetrakis (triphenylphosphine) palladium (193 mg), and potassium carbonate (693 mg) were suspended in dioxane (10 ml) and water (1 ml), and heated at 80 ° C. for 24 hours. After allowing to cool, the mixture was extracted with chloroform and dried over sodium sulfate.
• Step 2 3- (4-Amino-3-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine Compound (200 mg) obtained in Step 1 above, 2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (220 mg) in dioxane (5 ml) Water (1 ml), potassium carbonate (330 mg) and tetrakis (triphenylphosphine) palladium (50 mg) were added to the solution, and the mixture was stirred at 80 ° C. overnight. The mixture was allowed to cool, diluted with chloroform, washed with water, and dried over sodium sulfate.
• Step 3 N- ⁇ 4- [2-Amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] -2-methoxyphenyl ⁇ -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 49 mg was added at room temperature.
• Example 78 [Step 1] 3- (4-Amino-2-methylphenyl) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine Compound (110 mg) obtained in Step 1 of Example 77, 3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (110 mg) in dioxane Water (1 ml), potassium carbonate (190 mg) and tetrakis (triphenylphosphine) palladium (30 mg) were added to the (5 ml) solution, and the mixture was stirred at 100 ° C. for 5 hours.
• Step 2 N- ⁇ 4- [2-amino-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] -3-methylphenyl ⁇ -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 61 mg was added at room temperature. After stirring at 50 ° C. for 3 hours, the mixture was diluted with chloroform and washed with water.
• Step 2 3- (4-Amino-3-methoxyphenyl) -5- (3,4-dimethoxyphenyl) pyridin-2-amine Compound (200 mg) obtained in Step 1 above, 2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (153 mg) in dioxane (20 ml) Water (2 ml), potassium carbonate (268 mg) and tetrakis (triphenylphosphine) palladium (37 mg) were added to the solution, and the mixture was stirred at 100 ° C. for 5 hours.
• Step 3 2-Methyl-4-[(6-methylpyridin-2-yl) methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine- 6-carboxylic acid 1N
• Aqueous sodium hydroxide solution (0.24 ml) was added to a solution of the compound obtained in Step 1 of Example 47 (80 mg) in methanol (3 ml), and the mixture was stirred at room temperature for 2 hours. 78 mg of salt was obtained as a solid.
• Step 4 N- ⁇ 4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] -2-methoxyphenyl ⁇ -2-methyl-4-[(6-methylpyridine- 2-yl) methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pydimidine-6-carboxamide
• EDC ⁇ HCl 39 mg
• Example 80 [Step 1] 3- (4-Amino-2-methylphenyl) -5- (3,4-dimethoxyphenyl) pyridin-2-amine Compound (170 mg) obtained in Step 1 of Example 79, 3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (128 mg) in dioxane To the (20 ml) solution, water (2 ml), potassium carbonate (228 mg) and tetrakis (triphenylphosphine) palladium (31 mg) were added and stirred at 100 ° C. for 5 hours.
• Step 2 N- ⁇ 4- [2-amino-5- (3,4-dimethoxyphenyl) pyridin-3-yl] -3-methylphenyl ⁇ -2-methyl-4-[(6-methylpyridine- 2-yl) methyl] -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pydimidine-6-carboxamide
• EDC ⁇ HCl 31 mg
• Example 81 [Step 1] 3- (4-Amino-2-fluorophenyl) -5-bromopyridin-2-amine 5-Bromo-3-iodopyridin-2-amine (300 mg), 3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (238 mg) Tetrakis (triphenylphosphine) palladium (58 mg) and potassium carbonate (416 mg) were suspended in dioxane (5 ml) and water (0.5 ml), and the mixture was heated to reflux at 80 ° C. for 2 days.
• Step 4 N- [4- (2-Amino-5- ⁇ 1-[(2S) -1,4-dioxane-2-ylmethyl] -1H-pyrazol-4-yl ⁇ pyridin-3-yl)- 3-Fluorophenyl] -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide To a solution of the compound obtained in Step 1 of Example 4 (40 mg) and the compound obtained in Step 3 above (52 mg) and HOBt (19 mg) in DMF (2 ml), EDC ⁇ HCl (41 mg) was added at room temperature.
• Example 82 N- [4- (2-amino-5- ⁇ 1-[(2S) -1,4-dioxan-2-ylmethyl] -1H-pyrazol-4-yl ⁇ pyridin-3-yl) -3-fluorophenyl ] -2-Ethoxy-7-oxo-4- (pyridin-2-ylmethyl) -4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• 1N aqueous sodium hydroxide solution (0.15 ml)
• Example 84 [Step 1] 5-Bromo-3-iodo-4-methoxypyridin-2-amine NBS (171 mg) was added to a solution of 3-iodo-4-methoxypyridin-2-amine (200 mg) in DMF (2 ml), added at 0 ° C., and stirred at room temperature for 2 days. Water was added to the reaction solution, and the precipitated solid was collected by filtration and washed with water. The obtained solid was dried under reduced pressure to obtain the title compound as a crude product. MS (ESI) m / z: 329,331 (M + H) + .
• Step 2 3- (4-Aminophenyl) -5-bromo-4-methoxypyridin-2-amine
• 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (184 mg), Pd (PPh3) 4 (46 mg) and potassium carbonate (332 mg) were suspended in dioxane (5 ml) and water (0.5 ml), and the mixture was heated to reflux at 80 ° C. for 18 hours. After allowing to cool, a saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, and dried over sodium sulfate.
• Step 3 3- (4-Aminophenyl) -4-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine
• cesium fluoride (213 mg) were suspended in methanol (2.5 ml) and refluxed at 80 ° C. for 9 and a half hours.
• Step 4 N- ⁇ 4- [2-Amino-4-methoxy-5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl] phenyl ⁇ -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 44 mg
• Example 85 [Step 1] 3- (4-Aminophenyl) -4-methoxypyridin-2-amine 3-iodo-4-methoxypyridin-2-amine (350 mg), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (322 mg), [1, 1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (81 mg) and cesium fluoride (580 mg) were suspended in methanol (5 ml) and heated to reflux at 80 ° C. for 19 hours.
• Step 2 N- [4- (2-Amino-4-methoxypyridin-3-yl) phenyl] -4-benzyl-2-methyl-7-oxo-4,7-dihydro [1,2,4] Triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 101 mg was added at room temperature. After stirring at 50 ° C. for 5 hours, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate.
• Example 86 N- [4- (2-Amino-4-methoxypyridin-3-yl) phenyl] -4-benzyl-2-ethoxy-7-oxo-4,7-dihydro [1,2,4] triazolo [1, 5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 69 mg
• Example 87 [Step 1] 5-Bromo-6-methoxypyrimidin-4-amine NBS (864 mg) was added to a solution of 6-methoxypyrimidin-4-amine (500 mg) in DMF (5 ml), and the mixture was stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution was added, extracted with dichloromethane, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a crude product. MS (ESI) m / z: 204, 206 (M + H) + .
• Step 2 5- (4-Aminophenyl) -6-methoxypyrimidin-4-amine
• 4-amino-phenylboronic acid pinacol ester (963 mg), tetrakis (triphenylphosphine) palladium (231 mg), potassium carbonate (1.66 g) in dioxane (20 ml) and water (2. 0 ml) and heated to reflux for 12 hours. After allowing to cool, a saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and dried over sodium sulfate.
• Step 3 N- [4- (4-Amino-6-methoxypyrimidin-5-yl) phenyl] -4- (4-fluorobenzyl) -7-oxo-4,7-dihydro [1,2,4 ] Triazolo [1,5-a] pyrimidine-6-carboxamide
• EDC ⁇ HCl 50 mg
• test compound was diluted with DMSO, and 1 ⁇ L of this diluted solution was added to each well.
• substrate peptide FL-Peptide 30 (5FAM-KKKKEIEIFFF-CONH 2 ), Caliper Life Sciences, catalog number 760430) and a solution containing 1.5 ⁇ M and 10 ⁇ M of ATP, respectively, and 5 ⁇ L of this solution was added to each well to initiate the kinase reaction.
• the plate is incubated at 28 ° C.
• the reaction was stopped.
• the substrate peptide and phosphorylated peptide in the reaction solution were separated and quantified by EZ Reader II (Caliper Life Sciences).
• the kinase reaction was evaluated by the product ratio (P / (P + S)) calculated from the substrate peptide peak height (S) and the phosphorylated peptide peak height (P).
• the inhibition rate (Inhibition) was calculated by the following formula (automatically calculated by EZ Reader II system software).
• Inhibition (%) 100 ⁇ (1-C i / C 0 )
• C i represents the product ratio when the test compound is added
• C 0 represents the product ratio when DMSO is added instead of the test compound. From the inhibition rate data for the test compound concentration of 12 points, IC was performed by nonlinear regression (4 parameter logistic regression) using the following formula: 50 Asked.
• Inhibition (%) Bottom + (Top-Bottom) / (1 + ([Compound] / IC 50 ) slopc )
• Examples 2, 5, 8, 12-17, 21, 27, 29, 30, 32, 35, 37, 47-50, 58-63, 66-68, 74-77, 79, 81, 83 , 84, 86, 87 have compounds of 1 nM ⁇ IC 50 ⁇ 10 nM
• compounds of Examples 18 to 20, 33, 34, 39, 40, 46, 64, 65, 72, 73, 78, 80, 82, 85 have 10 nM ⁇ IC 50 ⁇ 50 nM
• a phosphorylated Axl (hereinafter, pAxl) inhibition test was performed using a human non-small cell lung cancer-derived cell line NCI-H1299.
• NCI-H1299 cells were suspended in a medium (RPMI1640 medium containing 10% fetal calf serum) and seeded in 96-well multiwell plates at 15000 cells / 100 ⁇ L / well, respectively, at 37 ° C., 5% CO 2 Cultured for 1 day in presence. On the next day, remove the medium, add 100 ⁇ L of medium, 37 ° C, 5% CO 2 Cultured for 1 day under.
• test compound was dissolved in DMSO and diluted with a medium to obtain a sample solution (DMSO concentration 2%). 25 ⁇ L of medium or specimen-added medium is added to the well (DMSO concentration 0.4%), 37 ° C., 5% CO 2 Incubated for 1 hour in the presence.
• GAS6 R & D, product number: 885-GS
• wash buffer a solution obtained by diluting Triton X-100 to 0.1% with PBS (hereinafter referred to as “wash buffer”) was added, discarded with a decanter, and excess water was removed on a paper towel.
• washing buffer 0.1%
• 0.1 mL was added to the well, and the mixture was allowed to stand at room temperature for 15 minutes.
• the buffer was discarded, 0.2 ml of the wash buffer was added, discarded with a decanter, and excess water was removed on a paper towel.
• Skimmed milk (Nacalai Tesque) was added to the wash buffer at a final concentration of 5% (blocking buffer), 0.25 mL was added to the well, and allowed to stand at room temperature for 1 hour.
• Blocking buffer was discarded, and Anti-phospho-Axl (Y702) (D12B2) rabbit monoclonal antibody (Cell Signaling, catalog number 5724) was reacted at a concentration of 1/1000 and allowed to stand overnight at 4 ° C. The washing operation was repeated 5 times with Wash buffer, and Peroxidase AffiniPure Donkey Anti-Rabbit IgG (H + L) (Jackson ImmunoResearch, catalog number 711-035-152) was allowed to react at a concentration of 1/2000 for 1 hour at room temperature.
• the washing operation was performed in the same manner, and 0.05 mL of Super Signal ELISA, pico chemi luminescent substrate (Thermo Scientific, catalog number 37069) was added, and the mixture was lightly stirred and incubated for 20 minutes. Thereafter, the luminescence was measured with ARVO sx (Perkin Elmer), and the pAxl (Y702) level was measured.
• the pAxl inhibitory activity was determined by the following formula.
• Inhibition% 100- (A-B) * 100 / (T-B)
• B Luminescence value of the reaction solution containing a positive control compound at a concentration that suppresses almost 100% phosphorylation (For example, luminescence value of the reaction solution to which 1 ⁇ M BMS-777607 was added)
• T Luminescence value of the reaction solution to which no compound was added
• GraphPad Prism 4 showed 50% inhibitory concentration (IC 50 )
• Examples 1 to 17, 19, 21 to 33, 35 to 38, 41 to 48, 50 to 61, 63 to 68, 75 to 79, 81, and 83 to 86 have compounds of 0 nM ⁇ IC 50 ⁇ 50 nM, compounds of Examples 18, 20, 34, 49, 62, 69, 70, 72-74, 82, 87, 50 nM ⁇ IC 50 ⁇ 100 nM, compounds of Examples 40, 71, 80, 100 n

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• 2013
  • 2013-04-25 WO PCT/JP2013/062802 patent/WO2013162061A1/fr not_active Ceased

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