Classifications

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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Definitions

• the present invention relates to a prophylactic and / or therapeutic agent for pulmonary hypertension, which contains a novel heterocyclic derivative as an active ingredient.
• Pulmonary arterial hypertension is a large-scale symposium on pulmonary hypertension held every five years in Europe and the United States, and at the 2008 Dana Point Conference, a right heart catheter test was performed at rest. Pulmonary hypertension was defined when the average pulmonary arterial pressure (PAP) measured using the drug (mean PAP) was 25 mmHg or higher, and this definition was continuously adopted at the 2013 Nice Conference. According to the Danapoint classification, pulmonary hypertension is classified into 5 groups: 1st group: PAH, 2nd group: pulmonary hypertension associated with left cardiac heart disease, 3rd group: pulmonary disease and / or lungs associated with hypoxemia.
• Hypertension Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH), Group 5: Pulmonary hypertension associated with a multifactorial mechanism of unknown details. This basic structure is also maintained in the revised pulmonary hypertension clinical classification (Nice classification [2013]) (Non-Patent Document 1). In addition, the latest definition of pulmonary hypertension was proposed at the 6th World Symposium on Pulmonary Hypertension (Nice Conference 2018). In the proposal, 24 mmHg ⁇ average pulmonary arterial pressure (mPAP)> 20 mmHg is also defined as included in the above-mentioned pulmonary hypertension.
• CTEPH Chronic thromboembolic pulmonary hypertension
• Group 5 Pulmonary hypertension associated with a multifactorial mechanism of unknown details. This basic structure is also maintained in the revised pulmonary hypertension clinical classification (Nice classification [2013]) (Non-Patent Document 1). In addition, the latest definition of pulmonary hypertension was proposed at the 6th World Symposium on Pulmonary Hypertension (Nice Conference 2018). In the proposal
• Platelet-Derived Growth Factor can stimulate the migration of arterial smooth muscle cells from the inside of the artery to the intima layer where the muscle cells can proliferate.
• Cell proliferation induced by all isotypes of PDGF is mediated by ligands that bind to PDGF receptors.
• PDGF receptors belong to the class III tyrosine kinase family and consist of two receptor subtypes called type A (or type alpha) and type B (or type beta).
• Other members of the PDGF receptor family include colony stimulating factor 1 receptor, CSF1R, KIT and FLT3.
• KIT is another receptor tyrosine kinase belonging to the PDGF receptor family, usually expressed in hematopoietic progenitor cells, mast cells and germ cells.
• the expression of KIT is mast cell leukemia, germ cell tumor, small cell lung cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), neuroblastoma, melanoma, ovarian cancer, It is known to be involved in several cancers including breast cancer (Non-Patent Document 1).
• Imatinib has a PDGF receptor kinase inhibitory effect and has been shown to be effective in a P3 study in pulmonary arterial hypertension. However, approval was not reached because the tolerability was insufficient due to side effects such as myelosuppression.
• Patent Document 1 describes that the compound of the general formula [1] or a pharmaceutically acceptable salt thereof is PDGF receptor kinase or PDGF receptor kinase and a KIT inhibitor.
• An object to be solved by the present invention is to provide a prophylactic and / or therapeutic agent for pulmonary arterial hypertension, which has an excellent balance between efficacy and safety.
• the present inventors have found a relationship between myelosuppressive action and inhibitory action of KIT, which is a receptor tyrosine kinase involved in bone marrow hematopoiesis. That is, the present inventors have a compound represented by the following general formula [1] having a high inhibitory activity on PDGF receptor kinase with respect to the inhibitory activity on KIT kinase, a pharmaceutically acceptable salt thereof, or a solvate thereof.
• a substance (sometimes referred to as a compound of the present invention in the specification) exhibits a growth inhibitory effect on pulmonary arterial smooth muscle cells and reduces the formation inhibitory effect of erythrocytic colonies. completed.
• the present invention can include the following inventions (item 1) to (item 8).
• (Item 1) The following equation [1] [During the ceremony, R 1 is hydrogen atom, halogen atom, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 1 -C 6 alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, nitro, when C 3 -C 6 cycloalkyl substituted by optionally heteroaryl substituted by aryl or optionally is substituted C 3 -C 6 cycloalkenyl substituted, optionally heterocycloalkyl substituted, optionally, R 2 is a bond, - (CR
• R 1 is a substituted hydrogen atom, a halogen atom, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, optionally C 3- C 6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
• R 1 is a hydrogen atom, C 1 -C 6 alkoxy, amino, aryl which is substituted monoalkylamino, when C 3 -C 6 cycloalkyl substituted by, optionally heterocycloalkyl substituted, optionally , Or optionally substituted heteroaryl, R 2 is a bond,-(CR a R b ) m -O-,-(CR a R b ) m- , or -NR c- .
• M in L 1 is 0 or 1
• X is N or C-R 3,
• R 3 is a hydrogen atom
• R 4 is a halogen atom or methyl
• L 2 is-(CR a R b ) m -NR c- ,
• Each R c in L 2 is a hydrogen atom independently
• M in L 2 is 1
• R 5 is hydroxy and Item 2.
• the compound according to Item 1 a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 form a C 3- C 6 cycloalkyl together with a carbon atom to which they are bonded.
• Solvation product is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 form a C 3- C 6 cycloalkyl together with a carbon atom to which they are bonded.
• (Item 4) Item 2.
• Item 5 The compound according to Item 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, which is selected from the group consisting of the following (1) to (15) or pharmaceutically acceptable thereof. A salt or a solvate thereof.
• AML acute myelogenous leukemia
• CML chronic myelogenous leukemia
• CML chronic myelogenous leukemia
• chronic eosinophilic leukemia elevated cutaneous fibrosarcoma
• glioma
• the compounds of the present invention inhibit PDGF receptor kinase, diseases involving PDGF receptor kinase (eg, respiratory diseases, cancer, smooth muscle proliferative diseases, vasoproliferative diseases, autoimmune / inflammatory diseases, etc. It is useful as a therapeutic agent for metabolic diseases, vascular obstructive diseases, etc.).
• diseases involving PDGF receptor kinase eg, respiratory diseases, cancer, smooth muscle proliferative diseases, vasoproliferative diseases, autoimmune / inflammatory diseases, etc. It is useful as a therapeutic agent for metabolic diseases, vascular obstructive diseases, etc.).
• Halogen atom represents a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
• alkyl includes, for example, an alkyl having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and more preferably 1 to 3 carbon atoms in a straight chain or a branched chain. Can be mentioned. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 1,2-dimethylpropyl, tert.
• alkyl moieties of "monoalkylamino", “alkylcarbonyloxy”, “monoalkylamino”, “dialkylamino”, “alkylcarbonylamino”, “alkylsulfonyl”, “aminoalkyl” and “alkylcarbonyl” are described above. The same “alkyl” as above can be mentioned.
• alkenyl 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, of a straight chain or a branched chain having one or more double bonds at arbitrary positions, more preferably. It represents a hydrocarbon group having 2 to 6, more preferably 2 to 4 carbon atoms. Specific examples thereof include vinyl, allyl, 2-methylpropenyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butazienyl, pentanyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, and hexadienyl.
• Amino represents -NH 2.
• Aminoalkyl represents a group in which an amino group replaces a hydrogen atom bonded to a carbon atom of the above “alkyl".
• specific examples thereof include aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, 2-aminopropane-2-yl, 3-aminopropyl and the like.
• the "monoalkylamino” represents a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. Specific examples thereof include methylamino, ethylamino, isopropylamino and the like.
• Hydroalkyl represents a group in which a hydroxy group replaces a hydrogen atom bonded to a carbon atom of the above “alkyl”.
• a hydroxy group replaces a hydrogen atom bonded to a carbon atom of the above “alkyl”.
• specific examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl and the like.
• Alkylcarbonyl means a group in which the above “alkyl” is bonded to a carbonyl group.
• methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like can be mentioned.
• Haloalkyl refers to a group in which the above-mentioned "halogen atom” is replaced with the above-mentioned “alkyl” hydrogen atom. Specific examples thereof include fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, dichloromethyl, difluoroethyl, trifluoromethyl, trichloromethyl, trifluoroethyl and the like.
• Alkoxy represents a group in which the above “alkyl” is bonded to an oxygen atom.
• an alkoxy having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms in a straight chain or a branched chain can be mentioned. Specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy and the like.
• aryl examples include aromatic hydrocarbon groups that are monocyclic to tricyclic and have 6 to 14 carbon atoms. Specifically, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 10-phenanthryl and the like can be mentioned. Can be done. Of these, phenyl is preferable.
• cycloalkyl is monocyclic to tricyclic and may include a cyclic non-aromatic hydrocarbon group. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• non-aromatic carbocyclic group may be a bridging hydrocarbon group.
• bridging hydrocarbon groups include, for example. Bicyclo [2.2.1] heptane (eg, bicyclo [2.2.1] heptane-1-yl, bicyclo [2.2.1] heptane-2-yl, bicyclo [2.2.1] heptane -7-Il,), Bicyclo [1.1.1] pentanyl (eg, bicyclo [1.1.1] pentane-1-yl, bicyclo [1.1.1] pentan-2-yl), Bicyclo [4.1.0] heptane (eg, bicyclo [4.1.0] heptane-1-yl, bicyclo [4.1.0] heptane-2-yl, bicyclo [4.1.0] heptane -3-yl, bicyclo [4.1.0] heptane-7-yl,), Bicyclo [2.2.2] o
• non-aromatic carbocyclic group may be a spirocyclic group.
• a spiro cyclic group include, for example. Spiro [3.3] heptane (eg, spiro [3.3] heptane-1-yl, spiro [3.3] heptane-2-yl), Spiro [4.4] nonanyl (eg, spiro [4.4] nonane-1-yl, spiro [4.4] nonane-2-yl), Spiro [5.5] undecanyl (eg, spiro [5.5] undecane-1-yl, spiro [5.5] undecane-2-yl, spiro [5.5] undecane-3-yl), or ...
• heteroaryl is, for example, monocyclic to tricyclic, has 1 to 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms as constituent atoms, and has 1 to 3 carbon atoms.
• Frills eg 2-frills, 3-frills
• -Thienil eg 2-thienyl, 3-thienyl
• Pyrrolyl eg, 1-pyrrolyl, 2-pyrrolill, 3-pyrrolill
• -Imidazolyl eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl
• ⁇ Pyrazolyl eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl
• Triazolyl eg, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-4-yl
• -Tetrazolyl eg, 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl
• -Oxazolyl eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl
• -Isoxazolyl
• heterocycloalkyl is a monocyclic or two or more cyclic non-aromatic heterocyclic group having one or more identical or different heteroatoms selected for nitrogen, oxygen and sulfur atoms in the ring.
• Oxetanyl eg 2-oxetanil, 3-oxetanil
• Azetidinel eg 2-azetidinel, 3-azetidinel
• -Tetrahydropyranyl eg 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl
• 1,4-Dioxanyl eg, 1,4-dioxane-2-yl
• 1,3-Dioxanyl eg, 1,3-dioxane-2-yl, 1,3-dioxane-4-yl, 1,3-dioxane-5-yl
• Pyrrolidinyl eg, 1-pyrrolidiny
• heterocycloalkyl may be a crosslinked cyclic group.
• a bridging cyclic group examples include, for example.
• 3-Azabicyclo [3.2.1] octanyl eg, 3-azabicyclo [3.2.1] octane-1-yl, 3-azabicyclo [3.2.1] octane-2-yl, 3-azabicyclo [3.2.1] octane-3-yl, 3-azabicyclo [3.2.1] octane-6-yl, 3-azabicyclo [3.2.1] octane-8-yl
• Quinuclidine eg, quinuclidine-2-yl, quinuclidine-3-yl, quinuclidine-4-yl
• 6-oxa-3-azabicyclo [3.1.1] heptanyl eg, 6-oxa-3-yl
• heterocycloalkyl may be a spirocyclic group.
• a spiro cyclic group include, for example. 6-Azaspiro [2.5] octane-1-yl (eg, 6-azaspiro [2.5] octane-1-yl, 6-azaspiro [2.5] octane-4-yl, 6-azaspiro [2] .5] Octane-5-il), 3,9-Diazaspiro [5.5] undecane-1-yl (eg, 3,9-diazaspiro [5.5] undecane-1-yl, 3,9-diazaspiro [5.5] undecane-2-yl) , 3,9-Diazaspiro [5.5] Undecane-3-yl), 2,7-Diazaspiro [3.5] nonane-1-yl (eg, 2,7-diazaspiro [3.5] nonane-1-yl, 2,7-diazaspiro [3.5] non
• R 1 in the formula [1] is a hydrogen atom, a halogen atom, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl , C 2- C 6 haloalkynyl, C 1- C 6 alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, alkylcarbonylamino, nitro, optionally substituted C 3- C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, which is optionally substituted, optionally heterocycloalkyl substituted, aryl which is optionally substituted, optionally heteroaryl substituted.
• R c in R 2 are each independently a hydrogen atom, a C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. A hydrogen atom is preferred.
• Het is a 5- to 10-membered heteroaryl.
• R c in L 1 are each independently a hydrogen atom, a C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. Hydrogen atom or a C 1 -C 6 alkyl are preferred, A hydrogen atom is more preferred.
• Coupling hands,-(CR a R b ) m -NR c- , -NR c- CO-NR c- are preferable.
• Ra and the carbon atom to which they are bonded form C O.
• R c in L 2 is a hydrogen atom, a C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
• a hydrogen atom is preferable as R c in L 2 independently of each other.
• R 4 is a hydrogen atom, a halogen atom, a methyl. Halogen atom and methyl are preferable.
• R 5 is a hydrogen atom, a halogen atom, a hydroxy, an amino, a C 1- C 6 alkyl, a C 1- C 6 haloalkyl, a C 1- C 6 alkoxy, or a C 1- C 6 haloalkoxy. Hydroxy is preferred.
• R 6 is a hydrogen atom, phenyl which is substituted halogen atom, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or optionally
• R 7 is a hydrogen atom, halogen atom, C 1- C 6 alkyl, C 1- C 6 haloalkyl, hydroxy alkyl, optionally substituted phenyl, or C 3- C 6 cycloalkyl, or R 6 And R 7 together with the carbon atoms to which they are attached form C 3- C 6 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
• R 6, a hydrogen atom, phenyl substituted by C 1 -C 6 alkyl or, preferably, R 7 is preferably phenyl substituted by C 1 -C 6 alkyl, hydroxyalkyl, or optionally, or, R 6 and R 7, taken together with the carbon atoms to which they are attached, it is preferable to form an aryl substituted by C 3 -C 6 cycloalkyl, or optionally, It is even more preferred that R 6 and R 7 combine with the carbon atom to which they are attached to form a C 3- C 6 cycloalkyl.
• present invention compounds include the type of L 1, the compounds shown in Table 1 below.
• 1-D In compound [1], a compound in which L 1 is -NR c- .
• 1-E In compound [1], L 1 is ⁇ (CR a R b ) m ⁇ NR c ⁇ , m is 1, and Ra and R b are hydrogen atoms.
• 1-F In compound [1], L 1 is -NR c- (CR a R b ) m- , m is 1, and Ra and R b are hydrogen atoms.
• R 1 in Compound 1-A includes H, halogen atom, C 1- C 6 alkyl, C 2- C 6 alkenyl, C 1- C 6 alkoxy, amino, alkylcarbonylamino, and optionally substituted C 3 -C 6 cycloalkyl, optionally heterocycloalkyl substituted, optionally preferably heteroaryl substituted with an aryl which is substituted or,, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, If C 3 -C 6 cycloalkyl substituted by, optionally heterocycloalkyl substituted, if heteroaryl substituted by aryl or optionally substituted by is more preferable.
• R 2 in compound 1-A 0, 1, 2 are preferable, and 0, and 1 are more preferable.
• thiazolyl, pyridyl, oxazolyl, or imidazole thiazolyl is preferable, and thiazolyl or pyridyl is more preferable.
• the R 4 in the compound 1-A a halogen atom or methyl are preferred, and methyl is more preferable.
• L 2 in compound 1-A -(CR a R b ) m-NRc-is preferable.
• m of L 2 in compound 1-A 1 is preferable.
• the R 5 in Compound 1-A hydroxy are preferred.
• R 6 in Compound 1-A it is preferable to form C 3- C 6 cycloalkyl together with H, C 1- C 6 alkyl, or R 7 and the carbon atom to which they are bonded. More preferably, R 7 and the carbon atoms to which they are attached form a C 3- C 6 cycloalkyl.
• R 7 in Compound 1-A includes C 1- C 6 alkyl, optionally substituted phenyl, or R 6, and C 3- C 6 cycloalkyl, together with the carbon atom to which they are attached. formation it is preferable to, and R 6, together with the carbon atoms to which they are attached is preferably formed a C 3 -C 6 cycloalkyl.
• R 1 in the compound 1-B H, halogen atom, C 1 -C 6 alkyl, amino, optionally C 3 -C 6 cycloalkyl substituted by, optionally aryl is substituted or optionally, heteroaryl preferably being a halogen atom, C 3 -C 6 cycloalkyl which is substituted by an aryl which is optionally substituted, or heteroaryl which is optionally substituted, and more preferred.
• R 2 in compound 1-B a bond, ⁇ (CR a R b ) m ⁇ NR c ⁇ is preferable, and a bond is more preferable.
• m of R 2 in compound 1-B 0 and 1 are preferable.
• pyridyl or pyrazinel is preferable.
• the R 4 in the compound 1-B a halogen atom, methyl are preferred, with methyl being preferred.
• L 2 in compound 1-B ⁇ (CR a R b ) m—NRc ⁇ is preferable.
• As the m of L 2 in compound 1-B 1 is preferable.
• the R 5 in Compound 1-B hydroxy are preferred.
• R 6 in the compound 1-B optionally substituted phenyl, or an R 7, taken together with the carbon atoms to which they are attached, it is preferable to form a C 3 -C 6 cycloalkyl, R 7, taken together with the carbon atoms to which they are attached, it is more preferable to form a C 3 -C 6 cycloalkyl.
• R 7 in Compound 1-B it is preferable to form C 3- C 6 cycloalkyl together with hydroxyalkyl or R 6 and the carbon atom to which they are bonded , and R 6 and them are preferable. More preferably, it is combined with the carbon atom to be bonded to form a C 3- C 6 cycloalkyl.
• R 1 in compound 1-C includes H, halogen atom, C 1- C 6 alkyl, C 2- C 6 alkenyl, C 1- C 6 alkoxy, amino, alkylcarbonylamino, and optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl are preferred, and optionally substituted aryl is more preferred.
• thiazolyl, pyridyl, oxazolyl, or imidazole thiazolyl is preferable, and pyridyl is more preferable.
• the R 4 in the compound 1-C a halogen atom or methyl are preferred, and methyl is more preferable.
• R 5 in Compound 1-C hydroxy are preferred.
• R 6 in Compound 1-C it is preferable to form C 3- C 6 cycloalkyl together with H, C 1- C 6 alkyl, or R 7 and the carbon atom to which they are bonded. More preferably, R 7 and the carbon atoms to which they are attached form a C 3- C 6 cycloalkyl.
• R 7 in Compound 1-C includes C 1- C 6 alkyl, optionally substituted phenyl, or R 6, and C 3- C 6 cycloalkyl, together with the carbon atom to which they are attached. formation it is preferable to, and R 6, together with the carbon atoms to which they are attached is preferably formed a C 3 -C 6 cycloalkyl.
• R 1 in the compound 1-D H, halogen atom, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C substituted monoalkylamino, optionally 6 Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl are preferred, more preferably monoalkylamino, optionally substituted heteroaryl.
• Het in Compound 1-D pyrimidinyl, pyridyl, or quinazolyl is preferable, and pyrimidinyl is more preferable.
• the R 4 in the compound 1-D a halogen atom or methyl are preferred, and methyl is more preferable.
• the R 5 in Compound 1-D hydroxy are preferred.
• R 6 in Compound 1-D it is preferable to form C 3- C 6 cycloalkyl together with optionally substituted aryl or R 7 and the carbon atom to which they are attached, and R 7, taken together with the carbon atoms to which they are attached, it is more preferable to form a C 3 -C 6 cycloalkyl.
• R 7 in Compound 1-D can be combined with hydroxyalkyl, optionally substituted phenyl, or R 6 and the carbon atom to which they are attached to form a C 3- C 6 cycloalkyl.
• R 6 and the carbon atoms to which they are attached form a C 3- C 6 cycloalkyl.
• R 2 is in the compound 1-E, bond, - (CR a R b) m -NR c -, - NR c -, - NR c -CO-NR c -, or -C ⁇ C- are preferred, The bond, ⁇ (CR a R b ) m ⁇ NR c ⁇ , or ⁇ NR c ⁇ is more preferred.
• m of R 2 in compound 1-E 0 and 1 are preferable.
• the Het in Compound 1-E includes thiazolyl, pyridyl, oxazolyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolethiazolyl, quinazolinyl, quinolinyl, 7,8-dihydropyrido [4,5-d] pyrimidin-6 (5H) -yl , Thieno [3,2-b] pyridinyl, 1H-pyrrolo [2,3-b] pyridinyl, imidazole [1,2-b] pyridadinyl, imidazole [1,2-a] pyrazinyl, pyrazolo [1,5-a] ] Pyrimidinel, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazinyl, pyrazolo [5,1-b] thiazolyl, pyrazolo [3,4-b] pyridyl, or
• the R 4 in the compound 1-E H, halogen atom or methyl are preferred, a halogen atom or methyl, and more preferable.
• the L 2 in the compound 1-E, - (CR a R b) m-NRc- are preferred.
• the R 5 in Compound 1-E hydroxy are preferred.
• As R 6 in Compound 1-E it is more preferable to form C 3- C 6 cycloalkyl together with R 7 and the carbon atom to which they are bonded.
• R 7 in Compound 1-E it is more preferable to form C 3- C 6 cycloalkyl together with R 6 and the carbon atom to which they are bonded.
• R 1 in the compound 1-F a halogen atom, C 3 -C 6 cycloalkyl which is substituted by, preferably heteroaryl substituted with an aryl or, optionally substituted, optionally C 3- C 6 cycloalkyls, optionally substituted aryls, or optionally substituted heteroaryls are preferred.
• R 2 in compound 1-F a bond or -C ⁇ C- is preferable, and a bond is preferable.
• pyridyl or pyrazinyl is preferable, and pyridil is more preferable.
• the R 4 in the compound 1-F, H, halogen atom or methyl are preferred,, H or methyl are more preferred.
• L 2 in compound 1-F -(CR a R b ) m-NRc- and -NRc-CO-NRc- are preferable.
• m of L 2 in compound 1-F 1 is preferable.
• the R 5 in Compound 1-F hydroxy are preferred.
• the R 6 in the compound 1-F optionally substituted phenyl, or an R 7, taken together with the carbon atoms to which they are attached, it is preferable to form a C 3 -C 6 cycloalkyl, R 7, taken together with the carbon atoms to which they are attached, it is more preferable to form a C 3 -C 6 cycloalkyl.
• R 7 in Compound 1-F it is preferable to form C 3- C 6 cycloalkyl together with hydroxyalkyl or R 6 and the carbon atom to which they are bonded , and R 6 and them are preferable. together with the carbon atom bonded to, it is more preferable to form a C 3 -C 6 cycloalkyl.
• the R 1 in the compound 1-G preferably heteroaryl substituted with an aryl or, optionally substituted, and more preferably heteroaryl which is optionally substituted.
• R 2 is in the compound 1-G, bond is preferred.
• Pyridyl is preferred as the Het in compound 1-G.
• the R 4 in the compound 1-G H, a halogen atom or methyl are preferred, a halogen atom or methyl, and more preferable.
• the R 5 in Compound 1-G hydroxy are preferred.
• R 6 in Compound 1-G it is preferable to form C 3- C 6 cycloalkyl together with R 7 and the carbon atom to which they are bonded.
• R 7 in compound 1-G it is preferable to form C 3- C 6 cycloalkyl together with R 6 and the carbon atom to which they are bonded.
• the R 1 in the compound 1-H when heteroaryl is substituted by are preferred.
• R 2 is in the compound 1-H, bond is preferred.
• Pyridyl is preferable as Het in Compound 1-H.
• the R 4 in the compound 1-H a halogen atom or methyl are preferred, and methyl is more preferable.
• the R 5 in Compound 1-H hydroxy are preferred.
• R 6 in Compound 1-H it is preferable to form C 3- C 6 cycloalkyl together with R 7 and the carbon atom to which they are bonded.
• R 7 in Compound 1-H it is preferable to form C 3- C 6 cycloalkyl together with R 6 and the carbon atom to which they are bonded.
• the R 1 in the compound 1-I aryl is preferably optionally substituted.
• R 2 is in the compound 1-I, a bond is preferred.
• Pyridyl is preferred as the Het in Compound 1-I.
• the R 4 in the compound 1-I methyl is preferred.
• the R 5 in Compound 1-I hydroxy are preferred.
• R 6 in Compound 1-I it is preferable to form C 3- C 6 cycloalkyl together with R 7 and the carbon atom to which they are bonded.
• R 7 in Compound 1-I it is preferable to form C 3- C 6 cycloalkyl together with R 6 and the carbon atom to which they are bonded.
• the R 1 in the compound 1-J aryl is preferably optionally substituted.
• R 2 is in the compound 1-J, a bond is preferred.
• Pyridyl is preferable as the Het in Compound 1-J.
• the R 4 in the compound 1-J methyl is preferred.
• the R 5 in Compound 1-J hydroxy are preferred.
• R 6 in Compound 1-J it is preferable to form C 3- C 6 cycloalkyl together with R 7 and the carbon atom to which they are bonded.
• R 7 in Compound 1-J it is preferable to form C 3- C 6 cycloalkyl together with R 6 and the carbon atom to which they are bonded.
• R 1 in the compound 1-K, H, halogen, amino, and substituted monoalkylamino, dialkylamino, optionally substituted cycloalkyl, optionally heterocycloalkyl are substituted, or optionally Heteroaryls are preferred, with halogen atoms, aminos, optionally substituted cycloalkyls, optionally substituted heterocycloalkyls, or optionally substituted heteroaryls being more preferred.
• the binding agent -(CR a R b ) m-NR c -,-(CR a R b ) m -O-,-(CR a R b ) m- , or- NR c -is preferred, and the bond,-(CR a R b ) m- NR c -,-(CR a R b ) m- , or -NR c -is more preferred.
• pyridyl, pyrimidinyl, pyrazinyl, or imidazole [1,2-b] pyridadinyl is preferable, and pyridyl, pyrimidinyl, or pyrazinyl is more preferable.
• the R 4 in the compound 1-K a halogen atom or methyl, is preferred.
• the L 2 in the compound 1-K, - (CR a R b) m-NRc- are preferred.
• the m of L 2 in compound 1-K 1 is preferable.
• the R 5 in Compound 1-K hydroxy are preferred.
• R 6 in Compound 1-K includes C 1- C 6 alkyl, or R 7, and C 3- C 6 cycloalkyl, optionally substituted aryl, together with the carbon atom to which they are attached. Formation it is preferable to, and R 7, together with the carbon atoms to which they are attached is preferably formed a C 3 -C 6 cycloalkyl.
• R 7 in Compound 1-K includes C 1- C 6 alkyl, or R 6, and C 3- C 6 cycloalkyl, optionally substituted aryl, together with the carbon atom to which they are attached. formation it is preferable to, and R 6, together with the carbon atoms to which they are attached is preferably formed a C 3 -C 6 cycloalkyl.
• the compound of the present invention can be produced from a known compound or an easily synthesizable intermediate, for example, according to the method described below, an example described later, or a known method.
• a known compound or an easily synthesizable intermediate for example, according to the method described below, an example described later, or a known method.
• it is common to carry out the reaction after protecting the raw material with an appropriate protecting group by a known method in advance.
• Protecting groups can be removed after the reaction by known methods.
• the compound represented by the formula [1] can be used as it is as a medicine, but it can also be used in the form of a pharmaceutically acceptable salt, solvate, or salt solvate by a known method. it can.
• Pharmaceutically acceptable salts include, for example, salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p.
• Organic acid salts such as toluene sulfonic acid, benzene sulfonic acid and methane sulfonic acid, alkali metal salts such as lithium, potassium and sodium, alkaline earth metal salts such as magnesium and calcium, and organic bases such as ammonium salt. Salt can be mentioned. These salts can be formed by conventional methods.
• the compound represented by the formula [1] can be used as an alcohol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, or cyclopentyl of hydrogen chloride. It can be obtained by dissolving it in a methyl ether solution or a diethyl ether solution of hydrogen chloride.
• stereoisomer is, for example, optically resolved from the racemate by a known method using an optically active acid (tartaric acid, dibenzoyl tartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) utilizing its basicity. It can also be produced using a pre-prepared optically active compound as a raw material. In addition, it can also be produced by optical resolution using a chiral column or asymmetric synthesis.
• an optically active acid tartaric acid, dibenzoyl tartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.
• the compound of the present invention is not limited to a specific isomer, but includes all possible isomers and racemates. (Method for producing the compound of the present invention)
• the compound of the present invention can be produced from a compound known per se or an intermediate that can be easily prepared from a known compound, for example, according to the following method, examples described later, or a known method.
• the commercially available product can be used as it is.
• the compound obtained in each step in the production method described later and the raw material used may form a salt, and can be converted into another kind of salt or a free form by a known method.
• the compound obtained in each step in the following production method or the raw material used is a free form, it can be converted into a target salt by a known method.
• Examples of such salts include those similar to the salts used in the above-mentioned compounds of the present invention.
• the compound represented by the formula [1] of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, a hydrate or the like) and / or a crystalline polymorph, and the present invention is such. Also includes various solvates and polymorphs.
• the "solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula [1].
• solvent molecules for example, water molecules
• the compound represented by the formula [1] or a pharmaceutically acceptable salt thereof When the compound represented by the formula [1] or a pharmaceutically acceptable salt thereof is left in the air, it may absorb water and adsorbed water may adhere to it or form a hydrate.
• the compound represented by the formula [1] or a pharmaceutically acceptable salt thereof may be recrystallized to form polymorphs thereof.
• a protecting group may be introduced into these substituents by a method known in advance, and if necessary after the reaction.
• the target compound can be obtained by removing the protecting group.
• the introduction of such protecting groups and the removal of protecting groups are described, for example, by Wuts and Greene, "Greene's Protective Groups in Organic Synthesis", 4th Edition, John Wiley & Sons Inc. , 2006, or "Protecting Groups” by PJ Kocienski, 3rd Edition, Timeme, 2005.
• the compounds obtained in each step of the following production methods can be isolated or purified by methods such as solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, and chromatography according to a conventional method. Alternatively, it can be used in the next step in the form of a reaction mixture or a crude product.
• reaction of each step in the following production method is a known method, for example, "Comprehensive Organic Transitions: A Guide to Functional Group Preparations 2nd Wiley” by RC Larock. Sons Inc. , 1999, "Experimental Chemistry Course” edited by the Chemical Society of Japan, 4th edition, Maruzen, 1992, by L. Kuerti and B. Czako, translated by Kiyoshi Tomioka, "Organic Synthesis Strategy Learned from Human Name Reactions” , Chemistry, 2006, by GS Zweifel and MH Nantz, translated by Tamejiro Hiyama, "Latest Organic Synthesis Method, Design and Strategy," Chemistry, 2009, etc. It is carried out by appropriately improving or using a combination of the methods described in the above-mentioned methods or the methods described in the examples.
• 1-B A compound in which L 1 is -C ⁇ C-.
• .. 1-D A compound in which L 1 is -NR c-.
• L 1 is-(CR a R b ) m -NR c- , and Ra and R b are independently H, halogen atom, C 1- C 6 alkyl, or C 1- C, respectively. 6 A compound that is a haloalkyl.
• L 1 is NR c- (CR a R b ) m- , and Ra and R b are independently H, halogen atom, C 1- C 6 alkyl, or C 1- C 6 respectively.
• L 1 is-(CR a R b ) m- O-, and Ra and R b are independently H, halogen atom, C 1- C 6 alkyl, or C 1- C 6 respectively.
• 1-H L 1 is -O- (CR a R b ) m- , and Ra and R b are independently H, halogen atom, C 1- C 6 alkyl, or C 1- C 6 respectively.
• 1-J A compound in which L 1 is-(CR a R b ) m- and Ra and R b are H.
• Step1 This step is a step of obtaining compound 1-A by condensing compound 1 or a reactive compound thereof with amine compound 2 in the presence of a condensing agent.
• Examples of the reactive compound of Compound 1 include acid halides (for example, acid chlorides and acid bromides), mixed acid anhydrides, imidazolides, active amides, and the like, which are usually used in amide condensation reactions.
• acid halides for example, acid chlorides and acid bromides
• mixed acid anhydrides imidazolides
• active amides active amides, and the like, which are usually used in amide condensation reactions.
• the appropriate amount of the condensing agent and amine compound 2 used in this step is in the range of 1 molar equivalent to 3 molar equivalent with respect to compound 1, respectively.
• Examples of the condensing agent used in this step include 1,1'-carbonyldiimidazole (hereinafter referred to as "CDI”) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (hereinafter referred to as "EDCI").
• CDI 1,1'-carbonyldiimidazole
• EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
• Diisopropylcarbodiimide hereinafter referred to as "DIC"
• diethyl cyanophosphonate O- (benzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (hereinafter, “" HBTU ”)
• O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate hereinafter referred to as“ HATU ”
• HATU O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate
• a base can be used if necessary.
• the bases that can be used include organic bases such as TEA, DIPEA, N, N-dimethylaniline, and DBU.
• the amount of such base used is appropriately in the range of 1 molar equivalent to 10 molar equivalent with respect to compound 1.
• HOBt 1-hydroxybenzotriazole
• HOAt 1-hydroxy-7-azabenzotriazole
• Additives can also be added.
• the amount of the additive used is appropriately in the range of 0.1 molar equivalent to 3 molar equivalent with respect to compound 1.
• the solvent used is not particularly limited as long as it is not involved in the reaction, and is, for example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF and DME, and amides such as DMF and DMA.
• hydrocarbons such as toluene and xylene
• ethers such as 1,4-dioxane, THF and DME
• amides such as DMF and DMA.
• examples thereof include halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile and propionitrile, or a mixed solvent thereof.
• the reaction temperature varies depending on the type of raw material and reagent used, but is usually in the range of -20 ° C to 150 ° C. Further, if necessary, a microwave reactor may be used.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually in the range of 0.1 hour to 72 hours.
• R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R c , Het, X are synonymous with the above.
• R is alkyl, eg, methyl, ethyl, n-butyl. Can be mentioned.
• Step1 is a step of obtaining compound 1-AA by condensing compound 1 or a reactive compound thereof with amine compound 3 in the presence of a condensing agent. It can be produced by the same method as Step 1 of the above-mentioned compound 1-A production method.
• Step2 is a step of obtaining compound 5 by condensing compound 1 or a reactive compound thereof with amine compound 4 in the presence of a condensing agent. It can be produced by the same method as Step 1 of the above-mentioned compound 1-A production method.
• Step3 is a step of obtaining compound 6 by hydrolyzing the ester moiety of compound 5 in a suitable solvent in the presence of a suitable acid or base.
• Examples of the acid used in this step include hydrochloric acid, inorganic acids such as sulfuric acid, trifluoroacetic acid (hereinafter referred to as "TFA"), methanesulfonic acid, and organic acids such as toluenesulfonic acid.
• Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide.
• the amount of acid or base used is appropriately in the range of 1 molar equivalent to 10 molar equivalent with respect to compound 5. If necessary, an excess amount of acid or base may be used with respect to compound 5.
• the solvent used is not particularly limited as long as it is not involved in the reaction, and for example, alcohols such as methanol, ethanol and 2-propanol, ethers such as THF, diethyl ether, 1,4-dioxane and DME, acetonitrile, etc. Examples thereof include nitriles such as propionitrile, ketones such as acetone, water, or a mixed solvent thereof.
• the reaction temperature varies depending on the type of raw material and reagent used, but is usually in the range of 20 ° C. to 200 ° C., preferably 20 ° C. to 100 ° C. Further, if necessary, a microwave reactor may be used.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually in the range of 0.5 hours to 4 days.
• Step4 is a step of obtaining compound 1-AA by condensing compound 6 or a reactive compound thereof with amine compound 7 in the presence of a condensing agent, and is the same method as in Step 1 of the above-mentioned production method of compound 1-A.
• Step1 This step is a step of obtaining compound 1-B by coupling the compound 8 and the compound 9 in the presence of a transition metal such as palladium.
• the amount of compound 9 to be used is appropriately in the range of 0.5 molar equivalent to 3 molar equivalent with respect to compound 8.
• the organometallic catalyst used in this reaction is not particularly limited.
• Preferred examples of the organic metal catalyst tris (dibenzylideneacetone) bis palladium chloroform adduct (hereinafter, referred to as "Pd 2 (dba) 3 ⁇ CHCl 3”), tris (dibenzylideneacetone) bis palladium (hereinafter, “Pd 2 (dba) 3 "), tetraxtriphenylphosphalladium (hereinafter referred to as” Pd (PPh 3 ) 4 "), [1,1'-bis (diphenylphosphino) ferrocene] -dichloropalladium (II) ⁇ dichloromethane Additives (hereinafter referred to as "Pd (dppf) Cl 2 ⁇ CH 2 Cl 2 "), bis (triphenylphosphine) palladium (II) dichloride (hereinafter referred to as "PdCl 2 (PPh 3
• the amount of transition metal used is, for example, appropriately in the range of 0.01 molar equivalent to 0.3 molar equivalent with respect to compound 8.
• a base or a salt may be used if necessary.
• the base or salt used include potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and their solutions, and triethylamine (hereinafter, "TEA”).
• TEA triethylamine
• DIPEA N, N-diisopropylethylamine
• bases or salts such as lithium chloride and copper (I) iodide.
• the amount of base used is appropriately in the range of, for example, 1 molar equivalent to 4 molar equivalent with respect to compound 8.
• a suitable ligand may be used if necessary.
• ligands that can be used include, for example, 1,1'-bis (diphenylphosphine) ferrocene (hereinafter referred to as "dppf") and 4,5-bis (diphenylphosphine) -9,9-dimethyl.
• Xantene hereinafter referred to as "Xantphos”
• 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl hereinafter referred to as "XPhos”
• 2,2'-bis (diphenylphosphino) -1 1, 1'-binaphthyl
• BINAP 2,2'-bis (diphenylphosphino) -1 , 1'-binaphthyl
• RuPhos 2-dicyclohexylphosphino-2', 6'-diisopropylbiphenyl
• Ph 3 triphenylphosphine
• Examples thereof include tricyclohexylphosphine (hereinafter referred to as “PCy 3 ”).
• the amount of the ligand to be used is, for example, appropriately in the range of 1 molar equivalent to 5 molar equivalent with respect to the transition metal to be used.
• the solvent used in this step is not particularly limited as long as it is not involved in the reaction, and is, for example, hydrocarbons such as toluene and xylene, 1,4-dioxane, tetrahydrofuran (hereinafter referred to as "THF"), and dimethoxyethane.
• Ethers such as (hereinafter referred to as "DME"), N, N-dimethylformamide (hereinafter referred to as “DMF”), N, N-dimethylacetamide (hereinafter referred to as "DMA”), N-methylpyrrolidone (hereinafter referred to as "DMA”).
• DME N, N-dimethylformamide
• DMA N-dimethylacetamide
• DMA N-methylpyrrolidone
• Examples thereof include amides (referred to as "NMP"), alcohols such as ethanol, 2-propanol, tert-butanol, water, or a mixed solvent thereof.
• the reaction temperature varies depending on the type of raw material and reagent used, but is usually in the range of 20 ° C to 200 ° C. Further, if necessary, a microwave reactor may be used.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually in the range of 0.1 hour to 24 hours.
• a compound in which L 2 is ⁇ (CR a R b ) m ⁇ NR c ⁇ , and Ra and R b are combined with the carbon atom to which they are bonded to form C O (compound).
• 1-BB can also be produced as follows.
• Step1 This step is a step of obtaining an alkyne compound 12 by coupling compound 10 and compound 11 in the presence of a transition metal such as palladium, respectively, and is produced by the same method as in Step 1 of compound 1-B. can do.
• Step2 This step is a step of deprotecting Z to obtain compound 13, for example, "Greene's Protective Groups in Organic Synthesis” by Wuts and Greene, 4th Edition, John Wiley & Sons. Inc. , 2006, or by PJ Kocienski, "Protecting Groups,” 3rd Edition, Thiem, 2005.
• Step3 is a step of obtaining compound 15 by coupling compound 13 and compound 14 in the presence of a transition metal such as palladium, respectively, and is produced by the same method as in Step 1 of compound 1-B. be able to.
• Step4 is a step of obtaining compound 16 by hydrolyzing the ester portion of compound 15 in a suitable solvent in the presence of a suitable acid or base, and is the same method as in Step 3 of the production method of compound 1-AA.
• Step5 This step is a step of obtaining compound 1-BB by condensing compound 16 or a reactive compound thereof with amine compound 17 in the presence of a condensing agent, and is the same method as in Step 1 of the above-mentioned production method of compound 1-A.
• Step1 This step is a step of obtaining compound 1-C by condensing compound 19 or a reactive compound thereof with amine compound 18 in the presence of a condensing agent, and is the same method as in Step 1 of the above-mentioned production method of compound 1-A.
• Step1 This step is a step of obtaining compound 1-D by coupling the compound 20 and the compound 21 in the presence of a transition metal such as palladium.
• the amount of compound 21 to be used is appropriately in the range of 0.5 molar equivalent to 3 molar equivalent with respect to compound 20.
• the organometallic catalyst used in this reaction is not particularly limited.
• Preferred examples of the organic metal catalyst tris (dibenzylideneacetone) bis palladium chloroform adduct (hereinafter, referred to as "Pd 2 (dba) 3 ⁇ CHCl 3”), tris (dibenzylideneacetone) bis palladium (hereinafter, “Pd 2 (dba) 3 "), tetraxtriphenylphosphalladium (hereinafter referred to as” Pd (PPh 3 ) 4 "), [1,1'-bis (diphenylphosphino) ferrocene] -dichloropalladium (II) ⁇ dichloromethane Additives (hereinafter referred to as "Pd (dppf) Cl 2 ⁇ CH 2 Cl 2 "), bis (triphenylphosphine) palladium (II) dichloride (hereinafter referred to as "PdCl 2 (PPh 3
• the amount of transition metal used is, for example, appropriately in the range of 0.01 molar equivalent to 0.3 molar equivalent with respect to compound 20.
• a base or a salt may be used if necessary.
• the base or salt used include potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and their solutions, and triethylamine (hereinafter, "TEA”).
• TEA triethylamine
• DIPEA N, N-diisopropylethylamine
• bases or salts such as lithium chloride and copper (I) iodide.
• the amount of base to be used is appropriately in the range of, for example, 1 molar equivalent to 4 molar equivalent with respect to compound 20.
• a suitable ligand may be used if necessary.
• ligands that can be used include, for example, 1,1'-bis (diphenylphosphine) ferrocene (hereinafter referred to as "dppf") and 4,5-bis (diphenylphosphine) -9,9-dimethyl.
• Xantene hereinafter referred to as "Xantphos”
• 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl hereinafter referred to as "XPhos”
• 2,2'-bis (diphenylphosphino) -1 1, 1'-binaphthyl
• BINAP 2,2'-bis (diphenylphosphino) -1 , 1'-binaphthyl
• RuPhos 2-dicyclohexylphosphino-2', 6'-diisopropylbiphenyl
• Ph 3 triphenylphosphine
• Examples thereof include tricyclohexylphosphine (hereinafter referred to as “PCy 3 ”).
• the amount of the ligand to be used is, for example, appropriately in the range of 1 molar equivalent to 5 molar equivalent with respect to the transition metal to be used.
• the solvent used in this step is not particularly limited as long as it is not involved in the reaction, and is, for example, hydrocarbons such as toluene and xylene, 1,4-dioxane, tetrahydrofuran (hereinafter referred to as "THF"), and dimethoxyethane.
• Ethers such as (hereinafter referred to as "DME"), N, N-dimethylformamide (hereinafter referred to as “DMF”), N, N-dimethylacetamide (hereinafter referred to as "DMA”), N-methylpyrrolidone (hereinafter referred to as "DMA”).
• DME N, N-dimethylformamide
• DMA N-dimethylacetamide
• DMA N-methylpyrrolidone
• Examples thereof include amides (referred to as "NMP"), alcohols such as ethanol, 2-propanol, tert-butanol, water, or a mixed solvent thereof.
• the reaction temperature varies depending on the type of raw material and reagent used, but is usually in the range of 20 ° C to 200 ° C. Further, if necessary, a microwave reactor may be used.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually in the range of 0.1 hour to 24 hours.
• Step1 This step is a step of obtaining compound 1-E by coupling the compound 22 and the compound 23 in the presence of a transition metal such as palladium, respectively, and is the same as the above-mentioned manufacturing method of compound 1-D, Step 1. It can be manufactured by the method.
• L 1 is ⁇ (CR a R b ) m ⁇ NR c ⁇ and Ra and R b are H, it can also be produced as follows.
• Step1 is a step of obtaining compound 1-EE by a reductive amination reaction of compound 24 and compound 23, and can be carried out according to a method known as a reductive amination reaction.
• imine formation (first step) and reduction of the imine portion (second step) can also be carried out stepwise.
• the amount of compound 23 to be used is appropriately in the range of 1 molar equivalent to 2.5 molar equivalent with respect to compound 24.
• an acid or an appropriate Lewis acid can be used if necessary.
• the acid that can be used in the reaction include acetic acid, and examples of the Lewis acid that can be used include tetraisopropyl orthotitanium.
• the amount of acid used is appropriately in the range of 2 molar equivalents to 3 molar equivalents with respect to the amount of compound 24.
• the amount of Lewis acid used is appropriately in the range of 1.5 molar equivalents to 2 molar equivalents with respect to the amount of compound 24.
• the solvent used in this step is not particularly limited as long as it is not involved in the reaction, but for example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF and DME, and halogens such as dichloromethane. Hydrocarbons or a mixed solvent thereof can be mentioned.
• the reaction temperature varies depending on the type of raw material and reagent used, but is usually in the range of 0 ° C to 100 ° C.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually in the range of 0.1 hour to 48 hours.
• Examples of the reducing agent used in this step include sodium triacetoxyborohydride and sodium cyanoborohydride.
• the amount of the reducing agent used in this step is appropriately in the range of 1 molar equivalent to 2 molar equivalent with respect to compound 24.
• the solvent used in this step is not particularly limited as long as it is not involved in the reaction, but for example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF and DME, and halogenation of dichloromethane and the like. Hydrocarbons or a mixed solvent thereof can be mentioned.
• Step1 This step is a step of obtaining compound 1-F by reacting compound 25 with compound 26 in the presence of a base.
• the amount of compound 26 to be used is appropriately in the range of 0.5 molar equivalent to 3 molar equivalent with respect to compound 25.
• Examples of the base used in this reaction include pyridine, TEA, DIPEA, potassium carbonate, and sodium hydrogen carbonate.
• the amount of base used is appropriately in the range of 1 molar equivalent to 10 molar equivalent with respect to compound 25.
• the solvent used is not particularly limited as long as it is not involved in the reaction, and for example, alcohols such as isopropanol, 1-butanol and 2-methoxyethanol, ethers such as THF and 1,4-dioxane, DMF and DMA, Examples thereof include amides such as NMP, hydrocarbons such as benzene and toluene, dimethyl sulfoxide (hereinafter referred to as "DMSO"), acetonitrile, or a mixed solvent thereof.
• alcohols such as isopropanol, 1-butanol and 2-methoxyethanol
• ethers such as THF and 1,4-dioxane
• DMF and DMA examples thereof include amides such as NMP, hydrocarbons such as benzene and toluene, dimethyl sulfoxide (hereinafter referred to as "DMSO"), acetonitrile, or a mixed solvent thereof.
• DMSO dimethyl sulfoxide
• the reaction temperature varies depending on the type of raw material and reagent used, but is usually in the range of 20 ° C to 200 ° C. Further, if necessary, a microwave reactor may be used.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually in the range of 1 hour to 24 hours.
• L 1 is -NR c- (CR a R b ) m- and Ra and R b are H, it can also be produced as follows.
• Step1 This step is a step of obtaining compound 1-FF by a reductive amination reaction between compound 27 and compound 28, and can be produced by the same method as Step 1 of the above-mentioned compound 1-EE production method.
• Step1 This step is a step of obtaining the ether compound 1-G by the Mitsunobu reaction of the alcohol compound 29 and the alcohol compound 30, and can be carried out according to a known method.
• This step is usually carried out in a suitable solvent in the presence of an azodicarboxylic acid ester reagent and a phosphine reagent.
• the amount of compound 29 to be used is appropriately in the range of 0.5 molar equivalent to 1.5 molar equivalent with respect to compound 30.
• Examples of the azodicarboxylic acid ester reagent used include diethyl azodicarboxylate (hereinafter referred to as "DEAD”), diisopropyl azodicarboxylate (hereinafter referred to as “DIAD”), and bis (2-methoxyethyl) azodicarboxy.
• DEAD diethyl azodicarboxylate
• DIAD diisopropyl azodicarboxylate
• DMEAD bis (2-methoxyethyl) azodicarboxy.
• a rate hereinafter referred to as "DMEAD” and the like can be mentioned.
• Examples of the phosphine reagent used include triphenylphosphine and tributylphosphine.
• the amount of the azodicarboxylate reagent used is appropriately in the range of 1 molar equivalent to 2 molar equivalent with respect to the compound 29.
• the amount of phosphine reagent used is appropriately in the range of 1 molar equivalent to 2 molar equivalent with respect to compound 29.
• the solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, THF and DME, or a mixed solvent thereof. Can be done.
• the reaction temperature varies depending on the type of raw material and reagent used, but is usually in the range of 0 ° C to 100 ° C.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually in the range of 0.5 hours to 24 hours.
• Step1 This step is a step of obtaining the ether compound 1-H by the Mitsunobu reaction of the alcohol compound 31 and the alcohol compound 32, and can be produced by the same method as Step 1 of the above-mentioned compound 1-G production method.
• Step1 This step is a step of obtaining compound 1-I by subjecting compound 33 and compound 34 to each coupling reaction in the presence of a transition metal such as palladium.
• the amount of compound 33 to be used is appropriately in the range of 0.5 molar equivalent to 3 molar equivalent with respect to compound 34.
• the organometallic catalyst used in this reaction is not particularly limited.
• Preferred examples of the organic metal catalyst tris (dibenzylideneacetone) bis palladium chloroform adduct (hereinafter, referred to as "Pd 2 (dba) 3 ⁇ CHCl 3”), tris (dibenzylideneacetone) bis palladium (hereinafter, “Pd 2 (dba) 3 "), tetraxtriphenylphosphalladium (hereinafter referred to as” Pd (PPh 3 ) 4 "), [1,1'-bis (diphenylphosphino) ferrocene] -dichloropalladium (II) ⁇ dichloromethane Additives (hereinafter referred to as "Pd (dppf) Cl 2 ⁇ CH 2 Cl 2 "), bis (triphenylphosphine) palladium (II) dichloride (hereinafter referred to as "PdCl 2 (PPh 3
• the amount of transition metal used is, for example, appropriately in the range of 0.01 molar equivalent to 0.3 molar equivalent with respect to compound 33.
• a base or a salt may be used if necessary.
• the base or salt used include potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and their solutions, and triethylamine (hereinafter, "TEA”).
• TEA triethylamine
• DIPEA N, N-diisopropylethylamine
• bases or salts such as lithium chloride and copper (I) iodide.
• the amount of base to be used is appropriately in the range of, for example, 1 molar equivalent to 4 molar equivalent with respect to compound 33.
• a suitable ligand may be used if necessary.
• ligands that can be used include, for example, 1,1'-bis (diphenylphosphine) ferrocene (hereinafter referred to as "dppf") and 4,5-bis (diphenylphosphine) -9,9-dimethyl.
• Xantene hereinafter referred to as "Xantphos”
• 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl hereinafter referred to as "XPhos”
• 2,2'-bis (diphenylphosphino) -1 1, 1'-binaphthyl
• BINAP 2,2'-bis (diphenylphosphino) -1 , 1'-binaphthyl
• RuPhos 2-dicyclohexylphosphino-2', 6'-diisopropylbiphenyl
• Ph 3 triphenylphosphine
• Examples thereof include tricyclohexylphosphine (hereinafter referred to as “PCy 3 ”).
• the amount of the ligand to be used is, for example, appropriately in the range of 1 molar equivalent to 5 molar equivalent with respect to the transition metal to be used.
• the solvent used in this step is not particularly limited as long as it is not involved in the reaction, and is, for example, hydrocarbons such as toluene and xylene, 1,4-dioxane, tetrahydrofuran (hereinafter referred to as "THF"), and dimethoxyethane.
• Ethers such as (hereinafter referred to as "DME"), N, N-dimethylformamide (hereinafter referred to as “DMF”), N, N-dimethylacetamide (hereinafter referred to as "DMA”), N-methylpyrrolidone (hereinafter referred to as "DMA”).
• DME N, N-dimethylformamide
• DMA N-dimethylacetamide
• DMA N-methylpyrrolidone
• Examples thereof include amides (referred to as "NMP"), alcohols such as ethanol, 2-propanol, tert-butanol, water, or a mixed solvent thereof.
• the reaction temperature varies depending on the type of raw material and reagent used, but is usually in the range of 20 ° C to 200 ° C. Further, if necessary, a microwave reactor may be used.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually in the range of 0.1 hour to 24 hours.
• This step is a step of obtaining compound 1-K by subjecting compound 35 and compound 36 to each coupling reaction in the presence of a transition metal such as palladium.
• the amount of compound 36 to be used is appropriately in the range of 0.5 molar equivalent to 3 molar equivalent with respect to compound 35.
• the organometallic catalyst used in this reaction is not particularly limited.
• Preferred examples of the organic metal catalyst tris (dibenzylideneacetone) bis palladium chloroform adduct (hereinafter, referred to as "Pd 2 (dba) 3 ⁇ CHCl 3”), tris (dibenzylideneacetone) bis palladium (hereinafter, “Pd 2 (dba) 3 "), tetraxtriphenylphosphalladium (hereinafter referred to as” Pd (PPh 3 ) 4 "), [1,1'-bis (diphenylphosphino) ferrocene] -dichloropalladium (II) ⁇ dichloromethane Additives (hereinafter referred to as "Pd (dppf) Cl 2 ⁇ CH 2 Cl 2 "), bis (triphenylphosphine) palladium (II) dichloride (hereinafter referred to as "PdCl 2 (PPh 3
• the amount of transition metal used is, for example, appropriately in the range of 0.01 molar equivalent to 0.3 molar equivalent with respect to compound 35.
• a base or a salt may be used if necessary.
• the base or salt used include potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium acetate, potassium acetate, trisodium phosphate, tripotassium phosphate and their solutions, and triethylamine (hereinafter, "TEA”).
• TEA triethylamine
• DIPEA N, N-diisopropylethylamine
• bases or salts such as lithium chloride and copper (I) iodide.
• the amount of base to be used is appropriately in the range of, for example, 1 molar equivalent to 4 molar equivalent with respect to compound 35.
• a suitable ligand may be used if necessary.
• ligands that can be used include, for example, 1,1'-bis (diphenylphosphine) ferrocene (hereinafter referred to as "dppf") and 4,5-bis (diphenylphosphine) -9,9-dimethyl.
• Xantene hereinafter referred to as "Xantphos”
• 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl hereinafter referred to as "XPhos”
• 2,2'-bis (diphenylphosphino) -1 1, 1'-binaphthyl
• BINAP 2,2'-bis (diphenylphosphino) -1 , 1'-binaphthyl
• RuPhos 2-dicyclohexylphosphino-2', 6'-diisopropylbiphenyl
• Ph 3 triphenylphosphine
• Examples thereof include tricyclohexylphosphine (hereinafter referred to as “PCy 3 ”).
• the amount of the ligand to be used is, for example, appropriately in the range of 1 molar equivalent to 5 molar equivalent with respect to the transition metal to be used.
• the solvent used in this step is not particularly limited as long as it is not involved in the reaction, and is, for example, hydrocarbons such as toluene and xylene, 1,4-dioxane, tetrahydrofuran (hereinafter referred to as "THF"), and dimethoxyethane.
• Ethers such as (hereinafter referred to as "DME"), N, N-dimethylformamide (hereinafter referred to as “DMF”), N, N-dimethylacetamide (hereinafter referred to as "DMA”), N-methylpyrrolidone (hereinafter referred to as "DMA”).
• DME N, N-dimethylformamide
• DMA N-dimethylacetamide
• DMA N-methylpyrrolidone
• Examples thereof include amides (referred to as "NMP"), alcohols such as ethanol, 2-propanol, tert-butanol, water, or a mixed solvent thereof.
• the reaction temperature varies depending on the type of raw material and reagent used, but is usually in the range of 20 ° C to 200 ° C. Further, if necessary, a microwave reactor may be used.
• the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually in the range of 0.1 hour to 24 hours.
• the compound of the present invention has PDGF receptor kinase inhibitory activity, as shown in the test examples described later.
• the compound of the present invention has PDGF receptor kinase inhibitory activity, respiratory disease, cancer, smooth muscle proliferative disease, vasoproliferative disease, autoimmune / inflammatory disease, metabolic disease, vascular obstruction It is effective for sexual diseases.
• the PDGF receptor kinase inhibitory activity of the compound of the present invention has high selectivity for the inhibitory activity of KIT kinase as shown in the test examples described later, the compound of the present invention can be used for bone marrow suppression and the like. It can be expected to provide a PDGF receptor kinase inhibitor in which undesired effects are suppressed.
• the compound of the present invention or a pharmaceutically acceptable salt thereof can be used, for example, as a prophylactic or therapeutic agent for diseases involving PDGF receptor kinase.
• Respiratory diseases to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied include lung disease and pulmonary hypertension.
• pulmonary hypertension is classified as follows according to the pathogenesis and pathophysiology.
• ⁇ Pulmonary arterial hypertension (PAH) Pulmonary arterial hypertension (PAH)
• ⁇ Pulmonary hypertension due to the following left heart diseases Left heart failure, which maintained ejection fraction, Left heart failure with reduced ejection fraction, Valvular disease, Congenital / acquired cardiovascular conditions leading to post-capillary PH that induces acquired capillary hypertension
• Lung disease associated with the following diseases and / or pulmonary hypertension due to hypoxemia Chronic Obstructive Pulmonary Disease (COPD), Interstitial (restrictive) lung disease,
• COPD Chronic Obstructive Pulmonary Disease
• COPD Interstitial (restrictive) lung disease
• Other lung diseases with a mixed disorder of restrictive and obstructive Hypoxia associated with lung disease, or the following pulmonary hypertension associated with stunte
• PAH pulmonary arterial hypertension
• Hereditary PAH especially BMPR2, TBX4, ACVRL1, ENG, SMAD9, KCNK3, SMAD1, CAV1, SMAD4, ATP13A3, SOX17, AQP1, GDF2, unknown genetic abnormality, Drug- and toxic-induced PAHs, PAH associated with the disease (where "disease” is, for example, connective tissue disease, HIV infection, portal hypertension, congenital shunt heart disease, schistosomiasis), PAH showing long-term response to calcium channel blockers (PAH long-term responders to calcium channel blockers), pulmonary vein obstructive disease / pulmonary capillary hemangioma (PVOD / PCH) (including PVOD / PCH with EIF2AK4 mutation) , Includes neonatal protracted pulmonary hypertension (PPHN).
• PVOD / PCH pulmonary vein obstructive disease / pulmonary capillary hemangioma
• the inflammatory diseases and autoimmune diseases to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied include dermatomyositis, asthma, obstructive bronchitis, pulmonary fibrosis, systemic lupus erythematosus (SLE), and mixed binding.
• Tissue disease Sjogren's syndrome, polymyositis / dermatomyositis, Crohn's disease, ulcerative colitis, hypocytopenia, hypersensitivity bowel syndrome (IBS), inflammatory bowel disease (IBD), allergic rhinitis, allergic Dermatomyositis, interstitial lung disease, idiopathic interstitial pneumonia, chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis with emphysema (CPFE), adult respiratory compression syndrome (ARDS), lupus, rheumatoid arthritis, Examples include obestitial cell disease, anaphylactic syndrome, vascular edema, lupus erythematosus, multiple erythematosus, dermatomyositis, skin inflammation / disease, urticaria, and allergic contact dermatitis.
• IBS hypersensitivity bowel syndrome
• IBD inflammatory bowel disease
• COPD chronic obstructive pulmonary disease
• Cancers to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied include acute myelogenous leukemia (AML), eosinophilia syndrome, T lymphoblastic leukemia, and chronic myelomonocytic leukemia.
• AML acute myelogenous leukemia
• eosinophilia syndrome eosinophilia syndrome
• T lymphoblastic leukemia eosinophilia syndrome
• chronic myelomonocytic leukemia chronic myelomonocytic leukemia.
• Chronic myelogenous leukemia CMML
• chronic myelogenous leukemia CML
• chronic myelogenous leukemia myelogenous leukemia
• elevated cutaneous fibrosarcoma glioma, ovarian cancer
• endometrial Tumors hepatocellular carcinoma, thyroid cancer
• small cell lung cancer non-small cell lung cancer, renal cancer, soft sarcoma
• neuroendocrine tumor skin cancer
• mesenteric tumor biliary tract cancer
• squamous epithelium of the head and neck Cancer colon cancer
• mesenchymal cell tumor adenocarcinoma
• pancreatic cancer myelocytosis
• gastrointestinal stromal tumor GIST
• Smooth muscle proliferative diseases to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied include vascular re-angina, atherosclerosis / arteriosclerosis obliterans, moyamoya disease (idiopathic Willis arterial ring occlusion), smooth muscle tumor, and the like.
• vascular re-angina vascular re-angina
• arteriosclerosis obliterans vascular re-angina
• moyamoya disease idiopathic Willis arterial ring occlusion
• smooth muscle tumor and the like.
• Examples include lymphovascular myomatosis, Williams syndrome, tuberous sclerosis, angina, myocardial infarction, peripheral arterial disease, hypertrophic / dilated cardiomyopathy, and restraint / diastolic cardiomyopathy.
• ASD age-related macular degeneration
• Osler's disease hereditary hemorrhagic peripheral vasodilation
• blood vessels Tumors, tumor angioma, arteriovenous fistula can be mentioned.
• Diabetes mellitus type 1 diabetes or type 2 diabetes
• a metabolic disease to which the compound of the present invention or a pharmaceutically acceptable salt thereof can be applied.
• the compound of the present invention may be used as it is or mixed with a pharmacologically acceptable carrier or the like to prepare a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%.
• a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%.
• it can be used as a therapeutic agent for the above-mentioned various diseases for mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys.
• the dosage is desirable to adjust the dosage as a drug in consideration of the patient's condition such as age, body weight, type and degree of disease, administration route, type of compound of the present invention, salt or not, type of salt, etc.
• the amount of the active ingredient of the compound of the present invention or a pharmaceutically acceptable salt thereof for an adult is in the range of 0.01 mg to 5 g / adult per day, preferably 1 mg to, in the case of oral administration.
• the range of 500 mg / adult is appropriate. In some cases, less than this may be sufficient, and vice versa.
• it is administered once or in several divided doses a day, or in the case of intravenous administration, it can be administered rapidly or continuously within 24 hours.
• One or more hydrogen, carbon and / or other atoms of the compounds of the invention may be substituted with isotopes of hydrogen, carbon and / or other atoms, respectively.
• isotopes include 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and, respectively.
• 36 Cl, ie hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
• Compounds substituted with such isotopes are also useful as pharmaceuticals and include all radioactive labels of the compounds of the invention.
• TFA Trifluoroacetate Pd-C: Palladium-carbon Pd 2 (dba) 3 : Tris (dibenzylideneacetone) Bispalladium Pd (PPh 3 ) 4 : Tetrakistriphenylphosphine palladium PdCl 2 (PPh 3 ) 2 : Bis (tri) Phenylphosphine) Palladium (II) Dichloride Pd (OAc) 2 : Palladium acetate (II) Tetrahydrofuran: 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene BINAP: 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl PPh 3 : triphenylphosphine Boc 2 O: 2 Di-tert-butyl HATU carbonate: O- (7-azabenzotriazole-1-yl)
• MS was measured by LCMS.
• ESI method was used as the ionization method.
• the observed mass spectrometric values are expressed in m / z.
• Initiator 60 manufactured by Biotage was used. Temperatures of 40-250 ° C can be achieved and pressures up to 20 bar can be reached.
• the r and s (lowercase) of the compound name indicate the stereochemistry of the pseudo-asymmetric carbon atom according to the IUPAC rules.
• the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, ethyl acetate was added to the obtained residue to suspend it, and the precipitate was collected by filtration to give the title compound (6.10 g).
• Step 2 Production of Methyl 4-Chloro-3-ethynylbenzoate
• the methyl 4-chloro-3-[(trimethylsilyl) ethynyl] benzoate (6.8 g) obtained in Step 1 was dissolved in THF (85 mL) and TBAF was added. (1 M THF solution, 31 mL) was added and stirred at room temperature for 30 minutes.
• reaction mixture was diluted with ethyl acetate and water was added.
• the reaction mixture was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure.
• the residue was purified by silica gel column chromatography to give the title compound (34 g).
• Step 2 Production of 5- (2H-1,2,3-triazole-2-yl) Pyridine-3-carbaldehyde by the method according to Step 2 of Reference Example 19 (Pyrazolo [5,1-b]] Instead of [1,3] thiazole-7-yl) methanol, [5- (2H-1,2,3-triazole-2-yl) pyridin-3-yl] methanol obtained in step 1 was used. The title compound (22 mg) was obtained.
• Reference Example 36 5-Bromo-N- (Oxan-4-yl) Pyridine-3-amine
• Step 1 of Reference Example 1 methyl 5-bromopyridin-3-carboxylate and 1-cyclopropylmethaneamine.
• 3,5-Dibromopyridine and oxane-4-amine were used in place of the title compound (230 mg).
• Step 2 Production of di-tert-butyl 5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-2-yl-2-imide dicarbonate
• the benzyl 2- obtained in step 1 [Bis (tert-butoxycarbonyl) amino] -7,8-dihydropyrido [4,3-d] pyrimidine-6 (5H) -carboxylate (960 mg) in a methanol (100 mL) solution, degassed, and then under an argon atmosphere. , 5% Pd-C (400 mg) was added while stirring at room temperature, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), and the solvent was evaporated under reduced pressure to give the title compound (700 mg).
• Example 1 2- (Cyclopropylamino) -N- (5- ⁇ [(1S, 2S) -2-hydroxycyclohexyl] carbamoyl ⁇ -2-methylphenyl) -1,3-thiazole-5-carboxamide [Step 1] ] Methyl 3-[(2-Bromo-1,3-thiazole-5-carbonyl) amino] -4-methylbenzoate production 2-bromo-1,3-thiazole-5-carboxylic acid (2.20 g) DMF Methyl 3-amino-4-methylbenzoate (1.75 g), HATU (4.83 g) and DIPEA (3.66 mL) were sequentially added to the (20 mL) solution, and the mixture was stirred at room temperature for 6 hours.
• reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.02 g).
• Step 2 Production of Methyl 3- ⁇ [2- (Cyclopropylamino) -1,3-thiazole-5-carbonyl] Amino ⁇ -4-methylbenzoate Methyl 3-[(2-) obtained in Step 1 Cyclopropanamine (121 mg) was added to a solution of bromo-1,3-thiazole-5-carbonyl) amino] -4-methylbenzoate (150 mg) in NMP (0.5 mL), and the mixture was stirred at 80 ° C. for 6 hours. The reaction mixture was allowed to cool and then purified by silica gel column chromatography to give the title compound (105 mg).
• Step 3 Production of 3- ⁇ [2- (cyclopropylamino) -1,3-thiazole-5-carbonyl] amino ⁇ -4-methylbenzoic acid Methyl 5 by the method according to step 2 of Reference Example 1. -[(Cyclopropylmethyl) amino] instead of pyridine-3-carboxylate, methyl 3- ⁇ [2- (cyclopropylamino) -1,3-thiazole-5-carbonyl] amino obtained in step 2. ⁇ -4-Methylbenzoate (103 mg) was used to give the title compound (90 mg).
• Step 4 Production of 2- (cyclopropylamino) -N- (5- ⁇ [(1S, 2S) -2-hydroxycyclohexyl] carbamoyl ⁇ -2-methylphenyl) -1,3-thiazole-5-carboxamide HATU (54 mg) in a DMF (1 mL) solution of 3- ⁇ [2- (cyclopropylamino) -1,3-thiazole-5-carbonyl] amino ⁇ -4-methylbenzoic acid (30 mg) obtained in step 3 ), And DIPEA (0.065 mL) were added sequentially, and the mixture was stirred at room temperature for 10 minutes.
• Example 2 N- (5- ⁇ [(1S, 2S) -2-hydroxycyclohexyl] carbamoyl ⁇ -2-methylphenyl) -5-phenylpyridine-3-carboxamide
• Step 1 Methyl 3-[(5-bromo) Production of Pyridine-3-carbonyl) Amino] -4-methylbenzoate
• 5-bromopyridine-instead of 2-bromo-1,3-thiazole-5-carboxylic acid was obtained using 3-carboxylic acid (1.00 g).
• Step 3 Production of 5- ⁇ [(1S, 2S) -2-hydroxycyclohexyl] carbamoyl ⁇ -2-methylphenyl) pyridine-3-carboxamide According to Step 4 of Example 1.
• 3- ⁇ [2- (cyclopropylamino) -1,3-thiazole-5-carbonyl] amino ⁇ -4-methylbenzoic acid 3-[(5-bromo) obtained in step 2 Pyridine-3-carbonyl) amino] -4-methylbenzoic acid (505 mg) was used to give the title compound (650 mg).
• Example 3 2- (Cyclopropylmethyl) -N- (5- ⁇ [(1S, 2S) -2-hydroxycyclohexyl] carbamoyl ⁇ -2-methylphenyl) -1,3-thiazole-5-carboxamide [Step 1] ] Methyl 3- ⁇ [2- (cyclopropylmethyl) -1,3-thiazole-5-carbonyl] amino ⁇ -4-methylbenzoate by the method according to step 1 of Example 1 2-bromo-1 , 3-Thiazole-5-carboxylic acid was replaced with 2- (cyclopropylmethyl) -1,3-thiazole-5-carboxylic acid (100 mg) to give the title compound (160 mg).
• Example 5 N- (5- ⁇ [(1S, 2S) -2-hydroxycyclohexyl] carbamoyl ⁇ -2-methylphenyl) -2-phenyl-1,3-oxazole-5-carboxamide
• 2-Phenyl-1,3-oxazole-5-carboxylic acid (30 mg) instead of 2-bromo-1,3-thiazole-5-carboxylic acid, methyl 3-amino-4-methylbenzoate by the same method.
• 3-Amino-N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide (43 mg) obtained in Reference Example 7 was used to obtain the title compound (53 mg).
• Example 6 N- (5- ⁇ [(1S) -2-Hydroxy-1-phenylethyl] carbamoyl ⁇ -2-methylphenyl) -5-phenylpyridine-3-carboxamide
• Step 1 Methyl 4-methyl-3 -[(5-Phenylpyridine-3-carbonyl) amino] Production of benzoate
• the step of Example 2 Using methyl 3-[(5-bromopyridin-3-carbonyl) amino] -4-methylbenzoate (1.00 g) and phenylboronic acid (419 mg) obtained in No.
• Example 17 5- [Cyclopropyl (methyl) amino] -N- (5- ⁇ [(1S, 2S) -2-hydroxycyclohexyl] carbamoyl ⁇ -2-methylphenyl) pyridine-3-carboxamide
• Step of Example 1 5- [Cyclopropyl (methyl) obtained in Reference Example 2 instead of 2-bromo-1,3-thiazole-5-carboxylic acid and methyl 3-amino-4-methylbenzoate by the method according to 1.
• Example 20 5- (3-Fluorophenyl) -N- (5- ⁇ [(1S, 2S) -2-hydroxycyclohexyl] carbamoyl ⁇ -2-methylphenyl) Pyridine-3-carboxamide A method according to Reference Example 14. In place of 2-chloropyrimidin-4-amine and isoquinolin-4-ylboronic acid, 5-bromo-N- (5- ⁇ [(1S, 2S) -2) obtained in step 3 of Example 2 was obtained.
• Example 24 5- (cyclopropylmethoxy) -N- (5- ⁇ [(1S, 2S) -2-hydroxycyclohexyl] carbamoyl ⁇ -2-methylphenyl) Pyridine-3-carboxamide According to Step 1 of Example 1.
• Example 26 2-[(2-Cyclopropylethyl) amino] -N- (5- ⁇ [(1S, 2S) -2-hydroxycyclohexyl] carbamoyl ⁇ -2-methylphenyl) -1,3-thiazole-5 -Carboxamide [Step 1] Preparation of methyl 3-[(2-chloro-1,3-thiazole-5-carbonyl) amino] -4-methylbenzoate Methyl 3-amino-4-methylbenzoate (6.89 g) THF A solution of 2-chloro-1,3-thiazole-5-carbonyl chloride (8.31 g) in THF (80 mL) was added dropwise to the (80 mL) solution under ice-cooled stirring, and the mixture was stirred at the same temperature for 30 minutes.
• Step 4 Production of N- (5- ⁇ [(1S, 2S) -2-hydroxycyclohexyl] carbamoyl ⁇ -2-methylphenyl) -5-phenylpyridine-3-carboxamide According to Step 2 of Example 1.
• 2-chloro-N- obtained in step 3 instead of methyl 3-[(2-bromo-1,3-thiazole-5-carbonyl) amino] -4-methylbenzoate, cyclopropaneamine.
• Example 57 3-[(5-Bromopyridine-3-yl) ethynyl] -4-chloro-N-[(1S, 2S) -2-hydroxycyclohexyl] benzamide
• Step 1 Methyl 3-[(5-bromo) Production of Pyridine-3-yl) ethynyl] -4-chlorobenzoate
• Reference Example 8 instead of ethynyl (trimethyl)silane and methyl 4-chloro-3-iodobenzoate by the method according to step 1 of Reference Example 8.
• Example 58 4-Chloro-N-[(1S, 2S) -2-hydroxycyclohexyl] -3-[(5-phenylpyridin-3-yl) ethynyl] benzamide
• 2-chloro instead of pyrimidine-4-amine, isoquinoline-4-ylboronic acid, 3-[(5-bromopyridin-3-yl) ethynyl] -4-chloro-N-[(1S, 1S,) obtained in Example 57.
• 2S) -2-Hydroxycyclohexyl] benzamide (50 mg) and phenylboronic acid (15 mg) were used to give the title compound (5 mg).
• Example 59 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3-[(5-methylpyridine-3-yl) ethynyl] benzamide
• ethynyl (trimethyl) silane instead of ethynyl (trimethyl) silane, methyl 4-chloro-3-iodobenzoate, 3-ethynyl-N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide obtained in Reference Example 9 (30 mg), 3-bromo-5-methylpyridine (30 mg) was used to give the title compound (14 mg).
• Example 61 3-[(5-Bromopyridine-3-yl) ethynyl] -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide
• step 1 of Reference Example 8 Instead of ethynyl (trimethyl)silane, methyl 4-chloro-3-iodobenzoate, 3-ethynyl-N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide obtained in Reference Example 9 (20.5 g), 3-bromo-5-iodopyridine (24.8 g) was used to give the title compound (14.5 g).
• Example 62 Obtained in N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [5- (pyrimidine-2-yl) pyridin-3-yl] ethynyl ⁇ benzamide
• Example 61 Obtained in N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [5- (pyrimidine-2-yl) pyridin-3-yl] ethynyl ⁇ benzamide
• Example 61 Obtained in N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [5- (pyrimidine-2-yl) pyridin-3-yl] ethynyl ⁇ benzamide
• Example 67 3-[(5-Cyclopropylpyridin-3-yl) ethynyl] -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide
• 2- isoquinoline-4-ylboronic acid
• 2-Hydroxycyclohexyl] -4-methylbenzamide 400 mg
• cyclopropylboronic acid (249 mg) were used to give the title compound (250 mg).
• Example 76 3-[(5-bromopyridin-3-yl) ethynyl] -N-[(1S, 2S) -1,3-dihydroxy-1-phenylpropan-2-yl] -4-methylbenzamide [step 1] Production of 3-[(5-bromopyridin-3-yl) ethynyl] -4-methylbenzoic acid By the method according to step 1 of Reference Example 8, ethynyl (trimethyl) silane, methyl 4-chloro-3- Instead of iodobenzoate, 3-ethynyl-4-methylbenzoic acid (40 mg) and 3-bromo-5-iodopyridine (71 mg) were used to give the title compound (47 mg).
• Example 78 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [2- (pyridin-3-yl) pyrimidin-4-yl] amino ⁇ benzamide
• Step 1 Methyl 4 Production of -Methyl-3- ⁇ [2- (pyridin-3-yl) pyrimidin-4-yl] amino ⁇ benzoate
• Methyl 5-bromopyridin-3-carboxylate according to the method according to step 1 of Reference Example 1.
• Step 3 Production of N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [2- (pyridin-3-yl) pyrimidin-4-yl] amino ⁇ benzamide
• Example 1 In place of 3- ⁇ [2- (cyclopropylamino) -1,3-thiazole-5-carbonyl] amino ⁇ -4-methylbenzoic acid, 4-methyl-3- ⁇ [2- (Pyridine-3-yl) pyrimidin-4-yl] amino ⁇ benzoic acid (50 mg) was used to give the title compound (50 mg).
• Example 83 3- (2-amino-7,8-dihydropyrido [4,3-d] pyrimidin-6 (5H) -yl) -N-[(1S, 2S) -1,3-dihydroxy-1-phenyl Propane-2-yl] -4-methylbenzamide [Step 1] Methyl 3- ⁇ 2- [bis (tert-butoxycarbonyl) amino] -7,8-dihydropyrido [4,3-d] pyrimidin-6 (5H) -Il ⁇ -4-methylbenzoate production Methyl 3-bromo-4- instead of methyl 5-bromopyridine-3-carboxylate and 1-cyclopropylmethaneamine by the method according to step 1 of Reference Example 1.
• Example 84 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [(1S) -1- (5-phenylpyridine-3-yl) ethyl] amino ⁇ benzamide [Step 1] ] Methyl 4-methyl-3- ⁇ [(1S) -1- (5-phenylpyridine-3-yl) ethyl] amino ⁇ benzoate production Methyl 5-bromopyridine by the method according to step 1 of Reference Example 1. Instead of -3-carboxylate, 1-cyclopropylmethaneamine, methyl 3-bromo-4-methylbenzoate (324 mg), obtained in Reference Example 15, (1S) -1- (5-phenylpyridine-3).
• Example 85 3- ⁇ [(1S) -1-([3,3'-bipyridine] -5-yl) ethyl] amino ⁇ -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl Benzamide [Step 1] Production of Methyl 3- ⁇ [(1S) -1-([3,3'-bipyridine] -5-yl) Ethyl] Amino ⁇ -4-methylbenzoate According to Step 1 of Reference Example 1. By the method, instead of methyl 5-bromopyridine-3-carboxylate, 1-cyclopropylmethaneamine, methyl 3-bromo-4-methylbenzoate (13.9 g), obtained in Reference Example 16 (1S)-.
• Example 89 3- ⁇ [(1S) -1-([2,3'-bipyridine] -5'-yl) ethyl] amino ⁇ -N-[(1S, 2S) -2-hydroxycyclohexyl] -4- methylbenzamide [step 1] methyl 3 - ⁇ [(1S) -1 - ([2,3'- bipyridine] -5-yl) ethyl] amino ⁇ in step 1 of reference example 10 4-methylbenzoate
• methyl 3- ⁇ [(1R) -1- (5-) obtained in step 1 of Example 87 was obtained.
• Example 92 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [(5-phenylpyridin-3-yl) methyl] amino ⁇ benzamide by the method according to Reference Example 14. Instead of 2-chloropyrimidine-4-amine, isoquinolin-4-ylboronic acid, 3- ⁇ [(5-bromopyridin-3-yl) methyl] amino ⁇ -N-[((5-bromopyridin-3-yl) methyl] amino ⁇ -N-[((5-bromopyridin-3-yl) methyl] amino ⁇ -N-[((5-bromopyridin-3-yl) methyl] amino ⁇ -N-[( 1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide (30 mg) and phenylboronic acid (10 mg) were used to give the title compound (23 mg).
• Example 94 3-( ⁇ [5- (cyclopropylethynyl) pyridin-3-yl] methyl ⁇ amino) -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide
• Reference Example 8 step In place of ethynyl (trimethyl) silane, methyl 4-chloro-3-iodobenzoate, ethynylcyclopropane (63 mg), 3- ⁇ [(5-bromopyridine), obtained in Example 91, by the method according to 1.
• Example 96 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [(quinoline-3-yl) methyl] amino ⁇ benzamide
• step 1 methyl 4-methyl-3- ⁇ Production of [(quinoline-3-yl) methyl] amino ⁇ benzoate
• methyl 3-amino-4-methyl The title compound (230 mg) was obtained using benzoate (210 mg) and quinoline-3-carbaldehyde (200 mg).
• Step 2 Production of 4-methyl-3- ⁇ [(quinoline-3-yl) methyl] amino ⁇ benzoic acid Methyl 5-[(cyclopropylmethyl) amino] by the method according to step 2 of Reference Example 1. Instead of pyridine-3-carboxylate, methyl 4-methyl-3- ⁇ [(quinoline-3-yl) methyl] amino ⁇ benzoate (230 mg) obtained in step 1 was used to give the title compound (200 mg). Obtained.
• Step 3 Production of N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [(quinolin-3-yl) methyl] amino ⁇ benzamide According to Step 4 of Example 1.
• Example 98 3-[( ⁇ 5- [4- (2-aminopropan-2-yl) phenyl] pyridin-3-yl ⁇ methyl) amino] -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-Methylbenzamide
• Step 1 of Reference Example 10 3- ⁇ [(()) obtained in Example 91 instead of 3-bromo-5- (methoxymethoxy) pyridine and 2-bromopyrimidine.
• Example 101 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [(6-phenylpyrazine-2-yl) methyl] amino ⁇ benzamide
• Step 1 Methyl 3- ⁇ [ Production of (6-Chloropyrazine-2-yl) Methyl] Amino ⁇ -4-methylbenzoate
• methyl 3 -Amino-4-methylbenzoate 449 mg
• 6-chloropyrazine-2-carbaldehyde (774 mg) were used to give the title compound (150 mg).
• Step 2 Production of Methyl 4-Methyl-3- ⁇ [(6-phenylpyrazine-2-yl) methyl] amino ⁇ benzoate
• 2-chloropyrimidine-4-amine isoquinolin-
• 4-ylboronic acid methyl 3- ⁇ [(6-chloropyrazine-2-yl) methyl] amino ⁇ -4-methylbenzoate (70 mg) and phenylboronic acid (35 mg) obtained in step 1 were used.
• the title compound (66 mg) was obtained.
• Step 3 Production of 4-methyl-3- ⁇ [(6-phenylpyrazine-2-yl) methyl] amino ⁇ benzoic acid Methyl 5-[(cyclopropylmethyl) by the method according to step 2 of Reference Example 1. ) Amino] Instead of pyridine-3-carboxylate, methyl 4-methyl-3- ⁇ [(6-phenylpyrazine-2-yl) methyl] amino ⁇ benzoate (66 mg) obtained in step 2 was used. The title compound (55 mg) was obtained.
• Step 4 Production of N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [(6-phenylpyrazine-2-yl) methyl] amino ⁇ benzamide
• Step 4 of Example 1 4-Methyl obtained in step 3 instead of 3- ⁇ [2- (cyclopropylamino) -1,3-thiazole-5-carbonyl] amino ⁇ -4-methylbenzoic acid by the method according to The title compound (19 mg) was obtained using -3- ⁇ [(6-phenylpyrazine-2-yl) methyl] amino ⁇ benzoic acid (25 mg).
• Example 109 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [(1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] amino ⁇ benzamide Reference Example By the method according to 34, instead of 1-methylpiperazin and 5-bromopyridin-3-carbaldehyde, 3-amino-N-[(1S, 2S) -2-hydroxycyclohexyl obtained in Reference Example 7 was obtained. ] -4-Methylbenzamide (73 mg), 1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde (43 mg) was used to give the title compound (84 mg).
• Example 110 N-[(1S, 2S) -2-hydroxycyclohexyl] -3- ⁇ [(imidazo [1,2-b] pyridazine-3-yl) methyl] amino ⁇ -4-methylbenzamide Reference Example 34
• 3-amino-N-[(1S, 2S) -2-hydroxycyclohexyl]-obtained in Reference Example 7- The title compound (18 mg) was obtained using 4-methylbenzamide (24 mg) and imidazo [1,2-b] pyridazine-3-carbaldehyde (15 mg).
• Example 113 3- ⁇ [(2-aminopyrimidine-5-yl) methyl] amino ⁇ -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide
• Step 1 3- ⁇ [((1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide
• step 1 2-Methylpyrimidine-5-yl) Methyl] Amino ⁇ -N-[(1S, 2S) -2-Hydroxycyclohexyl] -4-methylbenzamide Production of 1-methylpyrimidine, 5 In place of -bromopyridin-3-carbaldehyde, 3-amino-N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide (513 mg), 2-chloro obtained in Reference Example 7 The title compound (320 mg) was obtained using pyrimidine-5-carbaldehyde (310 mg).
• Step 2 Production of 3- ⁇ [(2-Aminopyrimidine-5-yl) Methyl] Amino ⁇ -N-[(1S, 2S) -2-Hydroxycyclohexyl] -4-methylbenzamide Obtained in Step 1 , 3- ⁇ [(2-Chloropyrimidine-5-yl) methyl] amino ⁇ -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide (320 mg), 1,4-dioxane ( 8 mL) and 28% aqueous ammonia (4 mL) were added, the tube was sealed using a stainless steel pressure-resistant container, and the mixture was stirred at 100 ° C.
• Example 116 3- ⁇ [(6-acetamidopyridin-3-yl) methyl] amino ⁇ -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide [Step 1] 3- ⁇ [((1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide [step 1] Production of 6-Bromopyridine-3-yl) Methyl] Amino ⁇ -N-[(1S, 2S) -2-Hydroxycyclohexyl] -4-methylbenzamide By the method according to Reference Example 34, 1-methylpiperazin, 5 -Bromopyridine-3-carbaldehyde, instead of 3-amino-N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide (380 mg), 6-bromo
• Example 118 3- ⁇ [([2,2'-bipyridine] -5-yl) methyl] amino ⁇ -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide
• Example 62 instead of 3-[(5-bromopyridin-3-yl) ethynyl] -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide, 2- (tributylstannyl) pyrimidine
• 3- ⁇ [(6-bromopyridin-3-yl) methyl] amino ⁇ -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl obtained in step 1 of Example 116
• the title compound (23 mg) was obtained using benzamide (60 mg) and 2- (tributylstannyl) pyridine (79 mg).
• Example 122 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3-( ⁇ [6- (1H-pyrazole-1-yl) pyridin-3-yl] methyl ⁇ amino) benzamide implementation 3- ⁇ [(6-bromopyridin-3-yl) methyl] amino ⁇ -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide (60 mg) obtained in step 1 of Example 116 , 1H-pyrazole (20 mg), copper iodide (11 mg), potassium phosphate (91 mg), trans-N, N'-dimethylcyclohexane-1,2-diamine (0.014 mL) and DMF (0.36 mL).
• Example 129 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [(6- ⁇ [(pyridin-3-yl) carbamoyl] amino ⁇ pyridin-3-yl) methyl] Amino ⁇ benzamide
• Step 1 Production of 3- ⁇ [(6-aminopyridin-3-yl) methyl] amino ⁇ -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide
• Reference Example 34 3-Amino-N-[(1S, 2S) -2-hydroxycyclohexyl] obtained in Reference Example 7 instead of 1-methylpiperazin and 5-bromopyridin-3-carbaldehyde by the method according to the above.
• Example 138 N-[(1S, 2S) -2-hydroxycyclohexyl] -3- ⁇ [(6- ⁇ [(1r, 3r) -3-methoxycyclobutane-1-carbonyl] amino ⁇ pyridine-3-yl)) Methyl] amino ⁇ -4-methylbenzamide [Step 1] 3- ⁇ [(6-aminopyridine-3-yl) methyl] amino ⁇ -N-[(1S, 2S) -2- ⁇ [tert-butyl (dimethyl) ) Preparation of Cyril] Oxy ⁇ Cyclohexyl] -4-methylbenzamide 3 obtained in Reference Example 41 instead of 1-methylpiperazin and 5-bromopyridine-3-carbaldehyde by the method according to Reference Example 34.
• Step 3 N-[(1S, 2S) -2-hydroxycyclohexyl] -3- ⁇ [(6- ⁇ [(1r, 3r) -3-methoxycyclobutane-1-carbonyl] amino ⁇ pyridine-3-yl ) Methyl] amino ⁇ -4-methylbenzamide
• the N obtained in step 2 instead of methyl 4-chloro-3-[(trimethylsilyl) ethynyl] benzoate by the method according to step 2 of Reference Example 8.
• Example 140 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3-( ⁇ [6- (1H-1,2,3-triazole-1-yl) pyridin-3-yl] Methyl ⁇ amino) benzamide
• 3-amino-N-[(1S, 1S,) obtained in Reference Example 7 was obtained.
• 2S) -2-hydroxycyclohexyl] -4-methylbenzamide (136 mg), 6- (1H-1,2,3-triazol-1-yl) pyridine-3-carbaldehyde (306 mg) obtained in Reference Example 24.
• Example 144 3- ⁇ [(3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxadin-7-yl) methyl] amino ⁇ -N-[(1S, 2S) -2 -Hydroxycyclohexyl] -4-methylbenzamide [Step 1] tert-butyl 7-[(5- ⁇ [(1S, 2S) -2-hydroxycyclohexyl] carbamoyl ⁇ -2-methylanilino) methyl] -2,3-dihydro Production of -4H-pyrido [3,2-b] [1,4] oxadin-4-carboxylate By the method according to Reference Example 34, instead of 1-methylpiperazin and 5-bromopyridine-3-carbaldehyde.
• Example 148 3- ⁇ [([2,3'-bipyridine] -5'-yl) amino] methyl ⁇ -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide
• Step 1 Production of 3- ⁇ [(5-Bromopyridine-3-yl) Amino] Methyl ⁇ -N-[(1S, 2S) -2-Hydroxycyclohexyl] -4-methylbenzamide
• Example 152 3- ⁇ [(5-bromopyridine-3-yl) amino] methyl ⁇ -N-[(1S, 2S) -1,3-dihydroxy-1-phenylpropan-2-yl] -4-methyl Benzamide
• Step 1 Production of 3- ⁇ [(5-bromopyridine-3-yl) amino] methyl ⁇ -4-methylbenzoic acid
• Step 2 of Reference Example 1 methyl 5-[(cyclopropyl).
• Example 153 N-[(1S, 2S) -1,3-dihydroxy-1-phenylpropan-2-yl] -4-methyl-3- ⁇ [(5-phenylpyridine-3-yl) amino] methyl ⁇ 3- ⁇ [(5-Bromopyridine-3-yl) obtained in Example 152 instead of 2-chloropyrimidine-4-amine and isoquinolin-4-ylboronic acid by a method according to Benzamide Reference Example 14. ) Amino] methyl ⁇ -N-[(1S, 2S) -1,3-dihydroxy-1-phenylpropan-2-yl] -4-methylbenzamide (50 mg), phenylboronic acid (16 mg), and the title compound (29 mg) was obtained.
• Example 155 3- ⁇ [([2,3'-bipyridine] -5'-yl) amino] methyl ⁇ -N-[(1S, 2S) -1,3-dihydroxy-1-phenylpropan-2-yl) ] -4-Methylbenzamide
• Example 156 N-[(1S, 2S) -1,3-dihydroxy-1-phenylpropan-2-yl] -4-methyl-3- ⁇ [(6-phenylpyrazine-2-yl) amino] methyl ⁇ Benzamide [Step 1] Methyl 3- ⁇ [(6-chloropyrazine-2-yl) amino] methyl ⁇ -4-methylbenzoate 2,6-dichloropyrazine (300 mg), methyl obtained in Reference Example 42 A mixture of 3- (aminomethyl) -4-methylbenzoate (397 mg), NMP (4 mL) and DIPEA (1.05 mL) was stirred at 100 ° C. for 4 hours.
• Example 158 N- [3-( ⁇ [6- (3,4-dimethoxyphenyl) pyrazine-2-yl] amino ⁇ methyl) phenyl] -N'-[(1R, 2S) -2-hydroxycyclohexyl] urea
• Step 1 Production of N-[(3-aminophenyl) methyl] -6-chloropyrazine-2-amine Methyl 3- (aminomethyl) -4-methylbenzoate by the method according to step 3 of Example 156.
• 3- (Aminomethyl) aniline (1.23 g) was used in place of the title compound (1.22 g).
• Step 2 Production of N-[(3-aminophenyl) methyl] -6- (3,4-dimethoxyphenyl) pyrazine-2-amine 2-chloropyrimidine-4-amine by the method according to Reference Example 14. , N-[(3-aminophenyl) methyl] -6-chloropyrimidine-2-amine (160 mg), (3,4-dimethoxyphenyl) obtained in step 1 instead of isoquinolin-4-ylboronic acid. Boronic acid (149 mg) was used to give the title compound (190 mg).
• Step 3 N- [3-( ⁇ [6- (3,4-dimethoxyphenyl) pyrazine-2-yl] amino ⁇ methyl) phenyl] -N'-[(1R, 2S) -2-hydroxycyclohexyl]
• Step 2 obtained in N-[(3-aminophenyl) methyl] -6- (3,4-dimethoxyphenyl) pyrazine-2-amine (40 mg), THF (1 mL), TEA (0.20 mL) ), Triphosgene (18 mg) was added, and the mixture was stirred at room temperature for 10 minutes.
• Example 159 N-[(1R, 2S) -2-hydroxycyclohexyl] -N'-[3-( ⁇ [5- (pyrimidine-2-yl) pyridin-3-yl] amino ⁇ methyl) phenyl] urea
• Step 1 Production of N-[(3-nitrophenyl) methyl] -5- (pyrimidine-2-yl) pyridine-3-amine
• 1-methylpiperazin and 5-bromopyridine- instead of 3-carbaldehyde, 5- (pyrimidine-2-yl) pyridine-3-amine (100 mg) and 3-nitrobenzaldehyde (88 mg) obtained in Reference Example 27 were used, and the title compound (40 mg) was used.
• Step 2 Production of N-[(3-Aminophenyl) Methyl] -5- (Pyrimidine-2-yl) Pyridine-3-amine N-[(3-Nitrophenyl) Methyl] obtained in Step 1 After degassing in a solution of -5- (pyrimidine-2-yl) pyridine-3-amine (40 mg) in methanol (5 mL) and THF (5 mL), 10% Pd-C (10% Pd-C) with stirring at room temperature in an argon atmosphere 50 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure.
• Celite registered trademark
• Example 161 N- [4-fluoro-3-( ⁇ [5- (pyrimidine-2-yl) pyridin-3-yl] amino ⁇ methyl) phenyl] -N'-[(1R, 2S) -2-hydroxy Cyclohexyl] Urea [Step 1] Production of N-[(2-fluoro-5-nitrophenyl) methyl] -5- (pyrimidine-2-yl) pyridine-3-amine
• Step 2 Production of tert-butyl [(2-fluoro-5-nitrophenyl) methyl] [5- (pyrimidine-2-yl) pyridin-3-yl] carbamate by the method according to step 1 of Reference Example 23. , 7-Bromo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] Oxazine, instead of N-[(2-fluoro-5-nitrophenyl) obtained in step 1. ) Methyl] -5- (pyrimidine-2-yl) pyridine-3-amine (150 mg) was used to give the title compound (105 mg).
• Step 3 Production of tert-butyl [(5-amino-2-fluorophenyl) methyl] [5- (pyrimidine-2-yl) pyridin-3-yl] carbamate
• the tert-butyl [step 3] obtained in step 2.
• (2-Fluoro-5-nitrophenyl) Methyl] [5- (pyrimidine-2-yl) Pyridine-3-yl] Carbamate (104 mg) in ethanol (2 mL) -water (0.2 mL) solution with tin chloride (2-fluoro-5-nitrophenyl) methyl II) Dihydrate (221 mg) was added, and the mixture was stirred at 65 ° C. for 2 hours.
• Step 4 tert-butyl ⁇ [2-fluoro-5-( ⁇ [(1R, 2S) -2-hydroxycyclohexyl] carbamoyl ⁇ amino) phenyl] methyl ⁇ [5- (pyrimidine-2-yl) pyridine-3 -Il] Carbamate Production Step 3 instead of N-[(3-aminophenyl) methyl] -6- (3,4-dimethoxyphenyl) pyrazine-2-amine by the method according to Step 3 of Example 158.
• Example 164 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ 1-[(6-phenylpyrazine-2-yl) amino] ethyl ⁇ benzamide [Step 1] Methyl 3- Preparation of ⁇ 1-[(6-chloropyrazine-2-yl) amino] ethyl ⁇ -4-methylbenzoate To methyl 3- (aminomethyl) -4-methylbenzoate by the method according to step 3 of Example 156.
• Step 4 Production of N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ 1-[(6-phenylpyrazine-2-yl) amino] ethyl ⁇ benzamide
• Example 1 4 obtained in step 3 instead of 3- ⁇ [2- (cyclopropylamino) -1,3-thiazole-5-carbonyl] amino ⁇ -4-methylbenzoic acid by the method according to step 4.
• -Methyl-3- ⁇ 1-[(6-phenylpyrazine-2-yl) amino] ethyl ⁇ benzoic acid (30 mg) was used to give the title compound (17 mg).
• Example 165 3-[([3,3'-bipyridine] -5-yl) methoxy] -N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide [Step 1] Methyl 3-[ Production of (5-Bromopyridine-3-yl) methoxy] -4-methylbenzoate Methyl 5-hydroxypyridin-3-carboxylate, 3,3-difluorocyclobutane-1 by the method according to step 1 of Reference Example 3. Instead of -ol, methyl 3-hydroxy-4-methylbenzoate (750 mg), (5-bromopyridin-3-yl) methanol (933 mg) was used to give the title compound (1.16 g).
• Example 166 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [5- (pyrimidin-2-yl) pyridin-3-yl] methoxy ⁇ benzamide
• Step 1 Methyl 4 Production of -Methyl-3- ⁇ [5- (pyrimidine-2-yl) Pyridine-3-yl] methoxy ⁇ benzoate 3-Bromo-5- (methoxymethoxy) pyridine by the method according to step 1 of Reference Example 10. Instead, methyl 3-[(5-bromopyridin-3-yl) methoxy] -4-methylbenzoate (250 mg) obtained in step 1 of Example 165 was used to give the title compound (127 mg). ..
• Step 3 Production of N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [5- (pyrimidine-2-yl) pyridin-3-yl] methoxy ⁇ benzamide
• Example 1 In place of 3- ⁇ [2- (cyclopropylamino) -1,3-thiazole-5-carbonyl] amino ⁇ -4-methylbenzoic acid, obtained in step 2 by the method according to step 4 of 4-Methyl-3- ⁇ [5- (pyrimidine-2-yl) pyridin-3-yl] methoxy ⁇ benzoic acid (60 mg) was used to give the title compound (76 mg).
• Example 170 4-Chloro-N-[(1S, 2S) -2-hydroxycyclohexyl] -3-( ⁇ [5- (pyrimidin-2-yl) pyridin-3-yl] oxy ⁇ methyl) benzamide
• Step 1 Methyl 4-chloro-3-( ⁇ [5- (pyrimidine-2-yl) pyridine-3-yl] oxy ⁇ methyl) Methyl) Methyl 5-hydroxypyridine by the method according to step 1 of Reference Example 3. Instead of -3-carboxylate, 3,3-difluorocyclobutane-1-ol, 5- (pyrimidine-2-yl) pyridine-3-ol (123 mg) obtained in step 2 of Reference Example 10, reference.
• Example 173 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3-[(E) -2- (5-phenylpyridine-3-yl) ethenyl] benzamide
• Step 1 3- Production of Ethenyl-N-[(1R, 2R) -2-Hydroxycyclohexyl] -4-methylbenzamide
• 2-chloropyrimidine-4-amine and isoquinolin-4-ylboronic acid instead of 2-chloropyrimidine-4-amine and isoquinolin-4-ylboronic acid, , 3-Bromo-N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methylbenzamide (20.0 g), 2-ethenyl-4,4,5,5- obtained in Reference Example 43.
• Example 174 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- [2- (5-phenylpyridine-3-yl) ethyl] benzamide obtained in Example 173, N- [(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3-[(E) -2- (5-phenylpyridine-3-yl) ethenyl] benzamide (15 mg) in an ethanol (5 mL) solution.
• Example 175 N-[(1S, 2S) -2-hydroxycyclohexyl] -4-methyl-3- ⁇ [methyl (5-phenylpyridine-3-yl) amino] methyl ⁇ benzamide
• Step 1 Methyl 3- ⁇ Production of [(5-bromopyridine-3-yl) (methyl) amino] methyl ⁇ -4-methylbenzoate Methyl 3- ⁇ [(5-bromopyridine-3-yl) obtained in step 1 of Example 147 ) Amino] Methyl ⁇ -4-methylbenzoate (850 mg) was added to a solution of THF (10 mL) under ice-cooling, 60% sodium hydride (79 mg) was added, and the mixture was stirred at room for 20 minutes.
• iodomethane (720 mg) was added, and the mixture was stirred at the same temperature overnight. Under ice-cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (200 mg).
• Example 180 5-[(Z) -2-([2,3'-bipyridine] -5'-yl) -2-fluoroethenyl] -N-[(1S, 2S) -2-hydroxycyclohexyl]- 6-Methylpyridine-3-Carboxamide
• Step 1 Production of Ethyl 5- (2,2-Difluoroethenyl) -6-Methylpyridine-3-carboxylate
• Example 192 3-[(Z) -2- (2-aminopyrimidine-5-yl) -2-fluoroethenyl] -4-fluoro-N-[(1S, 2S) -2-hydroxycyclohexyl] benzamide
• Step 1 Production of Methyl 3- (2,2-difluoroethenyl) -4-fluorobenzoate 4-Fluoro-3-formyl-N-[(1S, 2S) by the method according to Step 1 of Example 177.
• Methyl 4-fluoro-3-formylbenzoate (1.27 g) was used in place of -2-hydroxycyclohexyl] benzamide to give the title compound (1.30 g).
• Step 2 Production of Methyl 3-[(Z) -2- (2-Aminopyrimidine-5-yl) -2-Fluoroethaneyl] -4-fluorobenzoate Methyl 3- (2) obtained in Step 1. , 2-Difluoroethenyl) -4-fluorobenzoate (130 mg), bis (pinacolato) diboron (305 mg), potassium acetate (118 mg), tricyclohexylphosphine (34 mg) and copper (I) chloride (22 mg) in THF (4 mL) ) was added and deaerated, and the mixture was stirred at 40 ° C. for 8 hours under an argon atmosphere.
• a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
• the obtained residue contained 5-bromopyrimidine-2-amine (105 mg), potassium carbonate (166 mg), and Pd ( dppf) Cl 2 ⁇ CH 2 Cl 2 (49 mg), 1,4-dioxane (2 mL) and water (0.2 mL) were added and degassed, and the mixture was stirred overnight at 85 ° C. under an argon atmosphere.
• Step 4 3-[(Z) -2- (2-aminopyrimidine-5-yl) -2-fluoroethenyl] -4-fluoro-N-[(1S, 2S) -2-hydroxycyclohexyl] benzamide Production of Step 3 instead of 3- ⁇ [2- (cyclopropylamino) -1,3-thiazole-5-carbonyl] amino ⁇ -4-methylbenzoic acid by the method according to Step 4 of Example 1.
• Step 3 Production of methyl 3-[(Z) -2-fluoro-2- ⁇ 5-[(4-ethylpiperazin-1-yl) methyl] pyridin-3-yl ⁇ ethenyl] -4-methylbenzoate
• -4-Ethylpiperazine (6.3 g), methyl 3-[(Z) -2-fluoro-2- (4,4,5,5-tetramethyl-1,3,2-) obtained in step 2.
• Example 199 5-[(Z) -2- ⁇ 6-[(cyclopropylmethyl) amino] pyridin-3-yl ⁇ -2-fluoroethenyl] -N-[(1S, 2S) -2-hydroxycyclohexyl ] -6-Methylpyridin-3-Carboxamide
• Step 1 Ethyl 5-[(Z) -2- (6-aminopyridin-3-yl) -2-fluoroethenyl] -6-methylpyridin-3-carboxy Production of Rate
• 5-bromopyridin-2-amine (114 mg) was used instead of 2-chloropyrimidine-4-amine and isoquinolin-4-ylboronic acid in step 2 of Example 180.
• Tables 3 to 29 described below show reference examples and example compounds.
• the reference reference example means that the compound was produced using the corresponding raw material by a method according to the method for producing the compound of the reference example number corresponding to the number, for example, in the reference reference example.
• the reference example compound having the number 1 means that it was produced by a method according to Reference Example 1.
• the reference example means that the compound was produced using the corresponding raw material by a method according to the method for producing the compound of the example number corresponding to the number, for example, in the reference example.
• the Example compound having the number 1 means that it was produced by a method according to Example 1.
• the chemical name represents the name of the compound corresponding to the reference example and the number of the example
• the data represents the instrumental analysis data of the compound, for example, mass spectrometric data (m / z value).
• mass spectrometric data m / z value
• 1H NMR data peak ⁇ (ppm)
• elemental analysis data composition of C, H, N (%)
• test substance was prepared to 10 mM with dimethyl sulfoxide (DMSO) and diluted with DMSO to a concentration of 0.001 to 1000 ⁇ M. These DMSO solutions were added to assay buffer 1 (50 mM HEPES (pH 7.0), 0.02% NaN3, 0.01% Bovine Serum Albumin, 0.1 mM orthovandate, 1 mM Dilutionreitol, 5 mM MgCl 2 , 1 mM MnCl.
• DMSO dimethyl sulfoxide
• TEL-PDGFR ⁇ TEL-KIT fusion gene transfer cells
• Human TEL-PDGFR ⁇ fusion gene (see, for example, CELL, 1994, 77, 307-316) or human TEL-KIT fusion gene is used as a retrovirus expression vector pMYs-IRES-GFP.
• a vector for gene transfer was prepared by inserting it into the multi-cloning site of.
• the human TEL-KIT fusion gene identifies an amino sequence (Accession No. NP_000213.1, amino acid 521-928) important for the enzymatic activity of the KIT gene, and by appropriately binding to the amino acid sequence of the TEL gene, it is a ligand factor.
• a sequence showing activation was created even in the absence of.
• a gene transfer vector was introduced into PLAT-E, a packaging cell derived from a human fetal kidney cell line in the logarithmic growth phase, using a transfection reagent (FuGENE6, Promega). Since the culture supernatant of PLAT-E after gene transfer contained virus particles for gene transfer, it was collected and used as a medium for gene transfer. A gene transfer medium was added to a plate coated with RetroNectin and incubated to attach virus particles to the plate. Then, the mouse pro-B cell line Ba / F3 in the logarithmic growth phase was seeded on a plate and infected with the virus to prepare cells that proliferate in a PDGFR ⁇ or KIT-dependent manner.
• test substance was prepared to 10 mM with dimethyl sulfoxide (DMSO) and diluted with DMSO to a concentration of 0.0001 to 3 mM. Further, it was diluted 100 times with distilled water.
• DMSO dimethyl sulfoxide
• TEL-PDGFR ⁇ and TEL-KIT expression cells The day after seeding TEL-PDGFR ⁇ and TEL-KIT expression cells on a 96-well plate, the final concentration of the prepared test substance solution reaches 0.1 to 10,000 nM. Was added. After 72 hours, the number of living cells was measured using the amount of formazan produced by the reduction of the tetrazolium salt compound by the mitochondrial dehydrogenase of living cells as an index.
• test substance was prepared to 10 mM with dimethyl sulfoxide (DMSO) and diluted with DMSO to a concentration of 0.003 to 3 mM. Further, it was diluted 50 times with distilled water.
• DMSO dimethyl sulfoxide
• test substance was prepared to 10 mM with dimethyl sulfoxide (DMSO) and diluted with DMSO to a concentration of 0.1 to 3 mM to prepare a test substance solution having a final concentration of 1000 times.
• DMSO dimethyl sulfoxide
• Example of formulation The following pharmaceutical examples are merely examples, and are not intended to limit the scope of the invention.
• Pharmaceutical example 1 Tablet (oral tablet) Compound of the present invention of Example 1 5.0 mg in 80 mg of a prescription tablet Corn starch 46.6 mg Crystalline cellulose 24.0 mg Methyl cellulose 4.0 mg Magnesium stearate 0.4 mg The mixed powder of this ratio is tableted by a usual method to obtain an internal tablet.
• the compound of the present invention has PDGF receptor kinase inhibitory activity, respiratory disease, cancer, smooth muscle proliferative disease, vasoproliferative disease, autoimmune / inflammatory disease, metabolic disease, vascular obstruction It is useful as a therapeutic agent for sexual diseases and the like.

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