A compound represented by Formula [1](in the formula, Z 1 represents N, CH, or the like; X 1 represents NH or the like; R 1 represents a heteroaryl group or the like; each of R 2 , R 3 , and R 4 represents a hydrogen atom, a halogen atom, an alkoxy group, or the like; and R 5 represents a heteroaryl group or the like) or salt thereof. [structure]

Description

259 parts

›CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of International Application No. PCT/JP2014/050873, filed Jan. 14, 2014, which is incorporated herein by reference. Further, this application claims priority from Japanese Patent Application No. 2013-003832, filed Jan. 11, 2013, which is incorporated herein by reference.

›TECHNICAL FIELD

The present invention relates to a nitrogen-containing heterocyclic compound or salt thereof.

›BACKGROUND ART

The PI3K (phosphatidylinositol 3-kinase)-AKT(protein kinase B) pathway is an important signal transduction pathway that plays a central role in cell growth, proliferation, differentiation, invasion, migration, apoptosis, glucose metabolism, or the like. It is known that the PI3K-AKT pathway is constantly activated in plural malignant tumors (Nature Reviews Drug Discovery, Vol. 8, No. 8, pp. 627-644, 2009) by activation of a receptor on the upstream of the PI3K-AKT pathway, or mutation, defect, or amplification of molecules constituting the PI3K-AKT pathway.

It is reported that the PI3K-AKT pathway is involved in not only malignant tumors but also in other diseases, for example, a cell proliferative disease, an allergic disease, an autoimmune disease, a neurodegenerative disease, a circulatory system disease, an inflammatory disease, an endocrine disorder, a metabolic disorder, or an infection (Biochimica et Biophysica Acta Vol. 1784, No. 1, pp. 159-185, 2008).

Therefore, it is considered that regulating the PI3K-AKT pathway is beneficial in a treatment for various diseases.

In addition, the Ras-Raf-MEK (MAP kinase kinase)-ERK (extracellular signal-regulated kinase) pathway is located on the downstream of various receptors, and plays an important role in cell physiological functions, for example, cell proliferation, apoptosis, or cell differentiation (ChemMedChem Vol. 6, No. 1, pp. 38-48, 2011).

Examples of diseases in which the Ras-Raf-MEK-ERK pathway is involved include a malignant tumor, an allergic disease, an autoimmune disease, a neurodegenerative disease, and a circulatory system disease.

Therefore, it is expected that regulating the Ras-Raf-MEK-ERK pathway is beneficial in a treatment for various diseases.

Here, it is reported that the PI3K-AKT pathway and the Ras-Raf-MEK-ERK pathway complementarily functions regarding cell proliferation, and regulating both the pathways at the same time is beneficial in a treatment for malignant tumors (Cancer Biology & Therapy Vol. 7, No. 2, pp. 307-315, 2008 and Nature medicine, Vol. 14, No. 12, pp. 1351-1356, 2008).

In the treatment of diseases, since the PI3K-AKT pathway and the Ras-Raf-MEK-ERK pathway are very important, PI3K-AKT pathway inhibitors or Ras-Raf-MEK-ERK pathway inhibitors have been developed thus far. However, the number thereof which became commercially available is very small (Pamphlet of International Publication No. WO2011/064250). In addition, regarding compounds that inhibit both the signal pathways directly and at the same time, there are only a few reports (Japanese National-Phase Publication (JP-A) No. 2009-515854) thus far.

On the other hand, 1,5-naphthyridine derivatives having a urea structure in the molecule that inhibits AurolaB, the Ras-Raf-MEK-ERK pathway, and Erk2 have been known (Pamphlet of International Publication No. WO2011/064250).

›SUMMARY OF INVENTION · 1 of 5

Technical Problem

A compound or a pharmaceutical composition having excellent inhibitory activity with respect to the PI3K-AKT pathway and/or the Ras-Raf-MEK-ERK pathway is desired.

Solution to Problem

Under such circumstances, the present inventors have conducted extensive studies. As a result, they have found that the nitrogen-containing heterocyclic compound represented by the following Formula [1] or salt thereof has excellent inhibitory activity with respect to the PI3K-AKT pathway and/or the Ras-Raf-MEK-ERK pathway, and completed the invention.

(In the formula:

Z 1 represents N or CR 6 ;

R 6 represents a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 2-6 alkynyl group which may be substituted, a C 3-8 cycloalkyl group which may be substituted, an aryl group which may be substituted, a C 1-6 alkoxy group which may be substituted, an aryloxy group which may be substituted, a C 1-6 alkylthio group which may be substituted, an arylthio group which may be substituted, a heteroaryl group which may be substituted, a heteroaryloxy group which may be substituted, a heteroarylthio group which may be substituted, a heterocyclyl group which may be substituted, or NR 7 R 8 ;

each of R 7 and R 8 independently represents a hydrogen atom, a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 2-6 alkynyl group which may be substituted, a C 3-8 cycloalkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, a heterocyclyl group which may be substituted, or an amino protecting group;

X 1 represents NR 9 , O, S, or CR 10 R 11 ;

R 9 represents a hydrogen atom, a C 1-6 alkyl group which may be substituted, or an amino protecting group;

each of R 10 and R 11 independently represents a hydrogen atom or a C 1-6 alkyl group which may be substituted;

R 1 represents a monocyclic nitrogen-containing heteroaryl group which may be substituted, a monocyclic nitrogen- and oxygen-containing heteroaryl group which may be substituted, a monocyclic nitrogen- and sulfur-containing heteroaryl group which may be substituted, a bicyclic nitrogen-containing heteroaryl group which may be substituted, a bicyclic nitrogen- and oxygen-containing heteroaryl group which may be substituted, or a bicyclic nitrogen- and sulfur-containing heteroaryl group which may be substituted;

R 2 represents a hydrogen atom or a halogen atom;

R 3 represents a hydrogen atom or a halogen atom;

R 4 represents a hydrogen atom, a halogen atom, an amino group which may be protected, a hydroxyl group which may be protected, a C 1-6 alkyl group which may be substituted, or a C 1-6 alkoxy group which may be substituted;

R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, a carbamoyl group which may be substituted, a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 2-6 alkynyl group which may be substituted, a C 3-8 cycloalkyl group which may be substituted, an aryl group which may be substituted, a C 1-6 alkoxy group which may be substituted, an aryloxy group which may be substituted, a C 1-6 alkylthio group which may be substituted, an arylthio group which may be substituted, a heteroaryl group which may be substituted, a heteroaryloxy group which may be substituted, a heteroarylthio group which may be substituted, a heterocyclyl group which may be substituted, or NR 12 R 13 ;

each of R 12 and R 13 independently represents a hydrogen atom, a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 2-6 alkynyl group which may be substituted, a C 3-8 cycloalkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, a heterocyclyl group which may be substituted, or an amino-protecting group; and

wherein, in a case in which Z 1 represents N and R 4 represents a hydrogen atom, R 5 represents a halogen atom, a hydroxyl group which may be protected, a carbamoyl group which may be substituted, a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 2-6 alkynyl group which may be substituted, a C 3-8 cycloalkyl group which may be substituted, a C 1-6 alkoxy group which may be substituted, an aryloxy group which may be substituted, a C 1-6 alkylthio group which may be substituted, an arylthio group which may be substituted, a heteroaryl group which may be substituted, a heteroaryloxy group which may be substituted, a heteroarylthio group which may be substituted, a heterocyclyl group which may be substituted, or NR 12 R 13 , and

R 12 represents a hydrogen atom, a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 2-6 alkynyl group which may be substituted, a C 3-8 cycloalkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, a heterocyclyl group which may be substituted, or an amino protecting group, and

R 13 represents a C 3-8 cycloalkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, or a heterocyclyl group which may be substituted.)

Another aspect of the invention provides a pharmaceutical composition containing the nitrogen-containing heterocyclic compound or salt thereof of the invention, in particular, a pharmaceutical composition for treating a disease in which the PI3K and/or the ERK is involved, containing the nitrogen-containing heterocyclic compound or salt thereof of the invention, and a pharmaceutical composition for treating a disease selected from the group consisting of a malignant tumor, a cell proliferative disease, an allergic disease, an autoimmune disease, a neurodegenerative disease, a circulatory system disease, an inflammatory disease, an endocrine disorder, a metabolic disorder, and an infection, containing the nitrogen-containing heterocyclic compound or salt thereof of the invention.

›SUMMARY OF INVENTION · 2 of 5

Still another aspect of the invention provides an agent for treating a disease selected from the group consisting of a malignant tumor, a cell proliferative disease, an allergic disease, an autoimmune disease, a neurodegenerative disease, a circulatory system disease, an inflammatory disease, an endocrine disorder, a metabolic disorder, and an infection, containing the nitrogen-containing heterocyclic compound or salt thereof of the inventiond.

Still another aspect of the invention provides a PI3K and/or an ERK inhibitor containing the nitrogen-containing heterocyclic compound or salt thereof of the invention.

Still another aspect of the invention provides a prodrug of the nitrogen-containing heterocyclic compound or salt thereof of the invention.

Still another aspect of the invention provides a use of the nitrogen-containing heterocyclic compound or salt thereof of the invention for preparing of the pharmaceutical composition of the invention; a method of treating a disease in which the PI3K and/or the ERK is involved, the method including administering a therapeutically effective amount of the nitrogen-containing heterocyclic compound or salt thereof of the invention to a mammal including humans; and a method of treating a disease selected from the group consisting of a malignant tumor, a cell proliferative disease, an allergic disease, an autoimmune disease, a neurodegenerative disease, a circulatory system disease, an inflammatory disease, an endocrine disorder, a metabolic disorder, and an infection, the method including administering a therapeutically effective amount of the nitrogen-containing heterocyclic compound or salt thereof of the invention to a mammal including humans.

That is, the invention is as follows.

(1) A nitrogen-containing heterocyclic compound represented by Formula [1] or salt thereof.

(2) The nitrogen-containing heterocyclic compound or salt thereof according to (1), in which R 4 represents a hydrogen atom, a halogen atom, an amino group which may be protected, or a C 1-6 alkoxy group which may be substituted.

(3) The nitrogen-containing heterocyclic compound or salt thereof according to (1) or (2), in which Z 1 represents CR 6 (in the formula, R 6 has the same meaning as that described above).

(4) The nitrogen-containing heterocyclic compound or salt thereof according to any one of (1) to (3), in which R 2 is a hydrogen atom.

(5) The nitrogen-containing heterocyclic compound or salt thereof according to any one of (1) to (4), in which R 3 is a hydrogen atom.

(6) The nitrogen-containing heterocyclic compound or salt thereof according to any one of (1) to (5), in which X 1 represents NR 9a (in the formula, R 9a represents a hydrogen atom or an amino protecting group) or S.

(7) The nitrogen-containing heterocyclic compound or salt thereof according to any one of (1) to (6), in which R 1 represents a pyrazolyl group which may be substituted, an imidazolyl group which may be substituted, a triazolyl group which may be substituted, a thiazolyl group which may be substituted, an oxadiazolyl group which may be substituted, a thiadiazolyl group which may be substituted, a pyridyl group which may be substituted, or a pyridazinyl group which may be substituted.

(8) The nitrogen-containing heterocyclic compound or salt thereof according to any one of (1) to (6), in which R 1 represents a pyrazolyl group which may be substituted with one or more substituents selected from a substituent group A 1 , an imidazolyl group which may be substituted with one or more substituents selected from the substituent group A 1 , a triazolyl group which may be substituted with one or more substituents selected from the substituent group A 1 , a thiazolyl group which may be substituted with one or more substituents selected from the substituent group A 1 , an oxadiazolyl group which may be substituted with one or more substituents selected from the substituent group A 1 , a thiadiazolyl group which may be substituted with one or more substituents selected from the substituent group A 1 , a pyridyl group which may be substituted with one or more substituents selected from the substituent group A 1 , or a pyridazinyl group which may be substituted with one or more substituents selected from the substituent group A 1 .

(9) The nitrogen-containing heterocyclic compound or salt thereof according to any one of (1) to (6), in which R 1 represents a pyrazolyl group which may be substituted with one or more substituents selected from a substituent group α 1 , an imidazolyl group which may be substituted with one or more substituents selected from the substituent group α 1 , a triazolyl group which may be substituted with one or more substituents selected from the substituent group α 1 , a thiazolyl group which may be substituted with one or more substituents selected from the substituent group α 1 , an oxadiazolyl group which may be substituted with one or more substituents selected from the substituent group α 1 , a thiadiazolyl group which may be substituted with one or more substituents selected from the substituent group α 1 , a pyridyl group which may be substituted with one or more substituents selected from the substituent group α 1 , or a pyridazinyl group which may be substituted with one or more substituents selected from the substituent group α 1 .

(10) The nitrogen-containing heterocyclic compound or salt thereof according to any one of (1) to (9), in which: R 5 represents a hydrogen atom or a halogen atom; and Z 1 represents CR 6a (in the formula, R 6a represents an aryl group which may be substituted, a heteroaryl group which may be substituted, a heterocyclyl group which may be substituted, or NHR 8a (in the formula, R 8a represents an aryl group which may be substituted, a heteroaryl group which may be substituted, or a heterocyclyl group which may be substituted)).

(11) The nitrogen-containing heterocyclic compound or salt thereof according to any one of (1) to (9), in which: R 5 represents a hydrogen atom or a halogen atom; and Z 1 represents CR 6b (in the formula, R 6b represents an aryl group which may be substituted with one or more substituents selected from a substituent group α 2 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group α 2 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group α 2 , or NHR 8b (in the formula, R 8b represents an aryl group which may be substituted with one or more substituents selected from the substituent group α 2 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group α 2 , or a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group α 2 )).

›SUMMARY OF INVENTION · 3 of 5

(12) The nitrogen-containing heterocyclic compound or salt thereof according to any one of (1) to (9), in which: R 5 represents a hydrogen atom or a halogen atom; and Z 1 represents CR 6c (in the formula, R 6c represents a phenyl group which may be substituted with one or more substituents selected from a substituent group α 2 , a pyrazolyl group which may be substituted with one or more substituents selected from the substituent group α 2 , a pyridyl group which may be substituted with one or more substituents selected from the substituent group α 2 , a pyrimidinyl group which may be substituted with one or more substituents selected from the substituent group α 2 , a pyrazinyl group which may be substituted with one or more substituents selected from the substituent group α 2 , a pyridazinyl group which may be substituted with one or more substituents selected from the substituent group α 2 , a morpholinyl group which may be substituted with one or more substituents selected from the substituent group α 2 , or NHR 8c (in the formula, R 8c represents a phenyl group which may be substituted with one or more substituents selected from the substituent group α 2 , a pyridyl group which may be substituted with one or more substituents selected from the substituent group α 2 , a pyrimidinyl group which may be substituted with one or more substituents selected from the substituent group α 2 , a pyrazinyl group which may be substituted with one or more substituents selected from the substituent group α 2 , or a pyridazinyl group which may be substituted with one or more substituents selected from the substituent group α 2 )).

(13) The nitrogen-containing heterocyclic compound or salt thereof according to any one of (1), (2), or (4) to (9), in which Z 1 represents N or CR 6d (in the formula, R 6d represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may be substituted, a C 1-6 alkoxy group which may be substituted, or NHR 8d (in the formula, R 8d represents a hydrogen atom or a C 1-6 alkyl group which may be substituted)); and R 5 represents a C 3-8 cycloalkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, a heterocyclyl group which may be substituted, or NR 12a R 13a (in the formula, R 12a represents a hydrogen atom or a C 1-6 alkyl group which may be substituted; and R 13a represents a C 3-8 cycloalkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, or a heterocyclyl group which may be substituted).

(14) The nitrogen-containing heterocyclic compound or salt thereof according to any one of (1), (2), or (4) to (9), in which: Z 1 represents N or CH; and R 5 represents a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from a substituent group A 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group A 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group A 3 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group A 3 , or NR 12b R 13b (in the formula, R 12b represents a hydrogen atom or a C 1-6 alkyl group; and R 13b represents a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group A 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group A 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group A 3 , or a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group A 3 ).

(15) The nitrogen-containing heterocyclic compound or salt thereof according to any one of (1), (2), or (4) to (9), in which: Z 1 represents N or CH; and R 5 represents a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from a substituent group α 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group α 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group α 3 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group α 3 , or NR 12b R 13c (in the formula, R 12b represents a hydrogen atom or a C 1-6 alkyl group; and R 13c represents a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group α 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group α 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group α 3 , or a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group α 3 ).

(16) The nitrogen-containing heterocyclic compound or salt thereof according to any one of (1), (2), or (4) to (9), in which: Z 1 represents N or CH; and R 5 represents a phenyl group which may be substituted with one or more substituents selected from a substituent group α 3 , a pyrazolyl group which may be substituted with one or more substituents selected from the substituent group α 3 , an isoxazolyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyridyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrimidinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrazinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyridazinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , an azetidinyl which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrrolidinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a piperidinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a piperazinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a morpholinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a homopiperazinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , or NR 12b R 13d (in the formula, R 13d represents a phenyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrazolyl group which may be substituted with one or more substituents selected from the substituent group α 3 , an isoxazolyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyridyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrimidinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrazinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyridazinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrrolidinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a piperidinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , or a tetrahydropyridyl group which may be substituted with one or more substituents selected from the substituent group α 3 ; and R 12b has the same meaning as that described above).

›SUMMARY OF INVENTION · 4 of 5

(17) A nitrogen-containing heterocyclic compound represented by Formula [1a] or salt thereof.

(In the formula, each of R 14 , R 15 , and R 16 independently represents a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group which may be protected, a cyano group, a carbamoyl group which may be substituted with one or more substituents selected from a substituent group B 1 , a sulfamoyl group which may be substituted with one or more substituents selected from the substituent group B 1 , a C 1-6 alkyl group which may be substituted with one or more substituents selected from the substituent group B 1 , a C 2-6 alkenyl group which may be substituted with one or more substituents selected from the substituent group B 1 , a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group B 1 , an aryl group which may be substituted with one or more substituents selected from the substituent group B 1 , a C 1-6 alkoxy group which may be substituted with one or more substituents selected from the substituent group B 1 , a C 3-8 cycloalkoxy group which may be substituted with one or more substituents selected from the substituent group B 1 , an aryloxy group which may be substituted with one or more substituents selected from the substituent group B 1 , a C 1-6 alkylthio group which may be substituted with one or more substituents selected from the substituent group B 1 , an arylthio group which may be substituted with one or more substituents selected from the substituent group B 1 , a C 1-6 alkylamino group which may be substituted with one or more substituents selected from the substituent group B 1 , a di(C 1-6 alkyl)amino group which may be substituted with one or more substituents selected from the substituent group B 1 , an acyl group which may be substituted with one or more substituents selected from the substituent group B 1 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group B 1 , or a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group B 1 ; and each of R 17 , R 18 , and R 19 independently represents a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, an amino group which may be substituted with one or more substituents selected from a substituent group E 3 , a carboxyl group which may be protected, a cyano group, a carbamoyl group which may be substituted with one or more substituents selected from a substituent group B 3 , a sulfamoyl group which may be substituted with one or more substituents selected from the substituent group B 3 , a C 1-6 alkyl group which may be substituted with one or more substituents selected from the substituent group B 3 , a C 2-6 alkenyl group which may be substituted with one or more substituents selected from the substituent group B 3 , a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group B 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group B 3 , a C 1-6 alkoxy group which may be substituted with one or more substituents selected from the substituent group B 3 , an aryloxy group which may be substituted with one or more substituents selected from the substituent group B 3 , a C 1-6 alkylthio group which may be substituted with one or more substituents selected from the substituent group B 3 , an arylthio group which may be substituted with one or more substituents selected from the substituent group B 3 , a C 1-6 alkyl amino group which may be substituted with one or more substituents selected from the substituent group B 3 , a di(C 1-6 alkyl)amino group which may be substituted with one or more substituents selected from the substituent group B 3 , a C 1-6 alkylsulfonyl group which may be substituted with one or more substituents selected from the substituent group B 3 , an arylsulfonyl group which may be substituted with one or more substituents selected from the substituent group B 3 , an acyl group which may be substituted with one or more substituents selected from the substituent group B 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group B 3 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group B 3 , or a heterocyclyloxy group which may be substituted with one or more substituents selected from the substituent group B 3 .)

(18) The nitrogen-containing heterocyclic compound or salt thereof according to (17), in which each of R 14 and R 16 represents a hydrogen atom, and R 17 represents a hydrogen atom.

(19) A pharmaceutical composition comprising the nitrogen-containing heterocyclic compound or salt thereof according to any one of (1) to (18).

(20) An agent for treating a disease selected from the group consisting of a malignant tumor, a cell proliferative disease, an allergic disease, an autoimmune disease, a neurodegenerative disease, a circulatory system disease, an inflammatory disease, an endocrine disorder, a metabolic disorder, and an infection, the agent comprising the nitrogen-containing heterocyclic compound or salt thereof according to any one of (1) to (18).

(21) A PI3K- and/or ERK-inhibitor comprising the nitrogen-containing heterocyclic compound or salt thereof according to any one of (1) to (18).

In addition, the invention provides the following (a) to (d).

(a) The compound represented by Formula [1] or Formula [1a] defined above or salt thereof, for use as a medicine.

(b) A pharmaceutical composition including a pharmacologically acceptable additive together with the compound represented by Formula [1] or Formula [1a] or salt thereof.

(c) A use of the compound represented by Formula [1] or Formula [1a] or salt thereof in preparing a medicine for use in a treatment for a disease or a condition in which the PI3K and/or the ERK is involved, which is preferably for use in a treatment for a malignant tumor, a cell proliferative disease, an allergic disease, an autoimmune disease, a neurodegenerative disease, a circulatory system disease, an inflammatory disease, an endocrine disorder, a metabolic disorder, or an infection.

›SUMMARY OF INVENTION · 5 of 5

(d) A method for use in a treatment for a disease associated with the PI3K and/or the ERK, which is preferably for use in a treatment for a malignant tumor, a cell proliferative disease, an allergic disease, an autoimmune disease, a neurodegenerative disease, a circulatory system disease, an inflammatory disease, an endocrine disorder, a metabolic disorder, or an infection, and includes a step of administering a therapeutically effective amount of the compound represented by Formula [1] or Formula [1a] or salt thereof to a subject (mammal including humans) that requires such a treatment.

Effects of Invention

The nitrogen-containing heterocyclic compound or salt thereof of the invention has excellent inhibitory activity with respect to the PI3K-AKT pathway and/or the Ras-Raf-MEK-ERK pathway, is useful for a treatment such as prevention of or a cure for a disease such as a malignant tumor, a cell proliferative disease, an allergic disease, an autoimmune disease, a neurodegenerative disease, a circulatory system disease, an inflammatory disease, an endocrine disorder, a metabolic disorder, or an infection, and, is particularly useful for a treatment such as prevention of or cure for a malignant tumor.

In addition, the PI3K and/or the ERK inhibitor of the invention has excellent inhibitory activity with respect to the PI3K-AKT pathway and/or the Ras-Raf-MEK-ERK pathway, is useful for a treatment such as prevention of or cure for a disease such as a malignant tumor, a cell proliferative disease, an allergic disease, an autoimmune disease, a neurodegenerative disease, a circulatory system disease, an inflammatory disease, an endocrine disorder, a metabolic disorder, or an infection, and, is particularly useful for a treatment such as prevention of or cure for a malignant tumor.

›DESCRIPTION OF EMBODIMENTS · 1 of 16

In the present specification, “A and/or B” means “A and B, or A or B”.

Hereinafter, the invention will be described in detail.

In the specification, each term has the following meaning, unless specified otherwise.

A “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

A C 1-6 alkyl group means a linear or branched C 1-6 alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, or a hexyl group.

A C 2-6 alkenyl group means a linear or branched C 2-6 alkenyl group such as a vinyl group, an allyl group, a propenyl group, an isopropenyl group, a butenyl group, an isobutenyl group, a 1,3-butadienyl group, a pentenyl group, or a hexenyl group.

A C 2-6 alkynyl group means a linear or branched C 2-6 alkynyl group such as an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, or a hexynyl group.

A C 3-8 cycloalkyl group means a monocyclic C 3-8 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, or a C 4-8 crosslinked cyclic hydrocarbon ring group such as a bicyclo[2.1.0]pentyl group, a bicyclo[2.2.0]hexyl group, or a bicyclo[3.2.1]octyl group.

A condensed polycyclic hydrocarbon ring group means a bi- to tetra-cyclic hydrocarbon ring group such as a naphthyl group, an anthryl group, a phenanthryl group, a pyrenyl group, a fluorenyl group, an indenyl group, or an acenaphthylenyl group.

A partially-saturated condensed polycyclic hydrocarbon ring group is a condensed polycyclic hydrocarbon ring group which was partially hydrogenated, and means an indanyl group, an acenaphthenyl group, or the like.

An aryl group means a phenyl group, a condensed polycyclic hydrocarbon ring group, or a partially saturated condensed polycyclic hydrocarbon ring group.

An ar C 1-6 alkyl group means an ar C 1-6 alkyl group such as a benzyl group, a diphenylmethyl group, a trityl group, a phenethyl group, or a naphthylmethyl group.

A C 1-6 alkylene group means a linear or branched C 1-6 alkylene group such as a methylene group, an ethylene group, a propylene group, a butylene group, or a hexylene group.

A C 1-6 alkoxy group means a linear or branched C 1-6 alkyloxy group such as a methoxy group, an ethoxy group, a propyl oxy group, an isopropyl oxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, or a hexyloxy group.

A C 3-8 cycloalkoxy group means a C 3-8 cycloalkyloxy group such as a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, or a cyclohexyloxy group.

A C 1-6 alkoxy C 1-6 alkyl group means a C 1-6 alkyloxy C 1-6 alkyl group such as a methoxymethyl group or a 1-ethoxyethyl group.

The aryloxy group means a phenyloxy group, a naphthyloxy group, an indanyloxy group, or an indenyloxy group.

A C 1-6 alkylthio group means a linear or branched C 1-6 alkylthio group such as a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a sec-butylthio group, a tert-butylthio group, a pentylthio group, or a hexylthio group.

An arylthio group means a phenylthio group, a naphthylthio group, an indanylthio group, or an indenylthio group.

A C 1-6 alkylsulfonyl group means a linear or branched C 1-6 alkylsulfonyl group such as a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a sec-butylsulfonyl group, a tert-butylsulfonyl group, a pentylsulfonyl group, or a hexylsulfonyl group.

An arylsulfonyl group means a benzenesulfonyl group, a p-toluenesulfonyl group, a naphthylsulfonyl group, an indanylsulfonyl group, or an indenylsulfonyl group.

A C 1-6 alkylsulfonyloxy group means a C 1-6 alkylsulfonyloxy group such as a methylsulfonyloxy group or an ethylsulfonyloxy group.

An arylsulfonyloxy group means a benzenesulfonyloxy group or a p-toluenesulfonyloxy group.

A C 2-6 alkanoyl group means a linear or branched C 2-6 alkanoyl group such as an acetyl group, a propionyl group, a valeryl group, an isovaleryl group, or a pivaloyl group.

An aroyl group means a benzoyl group, or a naphthoyl group.

A heterocyclic carbonyl group means a nicotinoyl group, a thenyl group, a pyrrolidinocarbonyl group, or a furoyl group.

An (α-substituted) aminoacetyl group means an (α-substituted) aminoacetyl group of which the N-terminal may be protected, derived from an amino acid (glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine, tyrosine, tryptophan, proline, or hydroxyproline).

An acyl group means a formyl group, a succinyl group, a glutaryl group, a maleoyl group, a phthaloyl group, a C 2-6 alkanoyl group, an aroyl group, a heterocyclic carbonyl group, or an (α-substituted) aminoacetyl group.

A C 1-6 alkoxycarbonyl group means a linear or branched C 1-6 alkyloxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, an isopropyloxycarbonyl group, a tert-butoxycarbonyl group, or a 1,1-dimethylpropoxycarbonyl group.

An aryloxycarbonyl group means a phenyloxycarbonyl group or a naphthyloxycarbonyl group.

An ar C 1-6 alkoxycarbonyl group means an ar C 1-6 alkyloxycarbonyl group such as a benzyloxycarbonyl group or a phenethyloxycarbonyl group.

A C 1-6 alkylamino group means a linear or branched C 1-6 alkylamino group such as a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, a sec-butylamino group, a tert-butylamino group, a pentylamino group, or a hexylamino group.

A di(C 1-6 alkyl)amino group means a linear or branched di(C 1-6 alkyl)amino group such as a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, a dibutylamino group, a di(tert-butyl)amino group, a dipentylamino group, a dihexylamino group, an (ethyl)(methyl)amino group, a (methyl)(propyl)amino group, an (ethyl)(propyl)amino group, or an (ethyl)(isopropyl)amino group.

›DESCRIPTION OF EMBODIMENTS · 2 of 16

A nitrogen-containing heterocyclyl group means a heterocyclyl group of which a ring including at least one nitrogen atom does not have aromatic properties, and examples thereof include an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a homopiperidinyl group, an octahydroazocinyl group, an imidazolidinyl group, a pyrazolidinyl group, a piperazinyl group, and a homopiperazinyl group. The heterocyclyl group may be further condensed with another aromatic ring or another aliphatic ring.

An oxygen-containing heterocyclyl group means a tetrahydrofuranyl group, a tetrahydropyranyl group, an oxetanyl group, a 1,3-dioxanyl group or the like. The heterocyclyl group may be further condensed with another aromatic ring or another aliphatic ring.

A sulfur-containing heterocyclyl group means a tetrahydrothienyl group, a tetrahydrothiopyranyl group or the like. This heterocyclyl group includes a group of which the sulfur atom is oxidized, and may be further condensed with another aromatic ring or another aliphatic ring.

A nitrogen- and oxygen-containing heterocyclyl group means a morpholinyl group, a 1,4-oxazepanyl group or the like. This heterocyclyl group may be further condensed with another aromatic ring or another aliphatic ring.

A nitrogen- and sulfur-containing heterocyclyl group means a thiomorpholinyl or the like. This heterocyclyl group includes a group of which the sulfur atom is oxidized, and may be further condensed with another aromatic ring or another aliphatic ring.

A hetero, crosslinked ring group means a hetero, crosslinked ring group including at least one heteroatom (for example, an oxygen atom, a nitrogen atom, or a sulfur atom), and examples thereof include a 3-aza-6-oxabicyclo[3.1.1]heptyl group, a 3-aza-8-oxabicyclo[3.2.1]octyl group, and a 8-aza-3-oxabicyclo[3.2.1]octyl group.

A heterospiro ring group means a heterospiro ring group including at least one heteroatom (for example, an oxygen atom, a nitrogen atom, or a sulfur atom), and examples thereof include a 2-azaspiro[3.3]heptyl group, a 2-oxaspiro[3.3]heptyl group, a 6-aza-2-oxaspiro[3.3]heptyl group, a 1-azaspiro[4.5]decyl group, and a 1-oxaspiro[4.5]decyl group.

A heterocyclyl group means the nitrogen-containing heterocyclyl group, the oxygen-containing heterocyclyl group, the sulfur-containing heterocyclyl group, the nitrogen- and oxygen-containing heterocyclyl group, the nitrogen- and sulfur-containing heterocyclyl group, the hetero, crosslinked ring group, or the heterospiro ring group.

A heterocyclyloxy group means a group in which an oxy group is bonded to a heterocyclyl group, and examples thereof include an azetidinyloxy group, an oxetanyloxy group, a pyrrolidinyloxy group, a piperidinyloxy group, and a tetrahydropyranyloxy group.

A monocyclic, nitrogen-containing heteroaryl group means a heteroaryl group (which may be partially saturated) of which a ring including at least one nitrogen atom has aromatic properties, and examples thereof include a pyrrolinyl group, a pyrrolyl group, a tetrahydropyridyl group, a pyridyl group, an imidazolinyl group, an imidazolyl group, a pyrazolinyl group, a pyrazolyl group, a pyrazinyl group, a pyridazinyl group, a pyrimidinyl group, a triazolyl group, and a tetrazolyl group. This heteroaryl group may be further condensed with another aromatic ring or another aliphatic ring.

A monocyclic, oxygen-containing heteroaryl group means a heteroaryl group (which may be partially saturated) of which a ring including at least one oxygen atom has aromatic properties, and examples thereof include a furanyl group and a pyranyl group. This heteroaryl group may be further condensed with another aromatic ring or another aliphatic ring.

A monocyclic, sulfur-containing heteroaryl group means a heteroaryl group (which may be partially saturated) of which a ring including at least one sulfur atom has aromatic properties, and examples thereof include a thienyl group. This heteroaryl group may be further condensed with another aromatic ring or another aliphatic ring.

A monocyclic, nitrogen- and oxygen-containing heteroaryl group means an oxazolyl group, an isoxazolyl group, an oxadiazolyl group or the like. This heteroaryl group may be further condensed with another aromatic ring or another aliphatic ring.

A monocyclic, nitrogen- and sulfur-containing heteroaryl group means a thiazolyl group, an isothiazolyl group, a thiadiazolyl group or the like. This heteroaryl group may be further condensed with another aromatic ring or another aliphatic ring.

A bicyclic, nitrogen-containing heteroaryl group means a bicyclic heteroaryl group (which may be partially saturated) of which a ring including at least one nitrogen atom has aromatic properties, and examples thereof include an indolyl group, an isoindolyl group, a benzimidazolyl group, an indazolyl group, a benzotriazolyl group, a quinolyl group, an isoquinolyl group, a tetrahydroquinolyl group, a tetrahydroisoquinolyl group, a quinolizinyl group, a cinnolinyl group, a phthalazinyl group, a quinazolinyl group, a quinoxalinyl group, a naphthyridinyl group, a pyrrolopyridyl group, an imidazopyridyl group, a pyrazolopyridyl group, a pyridopyrazyl group, a purinyl group, a pteridinyl group, a 5,6,7,8-tetrahydrophthalazinyl group, a 5,6,7,8-tetrahydrocinnolinyl group, a 1,2,3,4-tetrahydropyrido[2,3-d]pyridazinyl group, a 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl group, a 5,6,7,8-tetrahydropyrido[3,4-d]pyridazinyl group, a 5,6,7,8-tetrahydropyrido[3,2-c]pyridazinyl group, a 5,6,7,8-tetrahydropyrido[4,3-c]pyridazinyl group, a 6,7-dihydro-5H-cyclopenta[d]pyridazinyl group, a 6,7-dihydro-5H-cyclopenta[c]pyridazinyl group, a 2,3-dihydro-1H-pyrrolo[2,3-d]pyridazinyl group, a 6,7-dihydro-5H-pyrrolo[3,4-d]pyridazinyl group, a 6,7-dihydro-5H-pyrrolo[3,2-c]pyridazinyl group, a 6,7-dihydro-5H-pyrrolo[3,4-c]pyridazinyl group, and a 6,7-dihydro-5H-pyrrolo[2,3-c]pyridazinyl group.

A bicyclic, oxygen-containing heteroaryl group means a bicyclic heteroaryl group (which may be partially saturated) of which a ring including at least one oxygen atom has aromatic properties, and examples thereof include a benzofuranyl group, an isobenzofuranyl group, and a chromenyl group.

›DESCRIPTION OF EMBODIMENTS · 3 of 16

A bicyclic, sulfur-containing heteroaryl group means a bicyclic heteroaryl group (which may be partially saturated) of which a ring including at least one sulfur atom has aromatic properties, and examples thereof include a benzothienyl group.

A bicyclic, nitrogen- and oxygen-containing heteroaryl group means a bicyclic heteroaryl group (which may be partially saturated) of which a ring including at least one nitrogen atom and at least one oxygen atom has aromatic properties, and examples thereof include a benzoxazolyl group, a benzoisoxazolyl group, a benzoxadiazolyl group, a dihydropyranopyridyl group, a dihydrodioxynopyridyl group, a dihydropyridooxadienyl group, a 3,4-dihydro-2H-pyrano[2,3-d]pyridazinyl group, a 7,8-dihydro-5H-pyrano[3,4-d]pyridazinyl group, a 7,8-dihydro-6H-pyrano[3,2-c]pyridazinyl group, a 7,8-dihydro-5H-pyrano[4,3-c]pyridazinyl group, a 2,3-dihydrofuro[2,3-d]pyridazinyl group, a 5,7-dihydrofuro[3,4-d]pyridazinyl group, a 6,7-dihydrofuro[3,2-c]pyridazinyl group, a 5,7-dihydrofuro[3,4-c]pyridazinyl group, and a 5,6-dihydrofuro[2,3-c]pyridazinyl group.

A bicyclic, nitrogen- and sulfur-containing heteroaryl group means a bicyclic heteroaryl group (which may be partially saturated) of which a ring including at least one nitrogen atom and at least one sulfur atom has aromatic properties, and examples thereof include a benzothiazolyl group, a benzoisothiazolyl group, a benzothiadiazolyl group, and a thiazolopyridyl group.

A heteroaryl group means the monocyclic, nitrogen-containing heteroaryl group, the monocyclic, oxygen-containing heteroaryl group, the monocyclic, sulfur-containing heteroaryl group, the monocyclic, nitrogen- and oxygen-containing heteroaryl group, the monocyclic, nitrogen- and sulfur-containing heteroaryl group, the bicyclic, nitrogen-containing heteroaryl group, the bicyclic, oxygen-containing heteroaryl group, the bicyclic, sulfur-containing heteroaryl group, the bicyclic, nitrogen- and oxygen-containing heteroaryl group, or the bicyclic, nitrogen- and sulfur-containing heteroaryl group.

A heteroaryloxy group means a group in which an oxy group is bonded to a heteroaryl group, and examples thereof include a pyridyloxy group, a pyridazinyloxy group, and a pyrimidinyloxy group.

A heteroarylthio group means a group in which a thio group is bonded to a heteroaryl group, and examples thereof include a pyridylthio group, a pyridazinylthio group, andr a pyrimidinylthio group.

A silyl group means a trimethylsilyl group, a triethylsilyl group, a tributylsilyl group, a tert-butyldimethylsilyl group or the like.

A leaving group means a halogen atom, a C 1-6 alkylsulfonyloxy group, an arylsulfonyloxy group or the like. The C 1-6 alkylsulfonyloxy group or the arylsulfonyloxy group may have a substituent.

Examples of a hydroxyl protecting group include any group that can be usually used as a protecting group of a hydroxyl group, and examples thereof include the groups described in “Protective Groups in Organic Synthesis” written by W. Greene et al., 4th edition, pp. 16-366, 2007 (John Wiley & Sons, INC.).

Specific examples thereof include a C 1-6 alkyl group, a C 2-6 alkenyl group, an ar C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an ar C 1-6 alkoxycarbonyl group, a C 1-6 alkylsulfonyl group, an arylsulfonyl group, a silyl group, a tetrahydrofuranyl group, and a tetrahydropyranyl group. These groups may have a substituent.

Examples of an amino protecting group include any group that can be usually used as a protecting group of a amino group, and examples thereof include the groups described in “Protective Groups in Organic Synthesis” written by W. Greene et al., 4th edition, pp. 696-926, 2007 (John Wiley & Sons, INC.).

Specific examples thereof include an ar C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an ar C 1-6 alkoxycarbonyl group, an aryloxycarbonyl group, a C 1-6 alkylsulfonyl group, an arylsulfonyl group, and a silyl group. These groups may have a substituent.

Examples of a carboxyl protecting group include any group that can be usually used as a protecting group of a carboxyl group, and examples thereof include the groups described in “Protective Groups in Organic Synthesis” written by W. Greene et al., 4th edition, pp. 533-646, 2007 (John Wiley & Sons, INC.).

Specific examples thereof include a C 1-6 alkyl group, a C 2-6 alkenyl group, an aryl group, an ar C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, and a silyl group. These groups may have a substituent.

An aliphatic hydrocarbon means pentane, hexane, cyclohexane or the like.

A halogenated hydrocarbon means methylene chloride, chloroform, dichloroethane or the like.

An alcohol means methanol, ethanol, propanol, 2-propanol, butanol, 2-methyl-2-propanol, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol or the like.

An ether means diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether or the like.

A ketone means acetone, 2-butanone, 4-methyl-2-pentanone or the like.

An ester means methyl acetate, ethyl acetate, propyl acetate, butyl acetate, cyclohexyl acetate, amyl acetate or the like.

An amide means N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or the like.

A sulfoxide means dimethyl sulfoxide or the like.

A carboxylic acid means formic acid, acetic acid, trifluoroacetic acid or the like.

An aromatic hydrocarbon means benzene, toluene, xylene or the like.

A palladium catalyst means a metal palladium such as palladium-carbon or palladium black; an inorganic palladium salt such as palladium chloride; an organic palladium salt such as palladium acetate; an organic palladium complex such as tetrakis(triphenylphosphine)palladium(0), bis(tri-tert-butylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), (E)-di(μ-acetate)bis(o-(di-o-tolylphosphino)benzyl)dipalladium(II), or tris(dibenzylideneacetone)dipalladium(0); a ploymer-immobilized organic palladium complex such as polymer-supported bis(acetate)triphenylphosphine palladium(II) or polymer-supported di(acetate)dicyclohexylphenylphosphine palladium(II); or the like. These may be used in combination.

›DESCRIPTION OF EMBODIMENTS · 4 of 16

Examples of a ligand include: a trialkylphosphine such as trimethylphosphine or tri-tert-butylphosphine; a tricycloalkylphosphine such as tricyclohexylphosphine; a triarylphosphine such as triphenylphosphine or tritolylphosphine; a trialkylphosphite such as trimethylphosphite, triethylphosphite, or tributylphosphite; a tricycloalkylphosphite such as tricyclohexylphosphite; a triarylphosphite such as triphenylphosphite; a imidazolium salt such as 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride; a diketone such as acetylacetone or octafluoroacetyl acetone; an amine such as trimethylamine, triethylamine, tripropylamine, or triisopropylamine; and 1,1′-bis(diphenylphosphino)ferrocene, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and 2-(di-tert-butylphosphino)biphenyl. These may be used in combination.

The monocyclic, nitrogen-containing heteroaryl group, the monocyclic, nitrogen- and oxygen-containing heteroaryl group, the monocyclic, nitrogen- and sulfur-containing heteroaryl group, the bicyclic, nitrogen-containing heteroaryl group, the bicyclic, nitrogen- and oxygen-containing heteroaryl group, or the bicyclic, nitrogen- and sulfur-containing heteroaryl group of R 1 may be substituted with one or more substituents selected from the substituent group A 1 .

Preferably, the monocyclic, nitrogen-containing heteroaryl group, the monocyclic, nitrogen- and oxygen-containing heteroaryl group, the monocyclic, nitrogen- and sulfur-containing heteroaryl group, the bicyclic, nitrogen-containing heteroaryl group, the bicyclic, nitrogen- and oxygen-containing heteroaryl group, or the bicyclic, nitrogen- and sulfur-containing heteroaryl group of R 1 may be substituted with one or more substituents selected from the substituent group α 1 .

The C 1-6 alkyl group or the C 1-6 alkoxy group of R 4 may be substituted with one or more substituents selected from the substituent group α 2 .

The carbamoyl group, the C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, the C 3-8 cycloalkyl group, the aryl group, the C 1-6 alkoxy group, the aryloxy group, the C 1-6 alkylthio group, the arylthio group, the heteroaryl group, the heteroaryloxy group, the heteroarylthio group, or the heterocyclyl group of R 5 may be substituted with one or more substituents selected from the substituent group A 3 .

Preferably, the carbamoyl group, the C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, the C 3-8 cycloalkyl group, the aryl group, the C 1-6 alkoxy group, the aryloxy group, the C 1-6 alkylthio group, the arylthio group, the heteroaryl group, the heteroaryloxy group, the heteroarylthio group, or the heterocyclyl group of R 5 may be substituted with one or more substituents selected from the substituent group α 3 .

The C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, the C 3-8 cycloalkyl group, the aryl group, the C 1-6 alkoxy group, the aryloxy group, the C 1-6 alkylthio group, the arylthio group, the heteroaryl group, the heteroaryloxy group, the heteroarylthio group, or the heterocyclyl group of R 6 may be substituted with one or more substituents selected from the substituent group α 2 .

The C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, the C 3-8 cycloalkyl group, the aryl group, the heteroaryl group, or the heterocyclyl group of R 7 or R 8 may be substituted with one or more substituents selected from the substituent group α 2 .

The C 1-6 alkyl group of R 9 may be substituted with one or more substituents selected from the substituent group α 2 .

The C 1-6 alkyl group of R 10 or R 11 may be substituted with one or more substituents selected from the substituent group α 2 .

The C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, the C 3-8 cycloalkyl group, the aryl group, the heteroaryl group, or the heterocyclyl group of R 12 or R 13 may be substituted with one or more substituents selected from the substituent group A 3 .

Preferably, the C 1-6 alkyl group, the C 2-6 alkenyl group, the C 2-6 alkynyl group, the C 3-8 cycloalkyl group, the aryl group, the heteroaryl group, or the heterocyclyl group of R 12 or R 13 may be substituted with one or more substituents selected from the substituent group α 3 .

Substituent group A 1 : A halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group which may be protected, a cyano group, a carbamoyl group which may be substituted with one or more substituents selected from a substituent group B 1 , a sulfamoyl group which may be substituted with one or more substituents selected from the substituent group B 1 , a C 1-6 alkyl group which may be substituted with one or more substituents selected from the substituent group B 1 , a C 2-6 alkenyl group which may be substituted with one or more substituents selected from the substituent group B 1 , a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group B 1 , an aryl group which may be substituted with one or more substituents selected from the substituent group B 1 , a C 1-6 alkoxy group which may be substituted with one or more substituents selected from the substituent group B 1 , a C 3-8 cycloalkoxy group which may be substituted with one or more substituents selected from the substituent group B 1 , an aryloxy group which may be substituted with one or more substituents selected from the substituent group B 1 , a C 1-6 alkylthio group which may be substituted with one or more substituents selected from the substituent group B 1 , an arylthio group which may be substituted with one or more substituents selected from the substituent group B 1 , a C 1-6 alkylamino group which may be substituted with one or more substituents selected from the substituent group B 1 , a di(C 1-6 alkyl)amino group which may be substituted with one or more substituents selected from the substituent group B 1 , an acyl group which may be substituted with one or more substituents selected from the substituent group B 1 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group B 1 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group B 1 , and an oxo group.

›DESCRIPTION OF EMBODIMENTS · 5 of 16

Substituent group B 1 : A halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group which may be protected, a cyano group, a carbamoyl group which may be substituted with one or more substituents selected from a substituent group C 1 , a sulfamoyl group which may be substituted with one or more substituents selected from the substituent group C 1 , a C 1-6 alkyl group which may be substituted with one or more substituents selected from the substituent group C 1 , a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group C 1 , an aryl group which may be substituted with one or more substituents selected from the substituent group C 1 , a C 1-6 alkoxy group which may be substituted with one or more substituents selected from the substituent group C 1 , a C 1-6 alkylamino group which may be substituted with one or more substituents selected from the substituent group C 1 , a di(C 1-6 alkyl)amino group which may be substituted with one or more substituents selected from the substituent group C 1 , a C 1-6 alkylsulfonyl group which may be substituted with one or more substituents selected from the substituent group C 1 , an arylsulfonyl group which may be substituted with one or more substituents selected from the substituent group C 1 , an acyl group which may be substituted with one or more substituents selected from the substituent group C 1 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group C 1 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group C 1 , and an oxo group.

Substituent group C 1 : A halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group which may be protected, a cyano group, a carbamoyl group which may be substituted with a C 1-6 alkyl group, a C 1-6 alkyl group which may be substituted with a halogen atom, an aryl group which may be substituted with a halogen atom or a C 1-6 alkyl group, a C 1-6 alkoxy group which may be substituted with a halogen atom, and an oxo group.

Substituent group α 1 : A halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group which may be protected, a cyano group, a carbamoyl group which may be substituted with one or more substituents selected from a substituent group β 1 , a sulfamoyl group which may be substituted with one or more substituents selected from the substituent group β 1 , a C 1-6 alkyl group which may be substituted with one or more substituents selected from the substituent group β 1 , a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group β 1 , an aryl group which may be substituted with one or more substituents selected from the substituent group β 1 , a C 1-6 alkoxy group which may be substituted with one or more substituents selected from the substituent group β 1 , an aryloxy group which may be substituted with one or more substituents selected from the substituent group β 1 , a C 1-6 alkylthio group which may be substituted with one or more substituents selected from the substituent group β 1 , an arylthio group which may be substituted with one or more substituents selected from the substituent group β 1 , a C 1-6 alkylamino group which may be substituted with one or more substituents selected from the substituent group β 1 , a di(C 1-6 alkyl)amino group which may be substituted with one or more substituents selected from the substituent group β 1 , an acyl group which may be substituted with one or more substituents selected from the substituent group β 1 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group β 1 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group β 1 , and an oxo group.

Substituent group β 1 : A halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group which may be protected, a cyano group, a carbamoyl group which may be substituted with one or more substituents selected from a substituent group γ 1 , a C 1-6 alkyl group which may be substituted with one or more substituents selected from the substituent group γ 1 , a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group γ 1 , an aryl group which may be substituted with one or more substituents selected from the substituent group γ 1 , a C 1-6 alkoxy group which may be substituted with one or more substituents selected from the substituent group γ 1 , a C 1-6 alkylamino group which may be substituted with one or more substituents selected from the substituent group γ 1 , a di(C 1-6 alkyl)amino group which may be substituted with one or more substituents selected from the substituent group γ 1 , a C 1-6 alkylsulfonyl group which may be substituted with one or more substituents selected from the substituent group γ 1 , an arylsulfonyl group which may be substituted with one or more substituents selected from the substituent group γ 1 , an acyl group which may be substituted with one or more substituents selected from the substituent group γ 1 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group γ 1 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group γ 1 , and an oxo group.

Substituent group γ 1 : A halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group which may be protected, a cyano group, a carbamoyl group which may be substituted with a C 1-6 alkyl group, a C 1-6 alkyl group which may be substituted with a halogen atom, a C 1-6 alkoxy group which may be substituted with a halogen atom, and an oxo group.

›DESCRIPTION OF EMBODIMENTS · 6 of 16

Substituent group α 2 : A halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group which may be protected, a cyano group, a carbamoyl group which may be substituted with one or more substituents selected from the substituent group β 2 , a C 1-6 alkyl group which may be substituted with one or more substituents selected from the substituent group β 2 , a C 1-6 alkoxy group which may be substituted with one or more substituents selected from the substituent group β 2 , and an oxo group.

Substituent group β 2 : A halogen atom, a C 1-6 alkyl group which may be substituted with one or more substituents selected from the substituent group γ 2 , a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group γ 2 , an aryl group which may be substituted with one or more substituents selected from the substituent group γ 2 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group γ 2 , and a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group γ 2 .

Substituent group γ 2 : A halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group which may be protected, a cyano group, a C 1-6 alkyl group which may be substituted with a halogen atom, a C 1-6 alkoxy group which may be substituted with a halogen atom, and an oxo group.

Substituent group A 3 : A halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, an amino group which may be substituted with one or more substituents selected from a substituent group E 3 , a carboxyl group which may be protected, a cyano group, a carbamoyl group which may be substituted with one or more substituents selected from a substituent group B 3 , a sulfamoyl group which may be substituted with one or more substituents selected from the substituent group B 3 , a C 1-6 alkyl group which may be substituted with one or more substituents selected from the substituent group B 3 , a C 2-6 alkenyl group which may be substituted with one or more substituents selected from the substituent group B 3 , a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group B 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group B 3 , a C 1-6 alkoxy group which may be substituted with one or more substituents selected from the substituent group B 3 , an aryloxy group which may be substituted with one or more substituents selected from the substituent group B 3 , a C 1-6 alkylthio group which may be substituted with one or more substituents selected from the substituent group B 3 , an arylthio group which may be substituted with one or more substituents selected from the substituent group B 3 , a C 1-6 alkyl amino group which may be substituted with one or more substituents selected from the substituent group B 3 , a di(C 1-6 alkyl)amino group which may be substituted with one or more substituents selected from the substituent group B 3 , a C 1-6 alkylsulfonyl group which may be substituted with one or more substituents selected from the substituent group B 3 , an arylsulfonyl group which may be substituted with one or more substituents selected from the substituent group B 3 , an acyl group which may be substituted with one or more substituents selected from the substituent group B 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group B 3 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group B 3 , a heterocyclyloxy group which may be substituted with one or more substituents selected from the substituent group B 3 , and an oxo group.

Substituent group B 3 : A halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group which may be protected, a cyano group, a carbamoyl group which may be substituted with one or more substituents selected from a substituent group C 3 , a C 1-6 alkyl group which may be substituted with one or more substituents selected from the substituent group C 3 , a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group C 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group C 3 , a C 1-6 alkoxy group which may be substituted with one or more substituents selected from the substituent group C 3 , an aryloxy group which may be substituted with one or more substituents selected from the substituent group C 3 , a C 1-6 alkylamino group which may be substituted with one or more substituents selected from the substituent group C 3 , a di(C 1-6 alkyl)amino group which may be substituted with one or more substituents selected from the substituent group C 3 , a C 1-6 alkylsulfonyl group which may be substituted with one or more substituents selected from the substituent group C 3 , an arylsulfonyl group which may be substituted with one or more substituents selected from the substituent group C 3 , an acyl group which may be substituted with one or more substituents selected from the substituent group C 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group C 3 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group C 3 , a heteroaryloxy group which may be substituted with one or more substituents selected from the substituent group C 3 , a heterocyclyloxy group which may be substituted with one or more substituents selected from the substituent group C 3 , and an oxo group.

Substituent group C 3 : A halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group which may be protected, a nitro group, cyano group, a carbamoyl group which may be substituted with one or more substituents selected from a substituent group D 3 , a C 1-6 alkyl group which may be substituted with one or more substituents selected from the substituent group D 3 , a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group D 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group D 3 , a C 1-6 alkoxy group which may be substituted with one or more substituents selected from the substituent group D 3 , an aryloxy group which may be substituted with one or more substituents selected from the substituent group D 3 , a C 1-6 alkylamino group which may be substituted with one or more substituents selected from the substituent group D 3 , a di(C 1-6 alkyl)amino group which may be substituted with one or more substituents selected from the substituent group D 3 , a C 1-6 alkylsulfonyl group which may be substituted with one or more substituents selected from the substituent group D 3 , an acyl group which may be substituted with one or more substituents selected from the substituent group D 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group D 3 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group D 3 , a silyl group which may be substituted with one or more substituents selected from the substituent group D 3 , and an oxo group.

›DESCRIPTION OF EMBODIMENTS · 7 of 16

Substituent group D 3 : A halogen atom, a hydroxyl group which may be protected, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, an aryl group, a C 1-6 alkoxy group, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group, a C 1-6 alkylsulfonyl group, a heteroaryl group, a heterocyclyl group, and an oxo group.

Substituent group E 3 : A C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from a substituent group F 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group F 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group F 3 , and a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group F 3 .

Substituent group F 3 : A halogen atom, a carboxyl group which may be protected, and a C 1-6 alkyl group.

Substituent group α 3 : A halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group which may be protected, a cyano group, a carbamoyl group which may be substituted with one or more substituents selected from a substituent group β 3 , a C 1-6 alkyl group which may be substituted with one or more substituents selected from the substituent group β 3 , a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group β 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group β 3 , a C 1-6 alkoxy group which may be substituted with one or more substituents selected from the substituent group β 3 , an aryloxy group which may be substituted with one or more substituents selected from the substituent group β 3 , a C 1-6 alkylthio group which may be substituted with one or more substituents selected from the substituent group β 3 , an arylthio group which may be substituted with one or more substituents selected from the substituent group β 3 , a C 1-6 alkylamino group which may be substituted with one or more substituents selected from the substituent group β 3 , a di(C 1-6 alkyl)amino group which may be substituted with one or more substituents selected from the substituent group β 3 , a C 1-6 alkylsulfonyl group which may be substituted with one or more substituents selected from the substituent group β 3 , an arylsulfonyl group which may be substituted with one or more substituents selected from the substituent group β 3 , an acyl group which may be substituted with one or more substituents selected from the substituent group β 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group β 3 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group β 3 , a heterocyclyloxy group which may be substituted with one or more substituents selected from the substituent group β 3 , and an oxo group.

Substituent group β 3 : A halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group which may be protected, a cyano group, a carbamoyl group which may be substituted with one or more substituents selected from a substituent group γ 3 , a C 1-6 alkyl group which may be substituted with one or more substituents selected from the substituent group γ 3 , a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group γ 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group γ 3 , a C 1-6 alkoxy group which may be substituted with one or more substituents selected from the substituent group γ 3 , a C 1-6 alkylamino group which may be substituted with one or more substituents selected from the substituent group γ 3 , a di(C 1-6 alkyl)amino group which may be substituted with one or more substituents selected from the substituent group γ 3 , a C 1-6 alkylsulfonyl group which may be substituted with one or more substituents selected from the substituent group γ 3 , an arylsulfonyl group which may be substituted with one or more substituents selected from the substituent group γ 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group γ 3 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group γ 3 , a heterocyclyloxy group which may be substituted with one or more substituents selected from the substituent group γ 3 , and an oxo group.

Substituent group γ 3 : A halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a carboxyl group which may be protected, a cyano group, a C 1-6 alkyl group which may be substituted with a halogen atom, a C 1-6 alkoxy group which may be substituted with a halogen atom, and an oxo group.

As the compound represented by Formula [1], the following compound is preferable.

X 1 is NR 9 (in the formula, R 9 has the same meaning as that described above), O, S, or CR 10 R 11 (in the formula, each of R 10 and R 11 has the same meaning as that described above).

X 1 is preferably NR 9 (in the formula, R 9 has the same meaning as that described above) or S, more preferably NR 9a (in the formula, R 9a represents a hydrogen atom or an amino protecting group) or S, still more preferably NR 9a (in the formula, R 9a has the same meaning as that described above), and most preferably NH.

Z 1 is N or CR 6 (in the formula, R 6 has the same meaning as that described above).

Z 1 is preferably CR 6 (in the formula, R 6 has the same meaning as that described above), more preferably CR 6a (in the formula, R 6a represents an aryl group which may be substituted, a heteroaryl group which may be substituted, a heterocyclyl group which may be substituted, or NHR 8a (in the formula, R 8a represents an aryl group which may be substituted, a heteroaryl group which may be substituted, or a heterocyclyl group which may be substituted)), still more preferably CR 6b (in the formula, R 6b represents an aryl group which may be substituted with one or more substituents selected from a substituent group α 2 , a heteroaryl group which may be substituted with one or more substituents selected from a substituent group α 2 , a heterocyclyl group which may be substituted with one or more substituents selected from a substituent group α 2 , or NHR 8b (in the formula, R 8b represents an aryl group which may be substituted with one or more substituents selected from a substituent group α 2 , a heteroaryl group which may be substituted with one or more substituents selected from a substituent group α 2 , or a heterocyclyl group which may be substituted with one or more substituents selected from a substituent group α 2 )), and most preferably CR 6a (in the formula, R 6a represents a phenyl group which may be substituted with one or more substituents selected from a substituent group α 2 , a pyrazolyl group which may be substituted with one or more substituents selected from a substituent group α 2 , a pyridyl group which may be substituted with one or more substituents selected from a substituent group α 2 , a pyrimidinyl group which may be substituted with one or more substituents selected from a substituent group α 2 , a pyrazinyl group which may be substituted with one or more substituents selected from a substituent group α 2 , a pyridazinyl group which may be substituted with one or more substituents selected from a substituent group α 2 , a morpholinyl group which may be substituted with one or more substituents selected from a substituent group α 2 , or NHR 8c (in the formula, R 8c represents a phenyl group which may be substituted with one or more substituents selected from a substituent group α 2 , a pyridyl group which may be substituted with one or more substituents selected from a substituent group α 2 , a pyrimidinyl group which may be substituted with one or more substituents selected from a substituent group α 2 , a pyrazinyl group which may be substituted with one or more substituents selected from a substituent group α 2 , a pyridazinyl group which may be substituted with one or more substituents selected from a substituent group α 2 )).

›DESCRIPTION OF EMBODIMENTS · 8 of 16

In a case in which Z 1 is CR 6a (in the formula, R 6a has the same meaning as that described above), CR 6b (in the formula, R 6b has the same meaning as that described above), or CR 6c (in the formula, R 6c has the same meaning as that described above), R 5 is preferably a hydrogen atom or a halogen atom, and more preferably a hydrogen atom.

In another aspect, Z 1 is preferably N or CR 6d (in the formula, R 6d represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may be substituted, a C 1-6 alkoxy group which may be substituted, or NHR 8d (in the formula, R 8d represents a hydrogen atom or a C 1-6 alkyl group which may be substituted)), more preferably N or CR 6e (in the formula, R 6e represents a hydrogen atom, a halogen atom, or a C 1-6 alkoxy group which may be substituted), and still more preferably N or CH.

In a case in which Z 1 is N or CR 6d (in the formula, R 6d has the same meaning as that described above), N or CR 6e (in the formula, R 6e has the same meaning as that described above), or N or CH, R 5 is preferably a C 3-8 cycloalkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, a heterocyclyl group which may be substituted, or NR 12a R 13a (in the formula, R 12a represents a hydrogen atom or a C 1-6 alkyl group which may be substituted; and R 13a represents a C 3-8 cycloalkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, or a heterocyclyl group which may be substituted), more preferably a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group A 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group A 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group A 3 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group α 3 , or NR 12b R 13b (in the formula, R 12b represents a hydrogen atom or a C 1-6 alkyl group; and R 13b represents a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group A 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group A 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group A 3 , or a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group A 3 ), still more preferably a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group α 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group α 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group α 3 , a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group α 3 , or NR 12b R 13c (in the formula, R 12b represents a hydrogen atom or a C 1-6 alkyl group; and R 13c represents a C 3-8 cycloalkyl group which may be substituted with one or more substituents selected from the substituent group α 3 , an aryl group which may be substituted with one or more substituents selected from the substituent group α 3 , a heteroaryl group which may be substituted with one or more substituents selected from the substituent group α 3 , or a heterocyclyl group which may be substituted with one or more substituents selected from the substituent group α 3 ), most preferably a phenyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrazolyl group which may be substituted with one or more substituents selected from the substituent group α 3 , an isoxazolyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyridyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrimidinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrazinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyridazinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , an aziridinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrrolidinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a piperidinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a piperazinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a morpholinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a homopiperazinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , or NR 12b R 13d (in the formula, R 12b represents a hydrogen atom or a C 1-6 alkyl group; and R 13d represents a phenyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrazolyl group which may be substituted with one or more substituents selected from the substituent group α 3 , an isoxazolyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyridyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrimidinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrazinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyridazinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a pyrrolidinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , a piperidinyl group which may be substituted with one or more substituents selected from the substituent group α 3 , or a tetrahydropyridyl group which may be substituted with one or more substituents selected from the substituent group α 3 ).

›DESCRIPTION OF EMBODIMENTS · 9 of 16

R 1 is a monocyclic, nitrogen-containing heteroaryl group which may be substituted, a monocyclic, nitrogen- and oxygen-containing heteroaryl group which may be substituted, a monocyclic, nitrogen- and sulfur-containing heteroaryl group which may be substituted, a bicyclic, nitrogen-containing heteroaryl group which may be substituted, a bicyclic, nitrogen- and oxygen-containing heteroaryl group which may be substituted, or a bicyclic, nitrogen- and sulfur-containing heteroaryl group which may be substituted.

R 1 is preferably a pyrazolyl group which may be substituted, an imidazolyl group which may be substituted, a triazolyl group which may be substituted, a thiazolyl group which may be substituted, an oxadiazolyl group which may be substituted, a thiadiazolyl group which may be substituted, a pyridyl group which may be substituted, or a pyridazinyl group which may be substituted, more preferably a pyrazolyl group which may be substituted with one or more substituents selected from a substituent group A 1 , an imidazolyl group which may be substituted with one or more substituents selected from the substituent group A 1 , a triazolyl group which may be substituted with one or more substituents selected from the substituent group A 1 , a thiazolyl group which may be substituted with one or more substituents selected from the substituent group A 1 , an oxadiazolyl group which may be substituted with one or more substituents selected from the substituent group A 1 , a thiadiazolyl group which may be substituted with one or more substituents selected from the substituent group A 1 , a pyridyl group which may be substituted with one or more substituents selected from the substituent group A 1 , or a pyridazinyl group which may be substituted with one or more substituents selected from the substituent group A 1 , still more preferably a pyrazolyl group which may be substituted with one or more substituents selected from the substituent group α 1 , an imidazolyl group which may be substituted with one or more substituents selected from the substituent group α 1 , a triazolyl group which may be substituted with one or more substituents selected from the substituent group α 1 , a thiazolyl group which may be substituted with one or more substituents selected from the substituent group α 1 , an oxadiazolyl group which may be substituted with one or more substituents selected from the substituent group α 1 , a thiadiazolyl group which may be substituted with one or more substituents selected from the substituent group α 1 , a pyridyl group which may be substituted with one or more substituents selected from the substituent group α 1 , or a pyridazinyl group which may be substituted with one or more substituents selected from the substituent group α 1 , and most preferably a thiadiazolyl group which may be substituted with one or more substituents selected from the substituent group α 1 or a pyridazinyl group which may be substituted with one or more substituents selected from the substituent group α 1 .

R 2 is a hydrogen atom or a halogen atom.

R 2 is preferably a hydrogen atom.

R 3 is a hydrogen atom or a halogen atom.

R 3 is preferably a hydrogen atom.

R 4 is a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, an amino group which may be protected, a C 1-6 alkyl group which may be substituted, or a C 1-6 alkoxy group which may be substituted.

R 4 is preferably a hydrogen atom, a halogen atom, an amino group which may be protected, or a C 1-6 alkoxy group which may be substituted, more preferably a hydrogen atom or an amino group which may be protected, and still more preferably a hydrogen atom.

R 5 is a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, a carbamoyl group which may be substituted, a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 2-6 alkynyl group which may be substituted, a C 3-8 cycloalkyl group which may be substituted, an aryl group which may be substituted, a C 1-6 alkoxy group which may be substituted, an aryloxy group which may be substituted, a C 1-6 alkylthio group which may be substituted, an arylthio group which may be substituted, a heteroaryl group which may be substituted, a heteroaryloxy group which may be substituted, a heteroarylthio group which may be substituted, a heterocyclyl group which may be substituted, or NR 12 R 13 (in the formula, each of R 12 and R 13 has the same meaning as that described above).

R 5 is preferably a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, a carbamoyl group which may be substituted, a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 2-6 alkynyl group which may be substituted, an aryl group which may be substituted, a C 1-6 alkoxy group which may be substituted, a heteroaryl group which may be substituted, a heteroaryloxy group which may be substituted, a heterocyclyl group which may be substituted, or NR 12 R 13 (in the formula, each of R 12 and R 13 has the same meaning as that described above).

Here, in a case in which Z 1 represents N, and R 4 is a hydrogen atom, R 5 is a halogen atom, a hydroxyl group which may be protected, a carbamoyl group which may be substituted, a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 2-6 alkynyl group which may be substituted, a C 3-8 cycloalkyl group which may be substituted, a C 1-6 alkoxy group which may be substituted, an aryloxy group which may be substituted, a C 1-6 alkylthio group which may be substituted, an arylthio group which may be substituted, a heteroaryl group which may be substituted, a heteroaryloxy group which may be substituted, a heteroarylthio group which may be substituted, a heterocyclyl group which may be substituted, or NR 12 R 13 (in the formula, R 12 represents a hydrogen atom, a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 2-6 alkynyl group which may be substituted, a C 3-8 cycloalkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, a heterocyclyl group which may be substituted, or an amino protecting group; and R 13 represents a C 3-8 cycloalkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, or a heterocyclyl group which may be substituted).

›DESCRIPTION OF EMBODIMENTS · 10 of 16

As the compound represented by Formula [1], the compound represented by Formula [1a] is preferable.

(In the formula, each of R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 has the same meaning as that described above.)

More preferably, each of R 14 and R 16 is a hydrogen atom, and R 17 represents a hydrogen atom in the compound.

Examples of a salt of the compound represented by Formula [1] include salts of a basic group such as an amino group or an acidic group such as a phenolic hydroxyl group or a carboxyl group, which are typically known.

Examples of the salt of the basic group include a salt of a mineral acid such as hydrochloric acid, hydrogen bromide, or sulfuric acid, a salt of an organic carboxylic acid such as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid, or trifluoroacetic acid, and a salt of a sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, or naphthalene sulfonic acid.

Examples of the salt of the acidic group include a salt of an alkali metal such as sodium or potassium; a salt of an alkali earth metal such as calcium or magnesium; an ammonium salt; and a salt of a nitrogen-containing organic base such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, or N,N′-dibenzylethylenediamine.

Furthermore, among the above-described salts, preferable examples of the compound represented by Formula[1] include pharmacologically acceptable salts.

In a case in which an isomer (for example, a tautomer, an optical isomes, or a geometric isomer) of the compound represented by Formula [1] or salt thereof is present, the invention includes the isomer, and further includes a solvate, a hydrate, and various shapes of crystal of the compound represented by Formula [1] or salt thereof.

Furthermore, the invention includes a prodrug of the compound represented by Formula [1].

The prodrug of the compound represented by Formula [1] may have characteristics such as the followings.

(1) The prodrug of the compound represented by Formula [1] may have excellent inhibitory activity with respect to the PI3K-AKT pathway and/or the Ras-Raf-MEK-ERK pathway, while this is not necessary.

(2) The prodrug of the compound represented by Formula [1] is converted to the compound represented by Formula [1] by cleavage of a functional group that functions as a prodrug by an enzyme in a body after administration. In this case, the compound represented by Formula [1] and the prodrug thereof may be coexsist in a mixed manner.

(3) To the prodrug of the compound represented by Formula [1], for example, enhancement of a drug efficacy action, duration of a drug efficacy action, reduction of side effects, reduction of toxicity and/or improvement of stability are expected.

Next, the method of preparing the compound of the invention will be described.

The compound of the invention is prepared by combining known methods, and for example, can be prepared according to the following preparation method.

[Preparation Method 1]

(In the formulae, R a represents a hydrogen atom or a C 1-6 alkyl group which may be substituted, R b represents a C 1-6 alkylene group which may be substituted, R 5a represents an aryl group which may be substituted or a heteroaryl group which may be substituted, L 1 represents a leaving group, L 2 represents a leaving group, and each of R 1 , R 2 , R 3 , R 4 , and Z 1 has the same meaning as that described above.)

(1-1)

As the compound represented by Formula A2a, for example, pyridine-3-boronic acid, 3-(methanesulfonamide)phenylboronic acid, thiophene-2-boronic acid, benzofuran-2-boronic acid, and 3-methoxyphenylboronic acid are known.

As the compound represented by Formula A2b, for example, 1-(3-(pyrrolidin-1-yl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan are known.

The compound represented by Formula A2a and the compound represented by Formula A2b can be prepared from a corresponding halogeno material, for example, according to the method described in Japanese Patent Application Laid-Open (JP-A) No. 2003-206290, or “The Journal of Organic Chemistry”, vol. 60, pp. 7508-7510, 1995.

The compound represented by Formula A3 can be prepared by reacting the compound represented by Formula A1 with the compound represented by Formula A2a or the compound represented by Formula A2b in the presence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand.

A solvent used in the reaction is not particularly limited as long as the solvent does not adversely affect the reaction. Examples thereof include an aliphatic hydrocarbon, a halogenated hydrocarbon, an ether, a ketone, an ester, an alcohol, an amide, a sulfoxide, an aromatic hydrocarbon, acetonitrile, and water. These may be used in a mixed manner.

Examples of the base used in the reaction include an inorganic base such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium acetate, or tripotassium phosphate, and an organic base such as 1,8-diazabicyclo[5.4.0]-7-undecene, triethylamine, or N,N-diisopropylethylamine.

An amount of the base used is from 1-fold by mole to 50-fold by mole, preferably from 1-fold by mole to 10-fold by mole, and more preferably from 2-fold by mole to 5-fold by mole, with respect to the compound represented by Formula A1.

An amount of the palladium catalyst used in the reaction is from 0.00001-fold by mole to 1-fold by mole, and preferably from 0.001-fold by mole to 0.1-fold by mole, with respect to the compound represented by Formula A1.

An amount of the ligand, which is used in the reaction if desired, is from 0.00001-fold by mole to 1-fold by mole, and preferably from 0.001-fold by mole to 0.1-fold by mole, with respect to the compound represented by Formula A1.

›DESCRIPTION OF EMBODIMENTS · 11 of 16

An amount of the compound represented by Formula A2a or the compound represented by Formula A2b used is from 1-fold by mole to 50-fold by mole, and preferably from 1-fold by mole to 2-fold by mole, with respect to the compound represented by Formula A1.

Preferably, the reaction may be performed at a temperature of from room temperature to 250° C. for from 10 minutes to 24 hours in an inert gas (for example, nitrogen or argon) atmosphere.

The reaction can also be performed using a tin reagent or a zinc reagent instead of the compound represented by Formula A2a or the compound represented by Formula A2b. The reaction may be performed, for example, according to the method described in “Organometallics in Synthesis)” written by M. Schlosser et al., 2nd edition, pp. 1123-1217, 2002 (John Wiley & Sons, INC.).

(1-2)

As the compound represented by Formula A4, for example, 2-aminothiazole, 2-aminopyridine, 3-aminopyridazine, or 2-aminothiadiazole is known.

The compound represented by Formula A5 can be prepared by reacting the compound represented by Formula A3 with the compound represented by Formula A4 in the presence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand.

A solvent used in the reaction is not particularly limited as long as the solvent does not adversely affect the reaction. Examples thereof include an aliphatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, a sulfoxide, an aromatic hydrocarbon, and acetonitrile. These may be used in a mixed manner.

Examples of the base used in the reaction include an inorganic base such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, or tripotassium phosphate, and an organic base such as 1,8-diazabicyclo[5.4.0]-7-undecene, triethylamine, N,N-diisopropylethylamine, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, or lithium 2,2,6,6-tetramethylpiperidide.

An amount of the compound represented by Formula A4 used is from 1-fold by mole to 50-fold by mole, and preferably from 1-fold by mole to 2-fold by mole, with respect to the compound represented by Formula A3.

Preferably, the reaction may be performed at a temperature of from room temperature to 250° C. for from 10 minutes to 24 hours in an inert gas (for example, nitrogen or argon) atmosphere.

[Preparation Method 2]

(In the formulae, R c represents an amino protecting group, and each of R a , R b , R 1 , R 2 , R 3 , R 4 , R 5a , L 1 , L 2 , and Z 1 has the same meaning as that described above.)

(2-1)

The compound represented by Formula A6 can be prepared by reacting the compound represented by Formula A1 with the compound represented by Formula A4 in the presence of a base or in the absence thereof, or in the presence of an acid or in the absence thereof.

A solvent used in the reaction is not particularly limited as long as the solvent does not adversely affect the reaction. Examples thereof include an aliphatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, a sulfoxide, an aromatic hydrocarbon, an amide, and acetonitrile. These may be used in a mixed manner.

Examples of the base, which is used in the reaction if desired, include an inorganic base such as sodium hydride, potassium carbonate, or cesium carbonate, and an organic base such as 1,8-diazabicyclo[5.4.0]-7-undecene, triethylamine, or N,N-diisopropylethylamine.

A amount of the base used is from 1-fold by mole to 50-fold by mole, preferably from 1-fold by mole to 10-fold by mole, and more preferably from 2-fold by mole to 5-fold by mole, with respect to the compound represented by Formula A1.

Examples of the acid, which is used in the reaction if desired, include an inorganic acid such as hydrochloric acid or sulfuric acid, and an organic acid such as p-toluenesulfonic acid, acetic acid, or trifluoroacetic acid.

An amount of the acid used is from 0.001-fold by mole to 10-fold by mole with respect to the compound represented by Formula A1.

Preferably, the reaction may be performed at a temperature of from room temperature to 250° C. for from 10 minutes to 24 hours.

(2-2)

The compound represented by Formula A7 can be prepared by protecting the amino group of the compound represented by Formula 6 in the presence of a base.

The reaction may be performed, for example, according to the method described in “Protective Groups in Organic Synthesis” written by W. Greene et al., 4th edition, pp. 696-926, 2007 (John Wiley & Sons, INC.).

(2-3)

The compound represented by Formula A8 can be prepared by reacting the compound represented by Formula A7 with the compound represented by Formula A2a or the compound represented by Formula A2b in the presence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand.

The reaction may be performed according to Preparation Method (1-1).

(2-4)

The compound represented by Formula A5 can be prepared by deprotecting the compound represented by Formula A8.

›DESCRIPTION OF EMBODIMENTS · 12 of 16

[Preparation Method 3]

(In the formulae, R 5b represents a heterocyclyl group which may be substituted or NR 12a R 13a , in which each of R 12a and R 13a has the same meaning as that described above, and each of R C , R 1 , R 2 , R 3 , R 4 , L 2 , and Z 1 has the same meaning as that described above.)

(3-1)

As the compound represented by Formula A9, for example, morpholine, 1-methylpiperazine, 4-aminopyridine, or 4-methoxyaniline is known.

The compound represented by Formula A10 can be prepared by reacting the compound represented by Formula A7 with the compound represented by Formula A9 in the presence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand.

The solvent used in the reaction is not particularly limited as long as the solvent does not adversely affect the reaction. Examples thereof include an aliphatic hydrocarbon, an ether, an ester, an aromatic hydrocarbon, and acetonitrile. These may be used in a mixed manner.

Examples of the base used in the reaction include an inorganic base such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, or tripotassium phosphate, and an organic base such as 1,8-diazabicyclo[5.4.0]-7-undecene, triethylamine, sodium tert-butoxide, potassium tert-butoxide, or N,N-diisopropylethylamine.

An amount of the compound represented by Formula A9 used is from 1-fold by mole to 50-fold by mole, and preferably from 1-fold by mole to 2-fold by mole, with respect to the compound represented by Formula A7.

Preferably, the reaction may be performed at a temperature of from room temperature to 250° C. for from 10 minutes to 24 hours in an inert gas (for example, nitrogen or argon) atmosphere.

(3-2)

The compound represented by Formula A11 can be prepared by deprotecting the compound represented by Formula A10.

The reaction may be performed according to Preparation Method (2-4).

[Preparation Method 4]

(In the formulae, R 6a represents an aryl group which may be substituted or a heteroaryl group which may be substituted, L 3 represents a leaving group, and each of R a , R b , R c , R 1 , R 2 , R 3 , R 4 , R 5 , and L 1 has the same meaning as that described above.)

(4-1)

The compound represented by Formula A13 can be prepared by reacting the compound represented by Formula A12 with the compound represented by Formula A4 in the presence of a base and a palladium catalyst.

The reaction may be performed according to Preparation Method (1-2).

(4-2)

The compound represented by Formula A14 can be prepared by protecting the amino group of the compound represented by Formula A13.

The reaction may be performed according to Preparation Method (2-2).

(4-3)

As the compound represented by Formula A15a, for example, 3-aminocarbonylphenylboronic acid, and 3-methoxypyridine-4-boronic acid are known.

As the compound represented by Formula A15b, for example, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine, and 1-(tert-butoxycarbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole are known.

In addition, the compound represented by Formula A15a and the compound represented by Formula A15b can be prepared from a corresponding halogeno material, for example, according to the method described in JP-A No. 2003-206290, or “The Journal of Organic Chemistry”, vol. 60, pp. 7508-7510, 1995.

The compound represented by Formula A16 can be prepared by reacting the compound represented by Formula A14 with the compound represented by Formula A15a or the compound represented by Formula A15b in the presence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand.

The reaction may be performed according to Preparation Method (1-1).

(4-4)

The compound represented by Formula A17 can be prepared by deprotecting the compound represented by Formula A16.

The reaction may be performed according to Preparation Method (2-4).

[Preparation Method 5]

(In the formulae, each of R a , R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , and L 3 has the same meaning as that described above.)

(5-1)

The compound represented by Formula A19 can be prepared by reacting the compound represented by Formula A18 with the compound represented by Formula A15a or the compound represented by Formula A15b in the presence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand.

The reaction may be performed according to Preparation Method (1-1).

(5-2)

The compound represented by Formula A20 can be prepared by reacting the compound represented by Formula A19 with trifluoromethanesulfonic acid anhydride or N-phenyl-bis(trifluoromethanesulfonimide) in the presence of a base.

The solvent used in the reaction is not particularly limited as long as the solvent does not adversely affect the reaction. Examples thereof include an aliphatic hydrocarbon, a halogenated hydrocarbon, an ether, a ketone, an ester, an amide, a sulfoxide, and an aromatic hydrocarbon. These may be used in a mixed manner.

Examples of the base used in the reaction include an inorganic base such as potassium carbonate or sodium hydride, and an organic base such as pyridine 2,6-lutidine, triethylamine, or N,N-diisopropylethylamine.

›DESCRIPTION OF EMBODIMENTS · 13 of 16

An amount of trifluoromethanesulfonic acid anhydride or N-phenyl-bis(trifluoromethanesulfonimide) used in the reaction is from 1-fold by mole to 10-fold by mole, and preferably from 1-fold by mole to 2-fold by mole, with respect to the compound represented by Formula A19.

Preferably, the reaction may be performed at a temperature of from 0° C. to 30° C. for from 30 minutes to 24 hours in an inert gas (for example, nitrogen or argon) atmosphere.

(5-3)

The compound represented by Formula A17 can be prepared by reacting the compound represented by Formula A20 with the compound represented by Formula A4 in the presence of a base and a palladium catalyst.

The reaction may be performed according to Preparation Method (1-2).

[Preparation Method 6]

(In the formulae, R d represents a C 1-6 alkylene group which may be substituted; R 5c represents an aryl group which may be substituted or a heteroaryl group which may be substituted; L 4 represents a leaving group; and each of R c , R 1 , R 2 , R 3 , R 4 , L 2 , and Z 1 has the same meaning as that described above.)

(6-1)

As the compound represented by Formula A21, for example, bis(pinacolato)diboron is known.

The compound represented by Formula A22 can be prepared by reacting the compound represented by Formula A7 with the compound represented by Formula A21 in the presence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand.

The reaction may be performed according to Preparation Method (1-1).

The compound represented by Formula A22 may be used in the following reaction as it is without being isolated.

(6-2)

As the compound represented by Formula A23, for example, 4-iodo-3-(2-methoxyethyl)-1-methyl-1H-pyrazole is known.

The compound represented by Formula A24 can be prepared by reacting the compound represented by Formula A22 with the compound represented by Formula A23 in the presence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand.

The solvent used in the reaction is not particularly limited as long as the solvent does not adversely affect the reaction. Examples thereof include an aliphatic hydrocarbon, a halogenated hydrocarbon, an ether, a ketone, an ester, a sulfoxide, an aromatic hydrocarbon, acetonitrile, an alcohol, an amide, and water. These may be used in a mixed manner.

An amount of the compound represented by Formula A23 used is from 1-fold by mole to 5-fold by mole, and preferably from 1-fold by mole to 2-fold by mole, with respect to the compound represented by Formula A22.

Preferably, the reaction may be performed at a temperature of from room temperature to 250° C. for from 1 hour to 24 hours in an inert gas (for example, nitrogen or argon) atmosphere.

(6-3)

The compound represented by Formula A25 can be prepared by deprotecting the compound represented by Formula A24.

The reaction may be performed according to Preparation Method (2-4).

[Preparation Method 7]

(In the formulae, each of R d , R 1 , R 2 , R 3 , R 4 , R 5c , L 4 , and Z 1 has the same meaning as that described above.)

(7-1)

The compound represented by Formula A27 can be prepared by reacting the compound represented by Formula A26 with the compound represented by Formula A21 in the presence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand.

The reaction may be performed according to Preparation Method (6-1).

(7-2)

The compound represented by Formula A28 can be prepared by reacting the compound represented by Formula A27 with the compound represented by Formula A23 in the presence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand.

The reaction may be performed according to Preparation Method (6-2).

(7-3)

The compound represented by Formula A29 can be prepared by reacting the compound represented by Formula A28 with the compound represented by Formula A4 in the presence of a base and a palladium catalyst.

The reaction may be performed according to Preparation Method (1-2).

Next, methods for preparing a compound which is a raw material for the compound of the invention will be described.

[Preparation Method A]

(In the formulae, R e represents a C 1-6 alkyl group, L 5 represents a leaving group; and each of R 2 , R 3 , R 4 , R 6 , and L 1 has the same meaning as that described above.)

(A-1)

As the compound represented by Formula B1, for example, 2-chloro-3-aminopyridine is known.

As the compound represented by Formula B2, for example, butyl acrylate, methyl acrylate, ethyl acrylate, and tert-butyl acrylate is known.

The compound represented by Formula B3 can be prepared by reacting the compound represented by Formula B1 with the compound represented by Formula B2 in the presence of a base, in the presence of a palladium catalyst, and in the presence or absence of a ligand.

The solvent used in the reaction is not particularly limited as long as the solvent does not adversely affect the reaction. Examples thereof include an aliphatic hydrocarbon, a halogenated hydrocarbon, an alcohol, an ether, a ketone, an ester, an amide, a sulfoxide, an aromatic hydrocarbon, and water. These may be used in a mixed manner.

›DESCRIPTION OF EMBODIMENTS · 14 of 16

Preferable examples of the solvent include an ester, and a more preferable example thereof is cyclohexyl acetate.

Examples of the base used in the reaction include an inorganic base such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, or tripotassium phosphate, and an organic base such as pyridine, 4-(dimethylamino)pyridine, triethylamine, N,N-diisopropylethylamine, or sodium tert-butoxide.

Preferable examples of the base include an organic base, and a more preferable example thereof is triethylamine.

An amount of the base used is from 1-fold by mole to 50-fold by mole, preferably from 1-fold by mole to 10-fold by mole, and more preferably from 1-fold by mole to 4-fold by mole, with respect to the compound represented by Formula B1.

Preferable examples of the palladium catalyst used in the reaction include an organic palladium complex, and a more preferable example thereof is bis(tri-tert-butylphosphine)palladium(0).

An amount of the palladium catalyst used is from 0.001-fold by mole to 1-fold by mole, preferably from 0.002-fold by mole to 0.5-fold by mole, and more preferably from 0.005-fold by mole to 0.1-fold by mole, with respect to the compound represented by Formula B1.

An amount of the ligand, which is used in the reaction if desired, is from 0.00001-fold by mole to 1-fold by mole, preferably from 0.0001-fold by mole to 0.5-fold by mole, and more preferably from 0.001-fold by mole to 0.5-fold by mole, with respect to the compound represented by Formula B1.

An amount of the compound represent by Formula B2 used is from 1-fold by mole to 10-fold by mole, preferably from 1-fold by mole to 5-fold by mole, and more preferably from 1-fold by mole to 2-fold by mole, with respect to the compound represented by Formula B1.

Preferably, the reaction may be performed at a temperature of from room temperature to 180° C. for from 30 minutes to 96 hours in an inert gas (for example, nitrogen or argon) atmosphere.

(A-2)

The compound represented by Formula B4 can be prepared by reacting the compound represented by Formula B3 with a halogenating agent, sulfonic acid anhydride, or a sulfonic halide.

The solvent used in the reaction is not particularly limited as long as the solvent does not adversely affect the reaction. Examples thereof include an aliphatic hydrocarbon, a halogenated hydrocarbon, and an aromatic hydrocarbon. These may be used in a mixed manner.

A halogenating agent or sulfonic acid anhydride may be used as the solvent.

Examples of the halogenating agent used in the reaction include phosphorus oxychloride, thionyl chloride, phosphorus tribromide, and thionyl bromide.

Preferable examples of the halogenating agent include phosphorus oxychloride and thionyl chloride, and a more preferable example thereof is phosphorus oxychloride.

An amount of the halogenating agent used is from 1-fold by mole to 10-fold by mole, preferably from 2-fold by mole to 8-fold by mole, and more preferably from 4-fold by mole to 6-fold by mole, with respect to the compound represented by Formula B3.

Examples of the sulfonic acid anhydride used in the reaction include trifluoromethanesulfonic acid anhydride.

Examples of the sulfonic halide used in the reaction include trifluoromethanesulfonyl chloride.

In the case of using the sulfonic halide, the reaction is preferably performed in the presence of a base.

Examples of the base used in the reaction include an organic base such as pyridine, 4-(dimethylamino)pyridine, triethylamine, or N,N-diisopropylethylamine.

In the reaction, the halogenating agent is preferably used as the solvent, and more preferably, phosphorus oxychloride is used as the solvent.

The reaction may be performed at a temperature of from room temperature to the boiling temperature of the solvent, that is preferably at the boiling temperature of the solvent, for from 30 minutes to 24 hours.

(A-3)

The compound represented by Formula B5 can be prepared by reacting the compound represented by Formula B4 with a brominating agent in the presence or absence of a base.

A solvent used in the reaction is not particularly limited as long as the solvent does not adversely affect the reaction. Examples thereof include an aliphatic hydrocarbon, a halogenated hydrocarbon, a carboxylic acid, and water. These may be used in a mixed manner.

Preferable examples of the solvent include a carboxylic acid, and a more preferable example thereof is acetic acid.

Examples of the brominating agent used in the reaction include bromine and thionyl bromide, and a more preferable example thereof is bromine.

An amount of the brominating agent used in the reaction is from 1-fold by mole to 2-fold by mole, and preferably from 1.0-fold by mole to 1.2-fold by mole, with respect to the compound represented by Formula B4.

Examples of the base, which is used in the reaction if desired, include preferably sodium acetate and potassium acetate, and a more preferable example thereof is sodium acetate.

An amount of the base used is from 1-fold by mole to 5-fold by mole, preferably from 1-fold by mole to 2-fold by mole, and more preferably from 1.0-fold by mole to 1.2-fold by mole, with respect to the compound represented by Formula B4.

The reaction may be performed at a temperature of from 60° C. to 120° C., that is preferably at a temperature of from 80° C. to 100° C., for from 30 minutes to 24 hours.

[Preparation Method B]

(In the formulae, R f represents a C 1-6 alkyl group, and each of R 2 , R 3 , R 4 , R 5 , and L 3 has the same meaning as that described above.)

(B-1)

As the compound represented by Formula B6, for example, 6-methoxy-1,5-naphthyridin-4(1H)-one is known.

The compound represented by Formula B7 can be prepared by reacting the compound represented by Formula B6 with an acid.

A solvent used in the reaction is not particularly limited as long as the solvent does not adversely affect the reaction. Examples thereof include an aliphatic hydrocarbon, a halogenated hydrocarbon, an alcohol, an ether, a ketone, an ester, an amide, a sulfoxide, an aromatic hydrocarbon, and water. These may be used in a mixed manner.

›DESCRIPTION OF EMBODIMENTS · 15 of 16

Examples of the acid used in the reaction include an inorganic acid such as hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid, and an organic acid such as acetic acid or trifluoroacetic acid.

An amount of the acid used is from 0.001-fold by mole to 50-fold by mole with respect to the compound represented by Formula B6.

Preferably, the reaction may be performed at a temperature of from 50° C. to 180° C. for from 10 minutes to 24 hours.

(B-2)

The compound represented by Formula B8 can be prepared by reacting the compound represented by Formula B7 with a brominating agent.

A solvent used in the reaction is not particularly limited as long as the solvent does not adversely affect the reaction. Examples thereof include an aliphatic hydrocarbon, a halogenated hydrocarbon, and an aromatic hydrocarbon. These may be used in a mixed manner.

Examples of the brominating agent used in the reaction include phosphorous oxybromide and phosphorus tribromide, and a more preferable example thereof is phosphorous oxybromide.

Preferably, the reaction may be performed at a temperature of from 50° C. to 180° C. for from 10 minutes to 24 hours in an inert gas (for example, nitrogen or argon) atmosphere.

The compounds obtained in the preparation methods described above can be derived to other compounds by a known reaction such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration, or hydrolysis, or by appropriately combining these reactions.

In a case in which an amino group, a hydroxyl group, or a carboxyl group is present in the compounds obtained by the preparation methods described above, the reaction can be performed after appropriately changing the protecting group thereof. In addition, in a case in which two or more protecting groups are present, the protecting groups can be selectively deprotected by a known reaction.

In a case in which isomers (for example, optical isomers, geometric isomers, or tautomers) are present in compounds used in the preparation methods described above, these isomers can also be used. In addition, in a case in which a solvate, a hydrate, or various shapes of crystal are present, the solvate, hydrate, or various shapes of crystal can also be used.

In a case in which the compound represented by Formula [1] or salt thereof is used as a medicine, a pharmaceutic aid such as an excipient, a carrier, or a diluent which is typically used in formulation may be used in an appropriately mixing manner.

Examples of an additive include an excipient, a disintegrating agent, a binding agent, a lubricant, a flavoring agent, a colorant, an aromatizer, a surfactant, a coating agent, and a plasticizer.

Examples of the excipient include a sugar alcohol such as erythritol, mannitol, xylitol, or sorbitol; a sugar such as white sugar, powdered sugar, lactose, or glucose; a cyclodextrin such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl β-cyclodextrin, or sodium sulfobutylether β-cyclodextrin; a cellulose such as crystalline cellulose or microcrystalline cellulose; and a starch such as a corn starch, a potato starch, or a pregelatinized starch.

Examples of the disintegrating agent include carmellose, carmellose calcium, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, low substituted hydroxypropyl cellulose, and a partly pregelatinized starch.

Examples of the binding agent include hydroxypropyl cellulose, croscarmellose sodium, and methylcellulose.

Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, hydrated silicon dioxide, light anhydrous silicic acid, and sucrose fatty acid ester.

Examples of the flavoring agent include aspartame, saccharin, stevia, thaumatin, and acesulfame potassium.

Examples of the colorant include titanium dioxide, ferric oxide, yellow ferric oxide, black iron oxide, Food Red No. 102, Food Yellow No. 4, and Food Yellow No. 5.

Examples of the aromatizer include an essential oil such as an orange oil, a lemon oil, a peppermint oil, or a pine oil; an essence such as an orange essence or a peppermint essence; a flavor such as a cherry flavor, a vanilla flavor, or a fruit flavor; a powder fragrance such as an apple micron, a banana micron, a peach micron, a strawberry micron, or an orange micron; vanillin; and ethyl vanillin.

Examples of the surfactant include sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbate, and polyoxyethylene hydrogenated castor oil.

Examples of the coating agent include hydroxypropyl methyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, a methacrylic acid copolymer L, a methacrylic acid copolymer LD, and a methacrylic acid copolymer S.

Examples of the plasticizer include triethyl citrate, macrogol, triacetin, and propylene glycol.

These additives may be used singly, or in combination of two or more kinds thereof.

A blending amount thereof is not particularly limited, and the additives may be appropriately blended such that the effect thereof is sufficiently exhibited depending on the respective purposes.

These additives can be administered orally or parenterally according to a usual method in a form such as a tablet, a capsule, a powder, a syrup, a granule, a pill, a suspension, an emulsion, a solution, a powdered formulation, a suppository, an eye drop, a nasal drop, an ear drop, a patch, an ointment, or an injection. In addition, an administration method, a dose, and a number of administration can be appropriately selected depending on a patient's age, body weight, and symptom. Typically, for an adult, 0.01 mg/kg to 1000 mg/kg may be administered orally or parenterally once or several times per day.

›DESCRIPTION OF EMBODIMENTS · 16 of 16

The compound or salt thereof of the invention can be used in a treatment such as prevention of or cure for diseases associated with PI3K and/or ERK.

Examples of the diseases associated with PI3K and/or ERK include a cell proliferative disease, an allergic disease, an autoimmune disease, a neurodegenerative disease, a circulatory system disease, an inflammatory disease, an endocrine disorder, a metabolic disorder, and an infection.

Preferable examples of diseases to which the compound or salt thereof of the invention can be applied include malignant tumors in which the PI3K-AKT pathway and/or the Ras-Raf-MEK-ERK pathway is accelerated.

Specifically, the compound or salt thereof of the invention can be used in a treatment such as prevention of or cure for malignant tumors which exhibit resistance with respect to a PI3K-AKT pathway inhibitor and/or a Ras-Raf-MEK-ERK pathway inhibitor.

›EXAMPLES

The invention will be described with reference to Reference Examples, Examples, and Test Examples, but the invention is not limited thereto.

Unless otherwise specified, in purification by column chromatography, an automated purification apparatus ISOLERA (manufactured by Biotage Japan Ltd.) or a medium-pressure liquid chromatograph YFLC W-PREP 2XY (manufactured by YAMAZEN CORPORATION) was used.

Unless otherwise specified, as a carrier in silica gel column chromatography, SNAP KP-Sil CARTRIDGE (manufactured by Biotage Japan Ltd.), or HIGH FLASH COLUMN W001, W002, W003, W004, or W005 (manufactured by YAMAZEN CORPORATION) was used.

As NH silica, SNAP KP-NH CARTRIDGE (manufactured by Biotage Japan Ltd.) was used.

In preparative thin layer silica gel chromatography, PLC GLASS PLATE SILICA GEL F 60 (manufactured by Merck KGaA) was used.

As a microwave reaction apparatus, INITIATOR SIXTY (manufactured by Biotage Japan Ltd.) was used.

As a flow-type hydrogenation reaction apparatus, H-CUBE (manufactured by ThalesNano Inc.) was used.

In preparative reversed phase HPLC, WATERS 2998 PHOTODIODE ARRAY (PDA) DETECTOR (manufactured by Waters), WATERS 600 CONTROLLER (manufactured by Waters), a WATERS 2767 SAMPLE MANAGER (manufactured by Waters) set, and a YMC-ACTUS PROC18 (30×50 mm column) (manufactured by YMC Co., Ltd.) were used.

A MS spectrum was measured by an ionization method in which ACQUITY SQD LC/MS SYSTEM (manufactured by Waters, ionization method: ElectroSpray Ionization (ESI) method) and LCMS-2010EV (manufactured by Shimadzu Corporation, ionization method: ESI and Atomospheric Pressure Chemical Ionization (APCI)) were performed at the same time.

In the measurement of an NMR spectrum, tetramethylsilane was used as an internal standard, BRUKER AV300 (manufactured by Bruker Corporation) was used, and all δ values were shown in ppm.

Abbreviations in NMR measurement have the following meanings.

s: Singlet

br: Broad

d: Doublet

dd: Double doublet

t: Triplet

q: Quartet

quin: Quintet

sext: Sextet

sep: Septet

m: Multiplet

DMSO-d 6 : Hexadeuterodimethylsulfoxide

Abbreviations in Reference Examples and Examples have the following meanings.

Ac: Acetyl

Bn: Benzyl

Boc: tert-Butoxycarbonyl

Bu: Butyl

t Bu: tert-Butyl

Et: Ethyl

Fmoc: 9-Fluorenylmethyloxycarbonyl

Me: Methyl

Ms: Methylsulfonyl

Ph: Phenyl

SEM: (2-(Trimethylsilyl)ethoxy)methyl

TBS: tert-Butyldimethylsilyl

Tf: Trifluoromethylsulfonyl

TFA: Trifluoroacetic acid

THP: Tetrahydropyranyl

TMS: Trimethylsilyl

Ts: Toluenesulfonyl

›Examples234

›Example 0001

0001-1

Triethylamine (13 mL), butyl acrylate (10 mL), and bis(tri-tert-butylphosphine)palladium(0) (350 mg) were added to a solution of 2-chloro-3-aminopyridine (6.00 g) in cyclohexyl acetate (60 mL), followed by stirring at 150° C. for 40 hours in a nitrogen atmosphere. Water (30 ml) was added to the reaction mixture at 70° C., and the resultant product was cooled to room temperature while stirring. The reaction mixture was subjected to an ultrasonic treatment for 30 minutes, and the solid matter was collected by filtration and washed with water. Ethyl acetate (3 mL)/2-propanol (4 mL) was added to the obtained solid matter, and the resultant product was subjected to an ultrasonic treatment. The solid matter was collected by filtration, thereby obtaining 1,5-naphthyridin-2-ol (2.51 g) as a pale yellow solid.

MSm/z(M+H):147.

0001-2

Phosphorus oxychloride (8.3 mL) was added to 1,5-naphthyridin-2-ol (2.76 g), followed by stirring at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, and added dropwise to a mixture of ethyl acetate (30 mL), water (30 mL), and sodium carbonate (9.57 g) over a period of 1 hour in an ice bath. Water (10 mL) was added thereto, and sodium carbonate was added thereto, followed by adjusting the pH of the resultant product to 8.3. The resultant product was stirred at room temperature for 10 minutes, and ethyl acetate (270 mL) and water (200 mL) were added thereto. The organic layer was collected by separation, and the aqueous layer was extracted two times with ethyl acetate (200 mL). The organic layer and the extraction liquid were combined, the resultant product was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 2-chloro-1,5-naphthyridine (2.86 g) as a pale yellow solid.

MSm/z(M+H):165.

0001-3

A solution of bromine (0.99 mL) in acetic acid (2.5 mL) was added dropwise to a mixture of 2-chloro-1,5-naphthyridine (2.88 g) and sodium acetate (2.89 g) in acetic acid (15 mL) at 85° C., and acetic acid (2 mL) was added thereto, followed by stirring at 85° C. for 3 hours. The reaction mixture was cooled to room temperature, and added dropwise to a 6 mol/L sodium hydroxide aqueous solution (60 mL) under ice-cooling. The solid matter was collected by filtration, suspended in methanol (5 mL), and subjected to an ultrasonic treatment. The solid matter was collected by filtration, and washed with methanol (3 mL). The obtained solid was suspended in a 75 v/v % methanol aqueous solution (8 mL), the resultant product was subjected to an ultrasonic treatment, and the solid matter was collected by filtration, thereby obtaining 7-bromo-2-chloro-1,5-naphthyridine (3.33 g) as a pale yellow solid.

MSm/z(M+H):243.

0001-4

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (30 mg), 1-(3-morpholinopropyl)-1H-pyrazole-4-boronic acid pinacol ester (59 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5 mg) and sodium carbonate (20 mg) in 1,4-dioxane (1.9 mL) and water (0.1 mL) was stirred at 100° C. for 7.5 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, ethanol (4 mL) was added thereto, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-ethyl acetate, NH silica), thereby obtaining 4-(3-(4-(6-chloro-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)propyl)morpholine (45.6 mg) as a white solid.

MSm/z(M+H):358.

0001-5

A mixture of 4-(3-(4-(6-chloro-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)propyl)morpholine (45.6 mg), 1,3,4-thiadiazole-2-amine (19 mg), tris(dibenzylideneacetone)dipalladium(0) (23 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28 mg) and cesium carbonate (120 mg) in 1,4-dioxane (1.9 mL) was stirred at 150° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and ethanol was added thereto. The insolubles were filtered off using celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining N-(7-(1-(3-morpholinopropyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (11 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:12.23(1H,s),9.17(1H,s),9.09(1H,d,J=2.0 Hz),8.57(1H,s),8.33(1H,d,J=2.0 Hz),8.28(1H,d,J=9.2 Hz),8.21(1H,s),7.44(1H,d,J=9.2 Hz),4.21(2H,t,J=7.1 Hz),3.58(4H,t,J=4.6 Hz),2.36-2.28(6H,m),2.05-1.99(2H,m).

MSm/z(M+H):423.

›Example 0002

The following compounds were obtained in the same manner as in Examples 0001-4 and 0001-5.

›Example 0003

0003-1

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (30 mg), 1,3,4-thiadiazole-2-amine (25 mg) and potassium carbonate (17 mg) in dimethylsulfoxide (0.5 mL) was stirred at 150° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and water was added thereto. The solid matter was collected by filtration, thereby obtaining N-(7-bromo-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine.

The same reaction was performed using 7-bromo-2-chloro-1,5-naphthyridine (60 mg), thereby obtaining N-(7-bromo-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine.

The obtained N-(7-bromo-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amines were combined, and N,N-dimethylformamide (1.8 mL), 2-(chloromethoxy)ethyltrimethylsilane (86 μL), and N,N-diisopropylethylamine (172 μL) were added thereto, followed by stirring at room temperature for 18 hours. 2-(Chloromethoxy)ethyltrimethylsilane (36 μL) was added thereto, followed by stirring at 50° C. for 2 hours. Water was added to the reaction mixture, the solid matter was collected by filtration, and washed with water and methanol, thereby obtaining N-(7-bromo-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (78.9 mg) as a pale yellow solid.

MSm/z(M+H):438.

0003-2

1,4-Dioxane (1 mL) and toluene (3 mL) were added to a mixture of N-(7-bromo-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (78.9 mg), morpholine (47 μL), tris(dibenzylideneacetone)dipalladium(0) (33 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (42 mg), and cesium carbonate (175 mg), followed by stirring at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate, NH silica), thereby obtaining N-(7-morpholino-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (17.1 mg) as a pale yellow solid.

MSm/z(M+H):445.

0003-3

Concentrated hydrochloric acid (1 mL) was added to a solution of N-(7-morpholino-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (50 mg) in ethanol (3 mL), followed by stirring at 90° C. for 17 hours. The reaction mixture was cooled to room temperature, and neutralized by the addition of a 6.0 mol/L sodium hydroxide aqueous solution under ice-cooling. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-ethyl acetate, chloroform-methanol, NH silica), thereby obtaining N-(7-morpholino-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (1.4 mg) as a pale yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.07(1H,s),9.09(1H,s),8.74(1H,d,J=2.6 Hz),8.16(1H,d,J=8.9 Hz),7.37(1H,d,J=2.6 Hz),7.24(1H,d,J=8.9 Hz),3.81(4H,t,J=4.8 Hz),3.40-3.35(4H,m).

MSm/z(M+H):315.

›Example 0004 · 1 of 2

0004-1

Phosphorous oxybromide (5.60 g) was added to a solution of 6-methoxy-1,5-naphthyridin-4(1H)-one (3.51 g) in N,N-dimethylformamide (20 mL), followed by stirring at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and added dropwise to a mixture solution of methanol-water (1:10). The resultant product was neutralized by the addition of a sodium hydroxide aqueous solution, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 8-bromo-2-methoxy-1,5-naphthyridine (3.20 g) as a yellow solid.

MSm/z(M+H):239,241.

0004-2

A mixture of 8-bromo-2-methoxy-1,5-naphthyridine (500 mg) in 5.1 mol/L hydrobromic acid (5 mL) was stirred at 80° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, and the solvent was distilled off under reduced pressure. The residue was neutralized by the addition of a saturated sodium hydrogen carbonate aqueous solution, and the solvent was distilled off under reduced pressure. The obtained residue was washed with water, thereby obtaining 8-bromo-1,5-naphthyridin-2-ol (360 mg) as a white solid.

MSm/z(M+H):225,227.

0004-3

A mixture solution of 8-bromo-1,5-naphthyridin-2-ol (6.0 g) in toluene (100 mL)/N,N-dimethylformamide (10 mL) was heated to 110° C., and a suspension of phosphorous oxybromide (10.13 g) in toluene (50 mL) was added dropwise thereto. The reaction mixture was stirred at 110° C. for 30 minutes, allowed to cool to room temperature, added dropwise to water, and neutralized by the addition of a sodium hydroxide aqueous solution, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 2,8-dibromo-1,5-naphthyridine (3.53 g) as a pale yellow solid.

MSm/z(M+H):287, 289, 291.

0004-4

A mixture of 2,8-dibromo-1,5-naphthyridine (3.54 g), 5-isopropyl-1,3,4-thiadiazole-2-amine (1.85 g), tris(dibenzylideneacetone)dipalladium(0) (0.56 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.71 g) and cesium carbonate (8.03 g) in 1,4-dioxane (17.6 mL) was reacted at 130° C. for 20 minutes using a microwave reaction apparatus. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate), and the resultant product was washed with methanol and chloroform, thereby obtaining N-(8-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-1,3,4-thiadiazole-2-amine (333 mg) as a pale yellow solid.

MSm/z(M+H):350,352.

0004-5

(2-(Chloromethoxy)ethyl)trimethylsilane (0.43 mL) was added to a suspension of N-(8-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-1,3,4-thiadiazole-2-amine (564 mg) in N-methylpyrrolidone (16.1 mL), and 60% sodium hydride (136 mg) was added thereto under ice-cooling, followed by stirring for 2 hours in a nitrogen atmosphere. The reaction was stopped by the addition of ethanol to the reaction mixture, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining N-(8-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-N-((2-trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (398 mg) as a pale yellow solid.

MSm/z(M+H):480,482.

0004-6

4-Aminopyridine (4.8 mg), tris(dibenzylideneacetone)dipalladium(0) (3.1 mg), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (3.3 mg), and sodium tert-butoxide (8.1 mg) were added to a solution of N-(8-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (16.5 mg) in 1,4-dioxane (1.4 mL), followed by reacting at 150° C. for 30 minutes using a microwave reaction apparatus. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane, methanol-ethyl acetate), thereby obtaining N 2 -(5-isopropyl-1,3,4-thiadiazol-2-yl)-N 8 -(pyridin-4-yl)-N 2 -((2-(trimethylsilyl)ethoxy)methyl)-1,5-naphthyridine-2,8-diamine (8.0 mg) as an orange solid.

MSm/z(M+H):494.

0004-7

A solution (3.0 mL) of 4.0 mol/L hydrogen chloride/1,4-dioxane was added to N 2 -(5-isopropyl-1,3,4-thiadiazol-2-yl)-N 8 -(pyridin-4-yl)-N 2 -((2-(trimethylsilyl)ethoxy)methyl)-1,5-naphthyridine-2,8-diamine (8.0 mg), followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, thereby obtaining N 2 -(5-isopropyl-1,3,4-thiadiazol-2-yl)-N 8 -(pyridin-4-yl)-1,5-naphthyridine-2,8-diamine (5.1 mg) hydrochloride as a yellow solid.

1 H-NMR(CD 3 OD)δ:8.93(1H,d,J=5.9 Hz),8.68(2H,d,J=6.6 Hz),8.48(1H,d,J=9.2 Hz),8.20(1H,d,J=5.9 Hz),7.84(3H,m,J=16.2,7.6 Hz),3.41(1H,t,J=6.9 Hz),1.47(6H,d,J=14.9 Hz).

MSm/z(M+H):364.

Examples 0005 to 0009

The following compounds were obtained in the same manner as in Examples 0004-6 and 0004-7.

TFA salt

1 H-NMR (DMSO-d 6 ) δ: 9.57 (1H, s), 8.85- 8.75 (2H, m), 8.52 (1H, d, J = 5.3 Hz), 8.40 (1H, d, J = 9.2 Hz), 7.98 (1H, t, J = 6.9 Hz), 7.73 (1H, d, J = 9.2 Hz), 7.43 (1H, d, J = 8.6 Hz), 7.25 (1H, t, J = 5.9 Hz), 1.46 (6H, d, J = 6.6 Hz). MS m/z (M + H): 364.

›Example 0004 · 2 of 2

0006

0006-1

MS m/z (M + H): 494.

0006-2

Formic acid salt

1 H-NMR (CD 3 OD) δ: 8.88 (1H, s), 8.65 (1H, d, J = 4.6 Hz), 8.49 (1H, d, J = 7.3 Hz), 8.32 (1H, d, J = 9.2 Hz), 8.20 (1H, d, J = 7.9 Hz), 7.79- 7.75 (2H, m), 7.36 (1H, d, J = 7.3 Hz), 2.18 (1H, d, J = 7.9 Hz), 1.45 (6H, d, J = 7.3 Hz). MS m/z (M + H): 364.

0007

0007-1

MS m/z (M + H): 495.

0007-2

TFA salt

1 H-NMR (CD 3 OD) δ: 9.19 (1H, d, J = 6.6 Hz), 9.09 (1H, s), 8.80- 8.76 (2H, m), 8.39 (1H, d, J = 9.2 Hz), 7.77 (1H, d, J = 9.2 Hz), 7.42 (1H, d, J = 5.3 Hz), 3.54- 3.51 (1H, m), 1.54 (6H, d, J = 6.6 Hz). MS m/z (M + H): 365.

0008

0008-1

MS m/z (M + H): 495.

0008-2

TFA salt

1 H-NMR (CD 3 OD) δ: 9.02 (1H, d, J = 3.3 Hz), 8.86- 8.84 (2H, m), 8.39 (1H, d, J = 9.2 Hz), 7.82 (1H, d, J = 5.3 Hz), 7.59 (1H, d, J = 8.6 Hz), 7.33- 7.31 (1H, m), 2.19 (1H, t, J = 7.6 Hz), 1.39 (6H, d, J = 7.3 Hz). MS m/z (M + H): 365.

0009

0009-1

MS m/z (M + H): 493.

0009-2

TFA salt

1 H-NMR (CD 3 OD) δ: 8.42 (1H, d, J = 6.6 Hz), 8.29 (1H, d, J = 9.2 Hz), 7.76 (1H, d, J = 9.2 Hz), 7.62 (2H, s), 7.61 (2H, s), 7.47 (1H, d, J = 4.6 Hz), 7.34 (1H, d, J = 7.3 Hz), 3.44 (1H, t, J = 6.9 Hz), 1.45 (6H, d, J = 6.6 Hz). MS m/z (M + H): 363.

›Example 0010

0010-1

1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (866 mg), tris(dibenzylideneacetone)dipalladium(0) (79.1 mg), tricyclohexylphosphine (92.5 mg), and potassium phosphate (1 g) were added to a mixture solution of 3-chloropyrido[2,3-b]pyrazine-6-amine (500 mg) in 1,4-dioxane (12.4 mL)/water (1.4 mL), followed by reacting at 120° C. for 10 minutes using a microwave reaction apparatus. Ethyl acetate/chloroform was added to the reaction mixture, the solid matter was collected by filtration, and washed with ethyl acetate, thereby obtaining 3-(1-methyl-1H-pyrazol-4-yl)pyrido[2,3-b]pyrazine-6-amine (326.6 mg).

MSm/z(M+H):227.

0010-2

Antimony bromide (127.8 mg) and tert-butyl nitrite (0.26 mL) were added to a solution of 3-(1-methyl-1H-pyrazol-4-yl)pyrido[2,3-b]pyrazine-6-amine (50 mg) in dibromomethane (1.26 mL) at 0° C. in a nitrogen atmosphere, followed by stirring at room temperature for 7 hours. The insolubles were filtered off, and the solid was washed with ethyl acetate/water. The filtrate and the washings were combined, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane, methanol-ethyl acetate), thereby obtaining 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)pyrido[2,3-b]pyrazine (10.8 mg) as a pale yellow solid.

MSm/z(M+H):290,292.

0010-3

5-Isopropyl-1,3,4-thiadiazole-2-amine (2.5 mg) and potassium carbonate (3.6 mg) were added to a solution of 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)pyrido[2,3-b]pyrazine (5.0 mg) in dimethylsulfoxide (0.35 mL), followed by stirring at 130° C. for 8 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative reversed phase HPLC (a 0.1% formic acid aqueous solution-a 0.1% formic acid acetonitrile solution), and the solvent was distilled off under reduced pressure, thereby obtaining 5-isopropyl-N-(3-(1-methyl-1H-pyrazol-4-yl)pyrido[2,3-b]pyrazine-6-yl)-1,3,4-thiadiazole-2-amineformate (1.1 mg) as a yellow solid.

1 H-NMR(CD 3 OD)δ:9.09(1H,s),8.56(1H,s),8.36(1H,s),8.29(1H,d,J=9.2 Hz),7.41(1H,d,J=8.6 Hz),4.03(3H,s),3.98-3.96(1H,m),1.50(6H,d,J=6.6 Hz).

MSm/z(M+H):353.

Examples 0011 to 0013

The following compounds were obtained in the same manner as in Examples 0004-6 and 0004-7.

TFA salt

1 H-NMR (CD 3 OD) δ: 8.42 (1H, d, J = 7.3 Hz), 8.29 (1H, d, J = 9.2 Hz), 7.74 (1H, d, J = 9.2 Hz), 7.52 (1H, t, J = 7.9 Hz), 7.40 (1H, d, J = 6.6 Hz), 7.18 (2H, m, J = 4.6 Hz), 7.02 (1H, dd, J = 8.3, 1.7 Hz), 3.88 (3H, d, J = 2.0 Hz), 3.44 (1H, t, J = 6.9 Hz), 1.45 (6H, d, J = 6.9 Hz). MS m/z (M + H): 393.

0013

0013-1

MS m/z (M + H): 523.

0013-2

1 H-NMR (DMSO-d 6 ) δ: 8.40 (1H, d, J = 5.3 Hz), 8.24 (1H, d, J = 9.2 Hz), 8.12 (1H, s), 7.52 (1H, d, J = 9.2 Hz), 7.45 (2H, d, J = 9.2 Hz), 7.07 (3H, m, J = 7.9, 3.7 Hz), 3.80 (3H, s), 3.41 (1H, t, J = 6.9 Hz), 1.38 (6H, d, J = 6.6 Hz). MS m/z (M + H): 393.

›Example 0014

0014-1

Isobutyric acid (4.67 mL) and silver nitrate (1.15 g) were added to a solution of 3,6-dichloropyridazine (5 g) in water (168 mL)/sulfuric acid (7.4 mL), and a solution of ammonium peroxodisulfate (26 g) in water (84 mL) was added dropwise thereto at room temperature over a period of 20 minutes, followed by stirring at 70° C. for 30 minutes. The reaction mixture was cooled to room temperature, adjusted to have a pH of 8 by the addition of ammonia water, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3,6-dichloro-4-isopropylpyridazine (6.33 g) as pale yellow oily substance.

MSm/z(M+H):191.

0014-2

2,4-Dimethoxybenzylamine (10 mL) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (14.9 mL) were added to a solution of 3,6-dichloro-4-isopropylpyridazine (6.33 g) in 1,4-dioxane (66 mL), followed by stirring at 100° C. for 19 hours. The reaction mixture was cooled to room temperature, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 6-chloro-N-(2,4-dimethoxybenzyl)-5-isopropylpyridazine-3-amine (2.64 g) as pale yellow oily substance.

MSm/z(M+H):322.

0014-3

A mixture of 10% palladium/carbon (0.5 g), 6-chloro-N-(2,4-dimethoxybenzyl)-5-isopropylpyridazine-3-amine (2.64 g) and methanol (27.3 mL) in acetic acid (0.94 mL) was stirred at room temperature for 3 hours under pressurized hydrogen (0.8 MPa). Furthermore, acetic acid (3.76 mL) was added thereto, followed by stirring at 50° C. for 2.5 hours under pressurized hydrogen (0.8 MPa). The insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure, thereby obtaining orange oily substance (4.33 g).

Water (0.82 mL) and trifluoroacetic acid (8.2 mL) were added to the obtained orange oily substance (4.33 g), followed by stirring at room temperature for 30 minutes. The insolubles were filtered off using celite, and the solid was washed with ethyl acetate/methanol. The filtrate and the washings were combined, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 5-isopropylpyridazine-3-amine (0.97 g) as a pale yellow solid.

MSm/z(M+H):138.

0014-4

1,4-Dioxane (0.79 mL) was added to a mixture of 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)pyrido[2,3-b]pyrazine (11.4 mg), 5-isopropylpyridazine-3-amine (8.1 mg), tris(dibenzylideneacetone)dipalladium(0) (3.6 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.5 mg), and cesium carbonate (32 mg), followed by reacting at 150° C. for 30 minutes using a microwave reaction apparatus. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining N-(5-isopropylpyridazin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)pyrido[2,3-b]pyrazine-6-amine (1.3 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:10.93(1H,s),9.13(1H,s),8.91(1H,d,J=2.0 Hz),8.69(1H,s),8.60(1H,s),8.28(2H,m,J=4.6 Hz),7.82(1H,d,J=9.2 Hz),3.96(3H,s),1.33(6H,d,J=6.6 Hz).

MSm/z(M+H):347.

›Example 0015

0015-1

3,6-Dichloro-4-cyclobutylpyridazine was obtained as pale yellow oily substance in the same manner as in Example 0014-1.

MSm/z(M+H):204.

0015-2

2,4-Dimethoxybenzylamine (1.48 mL) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (2.2 mL) were added to a solution of 3,6-dichloro-4-cyclobutylpyridazine (0.99 g) in 1,4-dioxane (7 mL), followed by reacting at 145° C. for 45 minutes using a microwave reaction apparatus. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 6-chloro-N-(2,4-dimethoxybenzyl)-5-cyclobutylpyridazine-3-amine (274 mg).

MSm/z(M+H):334.

0015-3

A mixture solution of 6-chloro-N-(2,4-dimethoxybenzyl)-5-cyclobutylpyridazine-3-amine (274 mg) in methanol (20.5 mL)/acetic acid (2 mL) was reacted using a flow-type hydrogenation reaction apparatus (30 bar, 1.0 mL/min, 55° C., 10% Pd/C). The solvent was distilled off under reduced pressure, thereby obtaining pale yellow oily substance.

Water (0.25 mL) and trifluoroacetic acid (5 mL) were added to the obtained pale yellow oily substance, followed by stirring at room temperature for 30 minutes. The insolubles were filtered off using celite, and the solid was washed with ethyl acetate/methanol. The filtrate and the washings were combined, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-chloroform, NH silica), thereby obtaining 5-cyclobutylpyridazine-3-amine (129 mg) as a pale yellow solid.

MSm/z(M+H):150.

0015-4

1,4-Dioxane (0.89 mL) was added to a mixture of 2-chloro-7-(1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (15.2 mg), 5-cyclobutylpyridazine-3-amine (10.1 mg), tris(dibenzylideneacetone)dipalladium(0) (4.2 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.3 mg), and cesium carbonate (36.3 mg), followed by reacting at 150° C. for 30 minutes using a microwave reaction apparatus. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica) and preparative reversed phase HPLC (a 0.1% formic acid aqueous solution-a 0.1% formic acid acetonitrile solution), and the solvent was distilled off under reduced pressure, thereby obtaining N-(5-cyclobutylpyridazin-3-yl)-7-(1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amineformate (0.8 mg) as a brown solid.

1 H-NMR(DMSO-d 6 ) δ 10.71(1H,s),9.05(1H,d,J=2.0 Hz),8.83(1H,d,J=1.3 Hz),8.69(1H,d,J=1.3 Hz),8.52(1H,s),8.21(3H,d,J=2.0 Hz),7.70(1H,d,J=9.2 Hz),4.24(2H,t,J=6.6 Hz),3.67(1H,t,J=8.6 Hz),2.71(8H,d,J=9.2 Hz),2.47-2.41(2H,m),2.24(2H,m,J=9.1,2.2 Hz),2.11-2.05(4H,m),1.78-1.75(2H,m).

MSm/z(M+H):455.

Examples 0016 to 0018

The following compounds were obtained in the same manner as in Examples 0015-1 to 0015-4.

›Example 0019

0019-1

Brown oily substance (1.54 g) was obtained in the same manner as in Example 0014 except that tetrahydrofuran-3-carboxylic acid was used instead of the isobutyric acid used in Example 0014.

2,4-Dimethoxybenzylamine (2.1 mL) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (3.2 mL) were added to a solution of the obtained brown oily substance (1.54 g) in 1,4-dioxane (14 mL), followed by stirring at 100° C. overnight. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 6-chloro-N-(2,4-dimethoxybenzyl)-5-(tetrahydrofuran-3-yl)pyridazine-3-amine (348 mg) as an orange solid.

MSm/z(M+H):350.

0019-2

5-(Tetrahydrofuran-3-yl)pyridazine-3-amine was obtained as a pale orange solid in the same manner as in Example 0016-3.

MSm/z(M+H):166.

0019-3

7-(1-(3-(Pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-N-(5-(tetrahydrofuran-3-yl)pyridazin-3-yl)-1,5-naphthyridine-2-amine was obtained as an orange solid in the same manner as in Example 0015-4.

1 H-NMR(CDCl 3 )δ:8.96(2H,m),8.84(1H,d,J=2.0 Hz),8.25(1H,d,J=9.2 Hz),8.11(1H,d,J=2.0 Hz),7.97(1H,s),7.89(1H,s),7.51(1H,d,J=8.6 Hz),4.29-4.24(4H,m),4.07-3.93(3H,m),2.57-2.47(7H,m),2.16-2.13(3H,m),1.82-1.80(4H,m).

MSm/z(M+H):471.

›Example 0020

0020-1

7-(1-(3-(Dimethylamino)propyl)-1H-pyrazol-4-yl)-N-(5-isopropylpyridazin-3-yl)-1,5-naphthyridine-2-amine (0.7 mg) was obtained as an orange solid in the same manner as in Example 0018 except that 3-(4-(6-chloro-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)-N,N-dimethylpropane-1-amine was used instead of the 2-chloro-7-(1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine used in Example 0018, and 5-isopropylpyridazine-3-amine was used instead of the 5-(methoxymethyl)pyridazine-3-amine used in Example 0018.

1 H-NMR(CDCl 3 )δ:8.93-8.81(3H,m),8.24(1H,d,J=8.6 Hz),8.10(1H,d,J=1.3 Hz),7.97(1H,s),7.90(1H,s),7.53(1H,d,J=8.6 Hz),5.34(1H,t,J=5.6 Hz),4.31(3H,t,J=6.9 Hz),3.45(1H,s),3.06-3.03(1H,m),2.41-2.37(2H,m),2.32(6H,s),1.42(6H,d,J=7.3 Hz).

MSm/z(M+H):417.

›Example 0021

0021-1

1-Bromo-3-chloropropane (0.25 mL) was added to a solution of 1-methylpiperazine (0.55 mL) in toluene (2.5 mL), followed by stirring at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and 2 mol/L hydrochloric acid was added thereto. The aqueous layer was collected by separation, adjusted to have a pH of 12 by the addition of a 2 mol/L sodium hydroxide aqueous solution, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 1-(3-chloropropyl)-4-methylpiperazine (187 mg) as a white solid.

1 H-NMR(CDCl 3 )δ:3.59(2H,t,J=6.6 Hz),2.49(8H,t,J=7.3 Hz),2.29(3H,s),1.95(2H,t,J=6.9 Hz).

0021-2

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (351.4 mg), cesium carbonate (1.17 g), and sodium iodide (58.0 mg) were added to a mixture solution of 1-(3-chloropropyl)-4-methylpiperazine (0.64 g) in acetonitrile (2.4 mL)/tetrahydrofuran (1.0 mL), followed by reacting at 80° C. for 19 hours. After the reaction mixture was cooled to room temperature, the insolubles were filtered off, and the residue was washed with ethyl acetate. The filtrate and the washings were combined, and the solvent was distilled off under reduced pressure, thereby obtaining orange oily substance (137 mg).

7-Bromo-2-chloro-1,5-naphthyridine (50 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (14.5 mg), and sodium carbonate (43.4 mg) were added to a mixture solution of the obtained orange oily substance (137 mg) in 1,4-dioxane (2.0 mL)/water (0.2 mL), followed by stirring at 100° C. for 2 hours. After the reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the residue was washed with ethyl acetate. The filtrate and the washings were combined, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane, methanol-ethyl acetate, NH silica), thereby obtaining 2-chloro-7-(1-(3-(4-methylpiperazin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (44.1 mg) as a pale yellow solid.

MSm/z(M+H):371.

0021-3

N-(5-isopropylpyridazin-3-yl)-7-(1-(3-(4-methylpiperazin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine was obtained as a pale yellow solid in the same manner as in Example 0015-4.

1 H-NMR(CDCl 3 )δ:8.93(1H,d,J=2.0 Hz),8.83-8.81(2H,m),8.24(1H,d,J=9.2 Hz),8.10(1H,s),7.97(1H,s),7.87(1H,s),7.52(1H,d,J=9.2 Hz),4.29(2H,t,J=6.6 Hz),3.06(1H,t,J=6.9 Hz),2.51-2.47(7H,m),2.38(3H,t,J=6.9 Hz),2.31(3H,s),2.13(2H,q,J=6.8 Hz),1.42(6H,d,J=7.3 Hz).

MSm/z(M+H):472.

›Example 0022

0022-1

Several drops of a 4 mol/L hydrogen chloride-1,4-dioxane solution (3 mL) and water were added to 7-bromo-2-chloro-1,5-naphthyridine (250 mg), followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, and water was added thereto. The solid matter was collected by filtration, and washed with a mixture solution of water and hexane-ethyl acetate (1:1), thereby obtaining 7-bromo-1,5-naphthyridin-2-ol (190 mg) as a grey solid.

1 H-NMR(DMSO-d 6 )δ:11.96(1H,brs),8.56(1H,d,J=2.3 Hz),7.93(1H,d,J=9.9 Hz),7.85(1H,d,J=2.30 Hz),6.79(1H,d,J=9.9 Hz).

0022-2

1,4-Dioxane (5 mL), 2 mol/L sodium carbonate aqueous solution (0.99 mL), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (46 mg) were added to a mixture of 7-bromo-1,5-naphthyridin-2-ol (150 mg) and 3,4-dimethoxyphenylboronic acid (150 mg) in a nitrogen atmosphere, followed by stirring at 100° C. for 2 days. The reaction mixture was cooled to room temperature, a mixed solvent of chloroform-methanol (10:1) was added thereto, and the solid matter was collected by filtration, thereby obtaining 7-(3,4-dimethoxyphenyl)-1,5-naphthyridin-2-ol (137 mg) as a yellow solid.

MSm/z(M+H):283.

0022-3

Phosphorus oxychloride (4 g) was added to 7-(3,4-dimethoxyphenyl)-1,5-naphthyridin-2-ol (134 mg), followed by stirring at 100° C. for 2 hours. After the reaction mixture was cooled to room temperature, water was added dropwise thereto, the resultant product was neutralized with a 5 mol/L sodium hydroxide aqueous solution, and chloroform was added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining 2-chloro-7-(3,4-dimethoxyphenyl)-1,5-naphthyridine (134 mg) as an orange solid.

1 H-NMR(CDCl 3 )δ:9.24(1H,d,J=2.6 Hz),8.43(1H,d,J=2.6 Hz),8.37(1H,d,J=9.2 Hz),7.60(1H,d,J=9.2 Hz),7.33(1H,dd,J=8.3,2.1 Hz),7.24(1H,d,J=2.1 Hz),7.05(1H,d,J=8.3 Hz),3.99(3H,s),3.97(3H,s).

0022-4

1,4-Dioxane (2 mL) was added to a mixture of 2-chloro-7-(3,4-dimethoxyphenyl)-1,5-naphthyridine (30 mg), 5-methylthiazole-2-amine (17 mg), tris(dibenzylideneacetone)dipalladium(0) (9.2 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg), and cesium carbonate (98 mg) in a nitrogen atmosphere, and the reaction vessel was sealed, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, and water was added thereto. The solid matter was collected by filtration, and purified by silica gel column chromatography (chloroform-methanol), thereby obtaining N-(7-(3,4-dimethoxyphenyl)-1,5-naphthyridin-2-yl)-5-methylthiazole-2-amine (32 mg) as a yellow solid.

1 H-NMR(CDCl 3 )δ:10.58(1H,brs),9.00(1H,d,J=2.0 Hz),8.35(1H,d,J=2.0 Hz),8.25(1H,d,J=8.6 Hz),7.35(1H,dd,J=8.6,2.0 Hz),7.30-7.27(1H,m),7.24-7.18(2H,m),7.05(1H,d,J=8.6 Hz),4.03(3H,s),3.98(3H,s),2.51(3H,s).

MSm/z(M+H):379.

›Example 0023

0023-1

1,4-Dioxane (2 mL) was added to a mixture of 2-chloro-7-(3,4-dimethoxyphenyl)-1,5-naphthyridine (30 mg), thiazole-2-amine (15 mg), tris(dibenzylideneacetone)dipalladium(0) (9.2 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg), and cesium carbonate (98 mg) in a nitrogen atmosphere, and the reaction vessel was sealed, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, and water was added thereto. The solid matter was collected by filtration, and purified by silica gel column chromatography (chloroform-methanol), thereby obtaining N-(7-(3,4-dimethoxyphenyl)-1,5-naphthyridin-2-yl)thiazole-2-amine (10 mg) as a yellow solid.

1 H-NMR(CDCl 3 )δ:10.60(1H,brs),9.02(1H,d,J=2.0 Hz),8.36(1H,d,J=2.0 Hz),8.28(1H,d,J=9.2 Hz),7.59(1H,d,J=3.7 Hz),7.36-7.22(3H,m),7.05(1H,d,J=7.9 Hz),7.00(1H,d,J=3.7 Hz),4.03(3H,s),3.98(3H,s).

MSm/z(M+H):365.

›Example 0024

0024-1

1,4-Dioxane (2 mL) was added to a mixture of 2-chloro-7-(3,4-dimethoxyphenyl)-1,5-naphthyridine (30 mg), 4-methylthiazole-2-amine (17 mg), tris(dibenzylideneacetone)dipalladium(0) (9.2 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg), and cesium carbonate (98 mg) in a nitrogen atmosphere, and the reaction vessel was sealed, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, water was added thereto, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining N-(7-(3,4-dimethoxyphenyl)-1,5-naphthyridin-2-yl)-4-methylthiazole-2-amine (10 mg) as a yellow solid.

1 H-NMR(CDCl 3 )δ:9.01(1H,s),8.33(1H,s),8.24(1H,d,J=8.3 Hz),7.33(1H,d,J=8.3 Hz),7.13(1H,d,J=8.6 Hz),7.04(1H,d,J=8.6 Hz),6.52(1H,s),6.09(1H,s),4.02(3H,s),3.97(4H,s),2.40(3H,s).

MSm/z(M+H):379.

›Example 0025

0025-1>

A 2 mol/L sodium carbonate aqueous solution (1.3 mL) and 1,4-dioxane (6.0 mL) were added to a mixture of 7-bromo-1,5-naphthyridin-2-ol (190 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (376 mg), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (60 mg) in a nitrogen atmosphere, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, and water was added thereto. The solid matter was collected by filtration, thereby obtaining 7-(1H-pyrazol-4-yl)-1,5-naphthyridin-2-ol (190 mg) as a grey solid.

1 H-NMR(DMSO-d 6 )δ:13.23(1H,brs),11.84(1H,brs),8.79(1H,d,J=2.0 Hz),8.20(2H,brs),7.90(1H,d,J=9.9 Hz),7.73(1H,d,J=2.0 Hz),6.66(1H,d,J=9.9 Hz).

0025-2

Phosphorus oxychloride (1.7 g) was added to 7-(1H-pyrazol-4-yl)-1,5-naphthyridin-2-ol (50 mg) at room temperature, followed by stirring at 80° C. for 30 minutes, and stirring at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, water was added thereto, and the resultant product was neutralized with a 5 mol/L sodium hydroxide aqueous solution. The solid matter was collected by filtration, thereby obtaining 2-chloro-7-(1H-pyrazol-4-yl)-1,5-naphthyridine (40 mg) as a grey solid.

MSm/z(M+H):231,233.

0025-3

N,N-dimethylformamide (2 mL) was added to 2-chloro-7-(1H-pyrazol-4-yl)-1,5-naphthyridine (15 mg) in a nitrogen atmosphere, and 60% sodium hydride (3 mg) was added thereto under ice-cooling, followed by stirring at the same temperature for 30 minutes. (2-(Chloromethoxy)ethyl)trimethylsilane (14 μL) was added to the reaction mixture under ice-cooling, followed by stirring at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer silica gel chromatography (hexane-ethyl acetate), thereby obtaining 2-chloro-7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (6 mg) as a white solid.

MSm/z(M+H):361,363.

0025-4

N-(7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a white solid in the same manner as in Example 0015-4.

1 H-NMR(CDCl 3 )δ:13.10(1H,brs),8.98(1H,d,J=2.0 Hz),8.85(1H,s),8.35(1H,d,J=9.2 Hz),8.28(1H,d,J=2.0 Hz),8.06(1H,s),8.03(1H,s),7.80(1H,d,J=9.2 Hz),5.53(2H,s),3.68-3.63(2H,m),0.99-0.94(2H,m),0.01(9H,s).

MSm/z(M+H):426.

›Example 0026

0026-1

2-Chloro-7-(1H-pyrazol-4-yl)-1,5-naphthyridine (65 mg) was dissolved in N,N-dimethylformamide in a nitrogen atmosphere, and 60% sodium hydride (17 mg) was added thereto under ice-cooling, followed by stirring for 30 minutes under ice-cooling. Methyl iodide (36 μL) was added to the reaction mixture, followed by stirring at room temperature for 50 minutes. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining 2-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine (20 mg) as a pale yellow solid.

MSm/z(M+H):245,247.

0026-2

N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a pale yellow solid in the same manner as in Example 0015-4.

1 H-NMR(DMSO-d 6 )δ:9.17(1H,s),9.08(1H,d,J=2.6 Hz),8.52(1H,s),8.32(1H,d,J=2.6 Hz),8.28(1H,d,J=9.2 Hz),8.20(1H,s),7.44(1H,d,J=9.2 Hz),3.93(3H,s).

MSm/z(M+H):310.

Examples 0027 to 0029

The following compounds were obtained in the same manner as in Example 0015-4.

›Example 0030

0030-1

Tetrahydrofuran (10 mL) was added to 2-nitro-1H-imidazole (226 mg) in a nitrogen atmosphere, 60% sodium hydride (96 mg) was added thereto under ice-cooling, followed by stirring for 30 minutes under ice-cooling, and, thereafter, (2-(chloromethoxy)ethyl)trimethylsilane (421 μL) was added thereto, followed by stirring at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining 2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (460 mg) as a yellow solid.

1 H-NMR(CDCl 3 )δ:7.37-7.36(2H,m),5.84(2H,s),3.73-3.68(2H,m),1.06-1.003(2H,m),0.07(9H,s).

0030-2

2-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (176 mg) was dissolved in methanol (15 mL), and the resultant product was reacted using a flow-type hydrogenation reaction apparatus (atmospheric pressure, 1.0 mL/min, room temperature, 10% Pd/C). The solvent was distilled off under reduced pressure, thereby obtaining 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-amine (150 mg) as brown oily substance.

1 H-NMR(CDCl 3 )δ:6.61(1H,d,J=1.7 Hz),6.56(1H,d,J=1.7 Hz),5.07(2H,s),4.19(2H,brs),3.54-4.48(2H,m),0.93-0.87(2H,m),0.00(9H,s).

0030-3

1,4-Dioxane (2 mL) was added to a mixture of 2-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine (20 mg), 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-amine (26 mg), tris(dibenzylideneacetone)dipalladium(0) (7.5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.5 mg), and cesium carbonate (80 mg) in a nitrogen atmosphere, and the reaction vessel was sealed, followed by stirring at 150° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate, NH silica), thereby obtaining 7-(1-methyl-1H-pyrazol-4-yl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1,5-naphthyridine-2-amine (15 mg) as an orange solid.

MSm/z(M+H):422.

0030-4

7-(1-Methyl-1H-pyrazol-4-yl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1,5-naphthyridine-2-amine (15 mg) was dissolved in a mixed solvent (4.1 mL) of methylene chloride-ethanol-trifluoroacetic acid (3:0.1:1), followed by stirring at room temperature for 7 hours. The reaction mixture was distilled off under reduced pressure, thereby obtaining trifluoroacetate (1.8 mg) of N-(1H-imidazol-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine as a pale yellow solid.

1 H-NMR(CD 3 OD)δ:9.10(1H,d,J=2.0 Hz),8.69(1H,d,J=2.0 Hz),8.35(1H,d,J=9.2 Hz),8.28(1H,s),8.08(1H,s),7.40(1H,d,J=9.2 Hz),7.23(2H,s),4.01(3H,s).

MSm/z(M+H):292.

›Example 0031

0031-1

A mixture solution of 7-bromo-2-chloro-1,5-naphthyridine (100 mg) in 1,4-dioxane (2 mL) and a 25% ammonia aqueous solution was stirred at 120° C. for 3 hours using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and a saturated sodium chloride aqueous solution and ethyl acetate were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 7-bromo-1,5-naphthyridine-2-amine (90 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:8.53(1H,d),8.02(1H,d),7.92(1H,d),7.01(1H,d),6.94(1H,s).

MSm/z(M+H):224,226.

0031-2

Pyridine (9 mL) was added to a mixture of 7-bromo-1,5-naphthyridine-2-amine (300 mg) and phenyl chloroformate (280 μL), followed by stirring at room temperature for 2 hours. Phenyl chloroformate (140 μL) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining phenyl (7-bromo-1,5-naphthyridin-2-yl)carbamate (310 mg) as a white solid.

MSm/z(M+H):344,346.

0031-3

Phenyl (7-bromo-1,5-naphthyridin-2-yl)carbamate (20 mg) was dissolved in 1,4-dioxane (2 mL), and acetohydrazide (6.5 mg) was added thereto, followed by stirring at 150° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the solid matter was collected by filtration, thereby obtaining 2-acetyl-N-(7-bromo-1,5-naphthyridin-2-yl)hydrazinecarboxamide (14 mg) as a white solid.

MSm/z(M+H):324,326.

0031-4

Phosphorus oxychloride (2.5 g) was added to 2-acetyl-N-(7-bromo-1,5-naphthyridin-2-yl)hydrazinecarboxamide (50 mg), followed by stirring at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and water was added dropwise thereto. The resultant product was neutralized with a 5 mol/L sodium hydroxide aqueous solution, and chloroform was added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining N-(7-bromo-1,5-naphthyridin-2-yl)-5-methyl-1,3,4-oxadiazole-2-amine (34 mg) as a yellow solid.

MSm/z(M+H):306,308.

0031-5

N-(7-bromo-1,5-naphthyridin-2-yl)-5-methyl-1,3,4-oxadiazole-2-amine (31 mg) was dissolved in N,N-dimethylformamide (2 mL) in a nitrogen atmosphere, and 60% sodium hydride (6 mg) was added thereto under ice-cooling, followed by stirring for 1 hour. (2-(Chloromethoxy)ethyl)trimethylsilane (14 μL) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining N-(7-bromo-1,5-naphthyridin-2-yl)-5-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-oxadiazole-2-amine (20 mg).

1 H-NMR(CDCl 3 )δ:8.85(1H,d,J=2.0 Hz),8.35(1H,d,J=2.0 Hz),8.32(1H,d,J=9.9 Hz),8.19(1H,d,J=9.9 Hz),5.77(2H,s),3.82-3.75(2H,m),2.56(3H,s),0.99-0.94(2H,m),−0.05(9H,s).

0031-6

1,4-Dioxane (2 mL) and a 2 mol/L sodium carbonate aqueous solution (69 μL) were added to a mixture of N-(7-bromo-1,5-naphthyridin-2-yl)-5-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-oxadiazole-2-amine (20 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14 mg), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3.2 mg) in a nitrogen atmosphere, and the reaction vessel was sealed, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate, NH silica), thereby obtaining 5-methyl-N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-oxadiazole-2-amine (18 mg) as a white solid.

MSm/z(M+H):438.

0031-7

A mixed solvent (4.1 mL) of chloroform-ethanol-trifluoroacetic acid (3:0.1:1) was added to 5-methyl-N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-oxadiazole-2-amine (18 mg), followed by stirring at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and a mixed solvent of methanol-ethyl acetate was added to the obtained residue. The solid matter was collected by filtration, thereby obtaining 5-methyl-N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-oxadiazole-2-amine hydrochloride (5 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:9.07(1H,d,J=2.0 Hz),8.49(1H,s),8.29-8.26(2H,m),8.18(1H,s),7.96-7.84(1H,m),3.92(3H,s),2.46(3H,s).

MSm/z(M+H):308.

›Example 0032

0032-1

1,4-Dioxane (2 mL) and a 2 mol/L sodium carbonate aqueous solution (315 μL) were added to a mixture of 7-bromo-2-chloro-1,5-naphthyridine (50 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (77 mg), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphino)dichloropalladium(II) (15 mg) in a nitrogen atmosphere, and the reaction vessel was sealed, followed by stirring at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining 2-chloro-7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (57 mg) as a white solid.

1 H-NMR(CDCl 3 )δ:9.15(1H,d,J=2.0 Hz),8.35-8.31(2H,m),8.04(1H,s),8.00(1H,s),7.57(1H,d,J=8.6 Hz),5.53(2H,s),3.68-3.63(2H,m),0.99-0.93(2H,m),0.00(9H,s).

0032-2

1,4-Dioxane (3 mL) was added to a mixture of 2-chloro-7-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (57 mg), 1,3,4-thiadiazole-2-amine (24 mg), tris(dibenzylideneacetone)dipalladium(0) (14 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18 mg), and cesium carbonate (154 mg) in a nitrogen atmosphere, followed by stirring at 100° C. for 7 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining N-(7-(1-((2-trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (23 mg).

MSm/z(M+H):426.

0032-3

Ethanol (3 mL) and 3 mol/L hydrochloric acid (3 mL) were added to N-(7-(1-((2-trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (23 mg), followed by stirring at 80° C. for 4 hours. The reaction mixture was cooled to room temperature, and the solvent was concentrated under reduced pressure. Methanol and ethyl acetate were added to the obtained residue, and the produced solid matter was collected by filtration, thereby obtaining N-(7-(1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine hydrochloride (6 mg) as a pale yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.30(1H,brs),9.19-9.18(2H,m),8.46(1H,d,J=1.2 Hz),8.44(2H,s),8.33(1H,d,J=9.2 Hz),7.49(1H,d,J=9.2 Hz).

MSm/z(M+H):296.

›Example 0033

0033-1

1,4-Dioxane (3 mL) was added to a mixture of 2-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine (15 mg), 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-amine (20 mg), tris(dibenzylideneacetone)dipalladium(0) (5.5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.9 mg), and cesium carbonate (59 mg) in a nitrogen atmosphere, and the reaction vessel was sealed, followed by stirring at 150° C. for 30 minutes using a microwave reaction apparatus. Tris(dibenzylideneacetone)dipalladium(0) (11 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14 mg) were added thereto, followed by stirring at 150° C. for 1 hour using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate, chloroform-methanol, NH silica), and further purified by preparative thin layer silica gel chromatography (chloroform-methanol), thereby obtaining 7-(1-methyl-1H-pyrazol-4-yl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1,5-naphthyridine-2-amine (4 mg) as oily substance.

MSm/z(M+H):422.

0033-2

7-(1-Methyl-1H-pyrazol-4-yl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1,5-naphthyridine-2-amine (4 mg) was dissolved in a mixed solvent (2.3 mL) of chloroform-trifluoroacetic acid-ethanol (1:1:0.3), followed by stirring at 50° C. for 6 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, thereby obtaining 7-(1-methyl-1H-pyrazol-4-yl)-N-(1H-pyrazol-3-yl)-1,5-naphthyridine-2-aminetrifluoroacetate (2 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:10.84(1H,brs),9.02(1H,d,J=2.0 Hz),8.48(1H,s),8.39(1H,br),8.20-8.17(2H,m),7.78(1H,d,J=2.0 Hz),7.40(1H,d,J=9.2 Hz),6.75(1H,s),3.95(3H,s).

MSm/z(M+H):292.

›Example 0034

0034-1

7-(1-Methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine (201 mg) was dissolved in 1,4-dioxane (8.9 mL), and benzoyl isothiocyanate (0.24 mL) was added thereto under ice-cooling, followed by stirring at room temperature for 1 hour, and stirring at 55° C. for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid matter was collected by filtration, thereby obtaining N-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)carbamothioyl)benzamide (232 mg) as a yellow solid.

MSm/z(M+H):389.

0034-2

N-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)carbamothioyl)benzamide (50 mg) was dissolved in 1,4-dioxane (1.3 mL), and a 2 mol/L sodium hydroxide aqueous solution (0.14 mL) was added thereto, followed by stirring at 80° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and water was added thereto. The solid matter was collected by filtration, thereby obtaining 1-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)thiourea (22 mg) as a pale yellow solid.

MSm/z(M+H):285.

0034-3

1-(7-(1-Methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)thiourea (20 mg) and ethyl 3-bromo-2-oxopropanoate (8.8 mL) were dissolved in N,N-dimethylformamide (2 mL), followed by stirring at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was collected by separation, washed sequentially with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining ethyl 2-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)thiazole-4-carboxylate (16 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.28(1H,s),9.07(1H,d,J=2.3 Hz),8.51(1H,s),8.31(1H,d,J=2.3 Hz),8.24(1H,d,J=9.2 Hz),8.19(1H,s),8.04(1H,s),7.33(1H,d,J=9.2 Hz),4.30(2H,q,J=7.0 Hz),3.92(3H,s),1.32(3H,t,J=7.0 Hz).

MSm/z(M+H):381.

›Example 0035

0035-1

1-(7-(1-Methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)thiourea (20 mg) and ethyl 2-chloro-3-oxopropanoate (10 mg) were dissolved in N,N-dimethylformamide (2 mL), followed by stirring at 80° C. overnight. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was collected by separation, washed sequentially with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in a mixed solvent of chloroform-methanol, and ethyl acetate was added thereto. The solid matter was collected by filtration, thereby obtaining ethyl 2-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)thiazole-5-carboxylate (8 mg) as a pale yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.35(1H,s),9.12(1H,d,J=2.0 Hz),8.58(1H,s),8.34(1H,d,J=2.0 Hz),8.30(1H,d,J=9.2 Hz),8.24(1H,s),8.17(1H,s),7.45(1H,d,J=9.2 Hz),4.33(2H,q,J=7.0 Hz),3.93(3H,s),1.34(3H,t,J=7.0 Hz).

MSm/z(M+H):381.

›Example 0036

0036-1

1,4-Dioxane (2 mL) was added to a mixture of 2-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine (12 mg), 2-aminopyridine (7 mg), potassium tert-butoxide (16 mg), tris(dibenzylideneacetone)dipalladium(0) (4.5 mg), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.6 mg) in a nitrogen atmosphere, and the reaction vessel was sealed, followed by stirring at 150° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining 7-(1-methyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)-1,5-naphthyridine-2-amine (4 mg) as a pale yellow solid.

1 H-NMR(DMSO-d 6 )δ:10.25(1H,s),9.00(1H,d,J=2.0 Hz),8.62(1H,d,J=8.6 Hz),8.48(1H,s),8.32-8.30(1H,m),8.25(1H,d,J=2.0 Hz),8.17(1H,s),8.15(1H,d,J=9.2 Hz),7.83-7.77(1H,m),7.67(1H,d,J=9.2 Hz),7.03-6.99(1H,m),3.92(3H,s).

MSm/z(M+H):303.

Examples 0037 and 0038

The following compounds were obtained in the same manner as in Example 0036-1.

›Example 0039

0039-1

A solution of 7-bromo-2-chloro-1,5-naphthyridine (2.04 g), 5-cyclopentyl-1,3,4-thiadiazole-2-amine (1.41 g), and potassium carbonate (1.73 g) in dimethylsulfoxide (16 mL) was stirred at 130° C. for 3 hours. After the reaction mixture was cooled to room temperature, water was added thereto, and the solid matter was collected by filtration, thereby obtaining N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-1,3,4-thiadiazole-2-amine (1.92 g).

1 H-NMR(DMSO-d 6 )δ:12.20(1H,s),8.84(1H,d,J=2.7 Hz),8.56(1H,d,J=2.7 Hz),8.31(1H,d,J=9.3 Hz),7.51(1H,d,J=9.3 Hz),3.56-3.40(1H,m),2.22-2.08(2H,m),1.94-1.34(6H,m).

MSm/z(M+H):376,378.

›Example 0040

0040-1

60% sodium hydride (256 mg) was added to a solution of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-1,3,4-thiadiazole-2-amine (1.21 g) and 2-(chloromethoxy)ethyltrimethylsilane (0.846 mL) in N-methylpyrrolidone (32 mL) under ice-cooling, followed by stirring at the same temperature for 1 hour, and stirring at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (601 mg) and (Z)-7-bromo-N-(5-cyclopentyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazol-2(3H)-ylidene)-1,5-naphthyridine-2-amine (206 mg).

MSm/z(M+H):506,508, 506,508.

0040-2

A mixture of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (200 mg), bis(pinacolato)diboron (150 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (32 mg) and potassium acetate (77 mg) in 1,4-dioxane (2.0 mL) was stirred at 80° C. for 2 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and 30% hydrogen peroxide water (0.1 mL) and a saturated sodium hydrogen carbonate aqueous solution (1.5 mL) were added thereto, followed by stirring at room temperature for 3 hours. A saturated sodium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-ol (99 mg) as a white solid.

MSm/z(M+H):444.

0040-3

Methanol (0.5 mL), 12 mol/L hydrochloric acid (0.5 mL), 1,4-dioxane (0.25 mL), N-methylpyrrolidone (0.125 mL), and methanol (0.5 mL) were added to 6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-ol (10 mg), followed by stirring at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Diisopropyl ether and water were added to the obtained residue, and the solid matter was collected by filtration, thereby obtaining 6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-ol hydrochloride (2.9 mg).

1 H-NMR(DMSO-d 6 )δ:12.06-11.80(1H,brs),10.74-10.56(1H,brs),8.44(1H,d,J=2.1 Hz),8.17(1H,d,J=9.0 Hz),7.43(1H,d,J=2.1 Hz),7.25(1H,d,J=9.0 Hz),3.54-3.38(1H,m),2.22-2.08(2H,m),1.90-1.62(6H,m).

MSm/z(M+H):314.

›Example 0041

0041-1

1-Bromo-2-methoxyethane (0.0064 mL) was added to a mixture of 6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-ol (20 mg) and potassium carbonate (19 mg) in N-methylpyrrolidone (0.5 mL), followed by stirring at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed sequentially with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 5-cyclopentyl-N-(7-(2-methoxyethoxy)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (13 mg).

MSm/z(M+H):502.

0041-2

12 mol/L hydrochloric acid (0.4 mL) was added to a solution of 5-cyclopentyl-N-(7-(2-methoxyethoxy)-1,5-naphthyridin-2-yl)-N-((2-trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (13 mg) in methanol (1.2 mL), followed by stirring at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and diisopropyl ether and water were added to the obtained residue. The solid matter was collected by filtration, thereby obtaining 5-cyclopentyl-N-(7-(2-methoxyethoxy)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine hydrochloride (3.3 mg).

1 H-NMR(DMSO-d 6 )δ:11.98(1H,brs),8.52(1H,d,J=2.7 Hz),8.21(1H,d,J=9.3 Hz),7.63(1H,d,J=2.7 Hz),7.30(1H,d,J=9.3 Hz),4.38-4.33(2H,m),3.78-3.73(2H,m),3.52-3.36(1H,m),3.38(3H,s),2.22-2.08(2H,m),1.94-1.64(6H,m).

MSm/z(M+H):372.

›Example 0042

0042-1

Tetrakis(triphenylphosphine)palladium(0) (16 mg), copper iodide (I) (5 mg), triethylamine (0.049 mL), and trimethylsilylacetylene (0.039 mL) were added to a solution of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (70 mg) in tetrahydrofuran (1.5 mL), followed by stirring for 1.5 hours under heating to reflux. N-methylpyrrolidone (0.75 mL) and trimethylsilylacetylene (0.2 mL) were added thereto, followed by stirring at the same temperature for 1 hour. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed sequentially with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-N-(7-((trimethylsilyl)ethynyl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (65 mg).

MSm/z(M+H):524.

0042-2

Methanol (1.2 mL) was added to 5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-N-(7-((trimethylsilyl)ethynyl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (65 mg) and potassium carbonate (34 mg), followed by stirring at room temperature for 2 hours. Ethyl acetate and a saturated sodium chloride aqueous solution were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 5-cyclopentyl-N-(7-ethynyl-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (30 mg).

MSm/z(M+H):452.

0042-3

12 mol/L hydrochloric acid (0.4 mL) was added to a solution of 5-cyclopentyl-N-(7-ethynyl-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (13 mg) in methanol (1.2 mL), followed by stirring at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, diisopropyl ether and water were added to the obtained residue, and the solid matter was collected by filtration, thereby obtaining 5-cyclopentyl-N-(7-ethynyl-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine hydrochloride (2.3 mg).

1 H-NMR(DMSO-d 6 )δ:12.15(1H,brs),8.78(1H,d,J=1.8 Hz),8.36(1H,d,1.8 Hz),8.31(1H,J=9.3 Hz),7.49(1H,d,J=9.3 Hz),4.64(1H,s),3.54-3.38(1H,m),2.22-2.08(2H,m),1.92-1.64(6H,m).

MSm/z(M+H):322.

›Example 0043

0043-1

A mixture of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (37 mg), tetrakis(triphenylphosphine)palladium(0) (8 mg), ammonium formate (18 mg) and triethylamine (0.082 mL) in N-methylpyrrolidone (1 mL) was stirred at 120° C. for 60 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed sequentially with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 5-cyclopentyl-N-(1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (21 mg).

MSm/z(M+H):427.

0043-2

12 mol/L hydrochloric acid (0.4 mL) was added to a solution of 5-cyclopentyl-N-(1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (21 mg) in methanol (1.2 mL), followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropyl ether and water were added thereto, and the solid matter was collected by filtration, thereby obtaining 5-cyclopentyl-N-(1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine hydrochloride (3.3 mg).

1 H-NMR(DMSO-d 6 )δ:12.07(1H,brs),8.79-8.76(1H,m),8.30(1H,d,J=9.0 Hz),8.24(1H,d,8.1 Hz),7.72-7.67(1H,m),7.49(1H,d,9.3 Hz),3.54-3.38(1H,m),2.22-2.08(2H,m),1.92-1.64(6H,m).

MSm/z(M+H):298.

›Example 0044

0044-1

A mixture of 6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-ol (20 mg), 3-pyridylboronic acid (8 mg), copper(II) acetate (25 mg), molecular sieve 4A (20 mg) and triethylamine (0.063 mL) in dichloromethane (0.5 mL) was stirred at room temperature for 3 hours, and stirred at 50° C. for 5 days. After the reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 5-cyclopentyl-N-(7-((pyridin-3-yl)oxy)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (3.5 mg).

MSm/z(M+H):521.

0044-2

12 mol/L hydrochloric acid (0.4 mL) was added to a solution of 5-cyclopentyl-N-(7-((pyridin-3-yl)oxy)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (3.5 mg) in methanol (1.2 mL), followed by stirring at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and diisopropyl ether, water, sodium hydroxide aqueous solution, and dichloromethane were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 5-cyclopentyl-N-(7-((pyridin-3-yl)oxy)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine hydrochloride (1.68 mg).

1 H-NMR(CDCl 3 )δ:8.69(1H,d,J=2.7 Hz),8.60-8.52(2H,m),8.31(1H,d,J=9.3 Hz),7.65-7.60(2H,m),7.50-7.38(2H,m),3.58-3.50(1H,m), 2.32-2.18(2H,m),2.00-1.72(6H,m).

MSm/z(M+H):391.

›Example 0045

0045-1

A mixture of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (20 mg), bis(pinacolato)diboron (15 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (3 mg) and potassium acetate (8 mg) in 1,4-dioxane (0.6 mL) was stirred at 120° C. for 50 minutes using a microwave reaction apparatus. 4-Bromofuran-2(5H)-one (13 mg), sodium carbonate (8 mg), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7 mg) were added to the reaction mixture, followed by stirring at 120° C. for 30 minutes using a microwave reaction apparatus. After the reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)furan-2(5H)-one (20 mg).

MSm/z(M+H):510.

0045-2

A 4 mol/L hydrogen chloride/1,4-dioxane solution (0.4 mL) was added to a solution of 4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)furan-2(5H)-one (20 mg) in 1,4-dioxane (1.2 mL), followed by stirring at room temperature for 6 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added thereto, and the solid matter was collected by filtration, thereby obtaining 4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)furan-2(5H)-one hydrochloride (8.0 mg).

1 H-NMR(DMSO-d 6 )δ:9.16(1H,d,J=2.7 Hz),8.46(1H,d,J=2.7 Hz),8.36(1H,d,9.3 Hz),7.57(1H,d,J=9.3 Hz),7.14(1H,s),5.61(2H,s),3.54-3.44(1H,m),2.22-2.10(2H,m),1.94-1.66(6H,m).

MSm/z(M+H):380.

›Example 0046

0046-1

A mixture of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (27 mg), 2-(piperazin-1-yl)ethanol (0.013 mL), tris(dibenzylideneacetone)dipalladium(0) (5 mg), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (5 mg) and sodium tert-butoxide (20 mg) in 1,4-dioxane (1 mL) was stirred at 100° C. for 7 hours. After the reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 2-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)piperazin-1-yl)ethanol (10 mg).

MSm/z(M+H):556.

0046-2

12 mol/L hydrochloric acid (0.4 mL) was added to a solution of 2-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)piperazin-1-yl)ethanol (10 mg) in methanol (1.2 mL), followed by stirring at room temperature for 3 hours. The solvent was distilled off under reduced pressure, diisopropyl ether and water were added to the obtained residue, and the solvent was distilled off under reduced pressure. Chloroform, methanol, and ethyl acetate were added to the obtained residue. The solid matter was collected by filtration, thereby obtaining 2-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)piperazin-1-yl)ethanol hydrochloride (2.4 mg).

1 H-NMR(DMSO-d 6 )δ:8.76(1H,d,J=2.7 Hz),8.16(1H,d,J=8.7 Hz),7.49(1H,d,J=2.7 Hz),7.25(1H,d,J=8.7 Hz),4.23-4.15(2H,m),3.84-3.77(2H,m),3.66-3.52(3H,m),3.36-3.52(6H,m),2.22-2.10(2H,m),1.94-1.66(6H,m).

MSm/z(M+H):426.

›Example 0047

0047-1

A mixture of 2-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine (10 mg), 5-methyl-1,3,4-thiadiazole-2-thiol (17 mg) and potassium carbonate (23 mg) in dimethylsulfoxide (0.5 mL) was stirred at 50° C. for 4.5 hours, and stirred at 100° C. for 4.5 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed sequentially with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 2-methyl-5-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)thio)-1,3,4-thiadiazole (5.9 mg).

1 H-NMR(DMSO-d 6 )δ:9.31(1H,d,J=2.1 Hz),8.57(1H,s),8.52(1H,d,J=2.1 Hz),8.39(1H,d,J=8.4 Hz),8.26(1H,s),7.83(1H,d,J=8.4 Hz),3.93(3H,s),2.83(3H,s).

MSm/z(M+H):341.

Examples 0048 to 0052

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

HCL salt

1 H-NMR (DMSO-d 6 ) δ: 8.78 (1H, d, J = 2.7 Hz), 8.18 (1H, d, J = 9.3 Hz), 7.52 (1H, d, J = 2.7 Hz), 7.26 (1H, d, J = 9.3 Hz), 3.69-3.28 (9H, m), 2.22- 2.08 (2H, m), 2.08 (3H, s), 1.93-1.66 (6H. m). MS m/z (M + H): 424.

0049

0049-1

MS m/z (M + H): 595.

0049-2

HCL salt

1 H-NMR (DMSO-d 6 ) δ: 8.75 (1H, d, J = 2.7 Hz), 8.16 (1H, d, J = 9.3 Hz), 7.47 (1H, d, J = 2.7 Hz), 7.24 (1H, d, J = 9.3 Hz), 3.66-3.28 (7H, m), 2.88-2.83 (4H, m), 2.22-2.06 (2H, m), 1.93-1.66 (6H. m). MS m/z (M + H): 464.

0050

0050-1

MS m/z (M + H): 570.

0050-2

HCL salt

1 H-NMR (CD 3 OD) δ: 8.64 (1H, d, J = 2.7 Hz), 8.09 (1H, d, J = 9.3 Hz), 7.53 (1H, d, J = 2.7 Hz), 7.16 (1H, d, J = 9.3 Hz), 3.70-3.45 (8H, m), 2.81-2.74 (4H, m), 2.65-2.58 (2H, m), 2.30-2.18 (2H, m), 1.96-1.74 (8H, m). MS m/z (M + H): 440.

0051

0051-1

MS m/z (M + H): 527.

0051-2

HCL salt

1 H-NMR (DMSO-d 6 ) δ: 11.83 (1H, brs), 8.69 (1H, d, J = 2.7 Hz), 8.09 (1Hd, J = 8.4 Hz), 8.34 (1H, d, J = 2.7 Hz), 7.16 (1H, d, J = 8.4 Hz), 4.77 (1H, d, J = 4.5 Hz), 3.83-3.66 (4H, m), 3.54-3.33 (1H, m), 3.16-3.03 (1H, m), 2.20-2.08 (2H, m), 1.94-1.46 (10H, m). MS m/z (M + H): 397.

0052

0052-1

MS m/z (M + H): 526.

0052-2

HCL salt

1 H-NMR (DMSO-d 6 ) δ: 10.72 (1H, brs), 8.78 (1H, d, J = 2.7 Hz), 8.19 (1H, d, J = 9.0 Hz), 7.58 (1H, d, J = 2.7 Hz), 7.28 (1H, d, J = 9.0 Hz), 4.25- 4.16 (2H, m), 3.66-3.14 (7H, m), 2.86 (3H, s), 2.23-2.08 (2H, m), 1.92-1.64 (6H, m). MS m/z (M + H): 396.

›Example 0053

0053-1

A mixture of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (20 mg), 1-(methylsulfonyl)piperazine (15 mg), tris(dibenzylideneacetone)dipalladium(0) (6 mg), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (7 mg) and cesium carbonate (32 mg) in 1,4-dioxane (1 mL) was stirred at 100° C. for 19 hours. After the reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 5-cyclopentyl-N-(7-(4-(methylsulfonyl)piperazin-1-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (12 mg).

MSm/z(M+H):590.

0053-2

12 mol/L hydrochloric acid (0.4 mL) was added to a solution of 5-cyclopentyl-N-(7-(4-(methylsulfonyl)piperazin-1-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (12 mg) in methanol (1.2 mL), followed by stirring at room temperature for 14 hours. The solvent was distilled off under reduced pressure, diisopropyl ether and methanol were added to the obtained residue, and the solid matter was collected by filtration, thereby obtaining 5-cyclopentyl-N-(7-(4-(methylsulfonyl)piperazin-1-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine hydrochloride (10 mg).

1 H-NMR(DMSO-d 6 )δ:8.76(1H,d,J=2.7 Hz),8.15(1H,d,J=9.3 Hz),7.46(1H,d,J=2.7 Hz),7.23(1H,d,J=9.3 Hz),3.58-3.22(9H,m),2.96(3H,s),2.20-2.08(2H,m),1.94-1.64(6H,m).

MSm/z(M+H):460.

Examples 0054 to 0057

The following compounds were obtained in the same manner as in Examples 0053-1 and 0053-2.

HCL salt

1 H-NMR (DMSO-d 6 ) δ: 8.76 (1H, d, J = 2.7 Hz), 8.17 (1H, d, J = 8.7 Hz), 7.49 (1H, d, J = 2.7 Hz), 7.24 (1H, d, J = 8.7 Hz), 4.06 (2H, brs), 3.81-3.75 (2H, m), 3.57-3.44 (3H, m), 2.94 (3H, s), 2.21-2.08 (2H, m), 1.94-1.64 (6H, m). MS m/z (M + H): 410.

0055

0055-1

MS m/z (M + H): 612.

0055-2

HCL salt

1 H-NMR (DMSO-d 6 ) δ: 9.02 (1H. brs), 8.76 (1H, d, J = 2.7 Hz), 8.17 (1H, d, J = 8.4 Hz), 7.51 (1H. d. J = 2.7 Hz), 7.26 (1H, d, J = 8.4 Hz), 3.68-3.26 (9H, m), 2.21-2.08 (2H, m), 1.94- 1.64 (6H, m). MS m/z (M + H): 381.

0056

0056-1

MS m/z (M + H): 583.

0056-2

HCL salt

1 H-NMR (DMSO-d 6 ) δ: 8.76 (1H, d, J = 2.7 Hz), 8.17 (1H, d, J = 9.0 Hz), 7.52 (1H, d, J = 2.7 Hz), 7.25 (1H, d, J = 9.0 Hz), 4.10 (2H, q, J = 7.5 Hz), 3.95-3.20 (6H, m), 2.30- 1.58 (10H, m), 2.08 (3H, s), 1./21 (3H, t, J = 7.5 Hz). MS m/z (M + H): 453.

0057

0057-1

MS m/z (M + H): 583.

0057-2

HCL salt

1 H-NMR (DMSO-d 6 ) δ: 8.79 (1H, d, J = 2.7 Hz), 8.19 (1H, d, J = 8.4 Hz), 7.57 (1H, d, J = 2.7 Hz), 7.26 (1H, d, J = 8.4 Hz), 4.10 (2H, q, J = 7.5 Hz), 4.02-3.94 (2H, m), 3.64- 3.50 (1H, m), 3.12-3.00 (2H, m), 2.22- 1.64 (13H, m), 1.21 (3H, t, J = 7.5 Hz). MS m/z (M + H): 453.

›Example 0058

0058-1

After a solution of 2-hydroxyacetic acid (6 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15 mg), and 1-hydroxy-1H-benzotriazolemonohydrate (11 mg) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 15 minutes, 5-cyclopentyl-N-(7-(piperazin-1-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (10 mg) and triethylamine (0.037 mL) were added thereto, followed by stirring at room temperature for 2 days. Water was added to the reaction mixture, the solid matter was collected by filtration, thereby obtaining 1-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)piperazin-1-yl)-2-hydroxyethanone (5.7 mg).

1 H-NMR(CD 3 OD)δ:8.66(1H,d,2.7 Hz),8.10(1H,d,J=9.3 Hz),7.55(1H,d,2.7 Hz),7.18(1H,d,J=9.3 Hz),4.60(2H,brs),3.87-3.81(2H,m),3.70-3.64(2H,m),3.54-3.44(5H,m),2.32-2.18(2H,m),1.98-1.74(6H,m).

MSm/z(M+H):440.

›Example 0059

0059-1

After a solution of 2-dimethylaminoacetic acid (8 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15 mg), and 1-hydroxy-1H-benzotriazolemonohydrate (11 mg) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 15 minutes, 5-cyclopentyl-N-(7-(piperazin-1-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (10 mg) and triethylamine (0.037 mL) were added thereto, followed by stirring at room temperature for 2 days. Water was added to the reaction mixture, the solid matter was collected by filtration, thereby obtaining 1-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)piperazin-1-yl)-2-(dimethylamino)ethanone (3.7 mg).

1 H-NMR(CD 3 OD)δ:8.65(1H,brs),8.09(1H,d,J=8.7 Hz),7.53(1H,brs),7.16(1H,d,J=8.7 Hz),4.06(2H,s),3.86-3.78(4H,m),3.56-3.42(5H,m),2.35(6H,s),2.31-2.18(2H,m),1.98-1.72(6H,m).

MSm/z(M+H):467.

Examples 0060 to 0063

The following compounds were obtained in the same manner as in Examples 0053-1 and 0053-2.

HCL salt

1 H-NMR (CD 3 OD) δ: 8.53 (1H, d, J = 2.7 Hz), 8.17 (1H, d, J = 9.3 Hz), 7.26 (1H, d, J = 2.7 Hz), 7.19 (1H, d, J = 9.3 Hz), 4.31- 4.23 (1H, m), 3.30 (3H, s), 2.21-1.64 (17H, m). MS m/z (M + H): 411.

0063

0063-1

MS m/z (M + H): 568.

0063-2

HCL salt

1 H-NMR (DMSO-d 6 ) δ: 8.37 (1H, d, J = 2.7 Hz), 8.07 (1H, d, J = 8.4 Hz), 7.17 (1H, d, J = 2.7 Hz), 7.11 (1H, d, J = 8.4 Hz), 4.28- 4.17 (2H, m), 3.86-3.74 (4H, m), 2.99- 2.87 (2H, m), 2.22-1.64 (10H, m), 2.03 (3H, s). MS m/z (M + H): 438.

›Example 0064

0064-1

Iodomethane (0.078 mL) and 60% sodium hydride (50 mg) were added sequentially to a mixture solution of tert-butyl 3-oxo-1,4-diazepane-1-carboxylate (180 mg) in tetrahydrofuran (2 mL) and acetonitrile (2 mL) at room temperature, followed by stirring for 5 hours. Ethyl acetate and water were added sequentially to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining tert-butyl 4-methyl-3-oxo-1,4-diazepane-1-carboxylate (225 mg).

1 H-NMR(CDCl 3 )δ:3.62-3.53(4H,m),3.41(2H,t,J=4.8 Hz),3.01(3H,s),2.65(2H,t,J=5.4 Hz),1.47(9H,s).

0064-2

Water (0.4 mL) and trifluoroacetic acid (4 mL) were added sequentially to a solution of tert-butyl 4-methyl-3-oxo-1,4-diazepane-1-carboxylate (225 mg) in dichloromethane (4 mL) at room temperature, followed by stirring for 21 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane, NH silica), thereby obtaining 1-methyl-1,4-diazepan-2-one (85 mg).

1 H-NMR(CDCl 3 )δ:3.45-3.40(2H,m),3.00(3H,s),2.97-2.92(4H,m),2.69-2.64(2H,m).

0064-3

1-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)-4-methyl-1,4-diazepan-5-one was obtained in the same manner as in Example 0053-1.

MSm/z(M+H):554.

0064-4

1-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-4-methyl-1,4-diazepan-5-one hydrochloride was obtained in the same manner as in Example 0053-2.

1 H-NMR(DMSO-d 6 )δ:8.71(1H,2.4 Hz),8.15(1H,d,J=9.3 Hz),7.43(1H,d,J=2.4 Hz),7.20(1H,d,J=9.3 Hz),3.76-3.42(7H,m),2.80-2.71(2H,m),2.22-2.08(2H,m),2.89(3H,s),1.94-1.64(6H,m).

MSm/z(M+H):424.

Examples 0065 to 0081

The following compounds were obtained in the same manner as in Examples 0046-1 snd 0046-2.

HCL salt

1 H-NMR (DMSO-d 6 ) δ: 8.38-8.33 (1H, m), 8.08 (1H, d, J = 9.3 Hz), 7.15- 7.11 (1H, m), 7.13 (1H, d, J = 9.3 Hz), 3.68- 3.42 (6H, m), 2.22- 2.08 (2H, m), 1.97 (3H, s), 1.92-1.64 (8H, m). MS m/z (M + H): 424.

0066

0066-1

MS m/z (M + H): 605.

0066-2

HCL salt

1 H-NMR (DMSO-d 6 ) δ: 8.97 (1H, brs), 8.52 (1H, d, J = 2.7 Hz), 8.16 (1H, d, J = 9.3 Hz), 8.07 (1H, d, J = 2.7 Hz), 7.90 (1H, dd, J = 9.9, 2.7 Hz), 7.41 (1H, d, J = 2.7 Hz), 7.28 (1H, d, J = 9.9 Hz), 7.22 (1H, d, J = 9.3 Hz), 3.80- 3.68 (7H, m), 2.18-2.04 (2H, m), 1.88-1.62 (8H, m). MS m/z (M + H): 475.

0067

0067-1

MS m/z (M + H): 550.

0067-2

HCL salt

1 H-NMR (DMSO-d 6 ) δ: 8.75 (1H, brs), 8.49 (1H, d, 2.4 Hz), 8.16 (1H, d, J = 2.7 Hz), 8.11 (1H, d, J = 8.4 Hz), 7.73 (1H, dd, J = 8.7, 2.7 Hz), 7.32 (1H, d, 2.4 Hz), 7.17 (1H, d, J = 8.7 Hz), 6.93 (1H, d, J = 8.4 Hz), 3.87 (3H, s), 3.54- 3.42 (1H, m), 2.16-2.04 (2H, m), 1.88-1.60 (6H, m). MS m/z (M + H): 420.

0068

0068-1

MS m/z (M + H): 534.

0068-2

HCL salt

1 H-NMR (DMSO-d 6 ) δ: 8.67-8.63 (1H, m), 8.45 (1H, d, J = 2.4 Hz), 8.05 (1H, d, J = 8.7 Hz), 7.99-7.93 (1H, m), 7.63- 7.38 (2H, m), 7.08 (1H, d, J = 8.7 Hz), 7.02 (1H, d, J = 2.4 Hz), 3.54-3.42 (3H, m), 2.20- 2.06 (2H, m), 1.88-1.62 (6H, m). MS m/z (M + H): 404.

0069

0069-1

MS m/z (M + H): 596.

0069-2

HCL salt

1 H-NMR (DMSO-d 6 ) δ: 13.85 (1H, brs), 11.72 (1H, brs), 9.90 (1H, brs), 9.69 (1H, brs), 8.71-8.61 (2H, m), 8.35-8.17 (3H, m), 8.10-8.00 (2H, m), 7.58- 7.42 (3H, m), 4.31-4.23 (1H, m), 1.92- 1.58 (8H, m). MS m/z (M + H): 466.

0070

0070-1

MS m/z (M + H): 596.

0070-2

HCL salt

›Example 0082

0082-1

A mixture of 5-bromopyridin-3-ol (500 mg), 4-(2-bromoethyl)morpholine hydrochloride (641 mg) and potassium carbonate (1.18 g) in acetonitrile (6 mL) was stirred for 5 hours under heating to reflux. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, and the aqueous layer was extracted with chloroform. The organic layer and the extraction liquid were combined, the resultant product was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-(2-((5-bromopyridin-3-yl)oxy)ethyl)morpholine (0.75 g).

MSm/z(M+H):287,289.

0082-2

A 25% ammonia aqueous solution (2 mL) was added to a mixture of 4-(2-((5-bromopyridin-3-yl)oxy)ethyl)morpholine (0.75 g) and copper(I) oxide (205 mg) in N-methylpyrrolidone (2 mL), followed by stirring at 120° C. for 30 minutes using a microwave reaction apparatus. The insolubles were filtered off using celite, and chloroform was added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 5-(2-morpholinoethoxy)pyridine-3-amine (226 mg).

MSm/z(M+H):224.

0082-3 and 0082-4

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0083

0083-1

A mixture of 5-bromopyridin-3-ol (500 mg), 1-(2-bromoethyl)pyrrolidine hydrochloride (585 mg) and potassium carbonate (1.18 g) in acetonitrile (6 mL) was stirred for 5 hours under heating to reflux. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, and the aqueous layer was extracted with chloroform. The organic layer and the extraction liquid were combined, the resultant product was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-bromo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine (0.54 g).

MSm/z(M+H):271,273.

0083-2

A 25% ammonia aqueous solution (2 mL) was added to a mixture of 3-bromo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine (0.54 g), copper(I) oxide (205 mg), and N-methylpyrrolidone (2 mL), followed by stirring at 120° C. for 30 minutes using a microwave reaction apparatus. The insolubles were filtered off using celite, and dichloromethane was added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 5-(2-(pyrrolidin-1-yl)ethoxy)pyridine-3-amine (104 mg).

MSm/z(M+H):208.

0083-3 and 0083-4

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0084

0084-1

A mixture of 5-bromopyridin-3-ol (500 mg), 3-morpholinopropyl methanesulfonate (832 mg) and cesium carbonate (2.80 g) in acetonitrile (8 mL) and tetrahydrofuran (4 mL) was stirred for 1.5 hours under heating to reflux. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-(3-((5-bromopyridin-3-yl)oxy)propyl)morpholine (788 mg).

MSm/z(M+H):301,303.

0084-2

A 25% ammonia aqueous solution (2 mL) was added to a mixture of 4-(3-((5-bromopyridin-3-yl)oxy)propyl)morpholine (788 mg) and copper(I) oxide (186 mg) in N-methylpyrrolidone (2 mL), followed by stirring at 120° C. for 60 minutes using a microwave reaction apparatus. Dichloromethane and water were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 5-(3-morpholinopropoxy)pyridine-3-amine (297 mg).

MSm/z(M+H):238.

0084-3 and 0084-4

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0085

0085-1

Methanesulfonyl chloride (0.104 mL) was added to a solution of tert-butyl (6-(hydroxymethyl)pyridin-3-yl)carbamate (202 mg) and triethylamine (0.189 mL) in dichloromethane (9 mL) under ice-cooling, followed by stirring at the same temperature for 30 minutes. The reaction mixture was divided into two.

Morpholine (0.117 mL) was added to half the amount of the reaction mixture, followed by stirring at room temperature for 9 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining tert-butyl (6-(morpholinomethyl)pyridin-3-yl)carbamate (121 mg).

MSm/z(M+H):294.

0085-2

Water (0.1 mL) and trifluoroacetic acid (1 mL) were added to a solution of tert-butyl (6-(morpholinomethyl)pyridin-3-yl)carbamate (42 mg) in dichloromethane (1 mL), followed by stirring at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 6-(morpholinomethyl)pyridine-3-amine (20 mg).

MSm/z(M+H):194.

0085-3 and 0085-4

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0086

0086-1

Pyrrolidine (0.111 mL) was added to half the amount of the reaction mixture, followed by stirring at room temperature for 9 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining tert-butyl (6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)carbamate (94 mg).

MSm/z(M+H):278.

0086-2

Water (0.1 mL) and trifluoroacetic acid (1 mL) were added to a solution of tert-butyl (6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)carbamate (49 mg) in dichloromethane (1 mL), followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 6-(pyrrolidin-1-ylmethyl)pyridine-3-amine (15 mg).

MSm/z(M+H):178.

0086-3 and 0086-4

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0087

0087-1

A mixture of 5-bromopyridin-3-ol (500 mg), 1-(3-chloropropyl)pyrrolidine (1.0 g) and potassium carbonate (1.18 g) in acetonitrile (4 mL) and tetrahydrofuran (4 mL) was stirred for 5 hours under heating to reflux. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-bromo-5-(3-(pyrrolidin-1-yl)propoxy)pyridine (740 mg).

MSm/z(M+H):285,287.

0087-2

A 25% ammonia aqueous solution (2 mL) was added to a mixture of 3-bromo-5-(3-(pyrrolidin-1-yl)propoxy)pyridine (740 mg) and copper(I) oxide (185 mg) in N-methylpyrrolidone (2 mL), followed by stirring at 120° C. for 60 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and dichloromethane and water were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 5-(3-(pyrrolidin-1-yl)propoxy)pyridine-3-amine (139 mg).

MSm/z(M+H):222.

0087-3 and 0087-4

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

Examples 0088 and 0089

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0090

0090-1

A 25% ammonia aqueous solution (2 mL) was added to a mixture of 4-(5-bromopyridin-3-yl)morpholine (447 mg) and copper(I) oxide (130 mg) in N-methylpyrrolidone (2 mL), followed by stirring at 120° C. for 60 minutes using a microwave reaction apparatus. Dichloromethane and water were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 5-morpholinopyridine-3-amine (34 mg).

MSm/z(M+H):180.

0090-2 and 0090-3

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

Examples 0091 and 0092

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0093

0093-1

60% sodium hydride (189 mg) was added to a solution of 2-chloro-5-nitropyridine (500 mg) and tetrahydro-2H-pyran-4-ol (386 mg) in tetrahydrofuran (6 mL) under ice-cooling, followed by stirring at the same temperature for 1 hour. A 1 mol/L potassium hydrogen sulfate solution and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 5-nitro-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine (838 mg).

MSm/z(M+H):225.

0093-2

5-Nitro-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine (838 mg) and ammonium formate (1.98 g) were added to a mixture of 10% palladium-carbon (100 mg) in methanol (15 mL), followed by stirring at room temperature for 6 hours. The insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 6-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-3-amine (349 mg).

1 H-NMR(CDCl 3 )δ:7.63(1H,d,J=2.7 Hz),7.03(1H,dd,J=9.2 Hz,2.7 Hz),6.60(1H,d,J=9.0 Hz),5.13-5.03(1H,m),4.02-3.93(2H,m),3.64-3.54(2H,m),2.09-1.98(2H,m),1.81-1.68(2H,m).

0093-3 and 0093-4

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

Examples 0094 to 0096

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0097

0097-1

Dihydropyran (0.262 mL) and camphorsulfonic acid (505 mg) were added sequentially to a solution of 2-((5-bromopyridin-3-yl)oxy)ethanol (318 mg) in dichloromethane (7 mL) at room temperature, followed by stirring at the same temperature for 26 hours. A saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-bromo-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (779 mg).

MSm/z(M+H):302.

0097-2

A 25% ammonia aqueous solution (2 mL) was added to a mixture of 3-bromo-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (779 mg) and copper(I) oxide (103 mg) in N-methylpyrrolidone (2 mL), followed by stirring at 120° C. for 60 minutes using a microwave reaction apparatus. Dichloromethane and water were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine-3-amine (456 mg).

MSm/z(M+H):239.

0097-3 and 0097-4

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0098

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0099

0099-1

3-Isopropyl-5-nitropyridine (103 mg) and ammonium formate (390 mg) were added to a mixture of 10% palladium-carbon (20 mg) in methanol (6 mL), followed by stirring at room temperature for 1 day. The insolubles were filtered off using celite, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane), thereby obtaining 5-isopropylpyridine-3-amine (18 mg).

MSm/z(M+H):137.

0099-2 and 0099-3

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0100

0100-1

A 25% ammonia aqueous solution (2 mL) was added to a mixture of 3-bromo-5-isopropyloxypyridine (590 mg) and copper(I) oxide (195 mg) in N-methylpyrrolidone (2 mL), followed by stirring at 120° C. for 60 minutes using a microwave reaction apparatus. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 5-isopropyloxypyridine-3-amine (302 mg).

MSm/z(M+H):153.

0100-2 and 0100-3

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0101

0101-1

A 25% ammonia aqueous solution (2 mL) was added to a mixture of 3-bromo-5-(piperidin-1-yl)pyridine (119 mg), and copper(I) oxide (36 mg) in N-methylpyrrolidone (2 mL), followed by stirring at 120° C. for 60 minutes using a microwave reaction apparatus. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 5-(piperidin-1-yl)pyridine-3-amine (28 mg).

MSm/z(M+H):178.

0101-2 and 0101-3

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0102

0102-1

A 25% ammonia aqueous solution (1 mL) was added to a mixture of 1-(5-bromopyridin-3-yl)-4-methylpiperazine (28 mg), and copper(I) oxide (8 mg) in N-methylpyrrolidone (1 mL), followed by stirring at 120° C. for 2.5 hours using a microwave reaction apparatus. Dichloromethane and water were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 5-(4-methylpiperazin-1-yl)pyridine-3-amine (11 mg).

MSm/z(M+H):193.

0102-2 and 0102-3

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0103

0103-1

3,3-Dimethylbutanal (200 mg) was added to a solution of 1-methyl-3,5-dinitropyridin-2(1H)-one (200 mg) and ammonium acetate (790 mg) in methanol (18 mL) and 7 mol/L ammonia/methanol (2 mL), followed by stirring at 100° C. for 1 hour using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium hydrogen sulfate. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 3-(tert-butyl)-5-nitropyridine (72 mg).

1 H-NMR(CDCl 3 )δ:9.28(1H,d,J=2.7 Hz),8.96(1H,d,J=2.1 Hz),8.47-8.44(1H,m),1.43(9H,s).

0103-2

3-(tert-Butyl)-5-nitropyridine (72 mg) and ammonium formate (503 mg) were added to a mixture of 10% palladium-carbon (20 mg) in methanol (4 mL), followed by stirring at room temperature for 6 hours, and for 1.5 hours under heating to reflux. The insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane), thereby obtaining 5-(tert-butyl)pyridine-3-amine (48 mg).

MSm/z(M+H):151.

0103-3 and 0103-4

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

Examples 0104 to 0109

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0110

0110-1

A 4 mol/L sodium hydroxide aqueous solution (2 mL) was added to a solution of ethyl 3-ethyl-1-methyl-1H-pyrazole-4-carboxylate (100 mg) in ethanol (2 mL), followed by stirring at room temperature for 3 hours, and stirring at 70° C. for 2 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, the resultant product was adjusted to pH 2 by the addition of 2 mol/L hydrochloric acid, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, thereby obtaining 3-ethyl-1-methyl-1H-pyrazole-4-carboxylic acid (71 mg).

MSm/z(M+H):155.

0110-2

N-bromosuccinimide (90 mg) was added to a mixture of 3-ethyl-1-methyl-1H-pyrazole-4-carboxylic acid (71 mg), and sodium hydrogen carbonate (132 mg) in N,N-dimethylformamide (2.3 mL), followed by stirring at room temperature for 16 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-bromo-3-ethyl-1-methyl-1H-pyrazole (74 mg).

MSm/z(M+H):189.

0110-3

A mixture of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine) (20 mg), bis(pinacolato)diboron (15 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (3 mg), and potassium acetate (8 mg) in 1,4-dioxane (0.8 mL) was stirred at 100° C. for 2 hours in a nitrogen atmosphere. 4-Bromo-3-ethyl-1-methyl-1H-pyrazole (14 mg), sodium carbonate (8 mg), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5 mg) were added to the reaction mixture, followed by reacting at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 5-cyclopentyl-N-(7-(3-ethyl-1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (33 mg).

MSm/z(M+H):536.

0110-4

Water (0.1 mL) and trifluoroacetic acid (2 mL) were added to 5-cyclopentyl-N-(7-(3-ethyl-1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (33 mg), followed by stirring at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 5-cyclopentyl-N-(7-(3-ethyl-1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (10 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.78(1H,d,J=2.1 Hz),8.24(1H,d,J=9.0 Hz),8.18(1H,d,J=2.1 Hz),7.70(1H,s),7.36(1H,d,J=9.0 Hz),3.54-3.42(1H,m),3.37(3H,s),2.89(2H,q,7.8 Hz),2.30-2.18(2H,m),1.94-1.72(6H,m). 1.31(3H,t,J=7.8 Hz).

MSm/z(M+H):406.

›Example 0111

The following compounds were obtained in the same manner as in Examples 0110-3 and 0110-4.

›Example 0112

0112-1 and 0112-2

The following compounds were obtained in the same manner as in Examples 0110-1 and 0110-2.

0112-3 and 0112-4

The following compounds were obtained in the same manner as in Examples 0110-3 and 0110-4.

›Example 0113

The following compounds were obtained in the same manner as in Examples 0110-3 and 0110-4.

›Example 0114

The following compounds were obtained in the same manner as in Examples 0110-1 to 0110-4.

›Example 0115

0115-1

A solution of methylhydrazine (0.37 mL) and ethyl formate (0.90 mL) in ethanol (3.5 mL) was stirred for 4 hours under heating to reflux, and ethyl 3-oxoheptanoate (2.4 mL) was added thereto, followed by stirring at the same temperature for 4 hours. The reaction mixture was cooled to room temperature, and a 20% sodium ethoxide-ethanol solution (3.5 mL) was added thereto, followed by stirring for 1.5 hours under heating to reflux. The reaction mixture was cooled to room temperature, and ethyl acetate and a 3 mol/L potassium hydrogen sulfate aqueous solution were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining ethyl 3-butyl-1-methyl-1H-pyrazole-4-carboxylate (669 mg).

MSm/z(M+H):211.

0115-2 to 0115-5

The following compounds were obtained in the same manner as in Examples 0110-1 to 0110-4.

›Example 0116

0116-1

A solution of (9H-fluoren-9-ylmethoxy)carbonyl chloride (826 mg) in 1,4-dioxane (4 mL) was added to a mixture of 2-(diethoxymethyl)pyrimidine-5-amine (629 mg), and sodium hydrogen carbonate (800 mg) in 1,4-dioxane (4 mL), and water (4 mL) at room temperature, followed by stirring at the same temperature for 3 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 9H-fluoren-9-yl)methyl (2-(diethoxymethyl)pyrimidin-5-yl)carbamate (810 mg).

MSm/z(M+H):420.

0116-2

1 mol/L hydrochloric acid was added to a solution of (9H-fluoren-9-yl)methyl (2-(diethoxymethyl)pyrimidin-5-yl)carbamate (810 mg) in acetone (2.4 mL), followed by stirring at room temperature for 2 hours, and (+)-10-camphorsulfonic acid (66 mg) was added thereto, followed by stirring at the same temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining (9H-fluoren-9-yl)methyl (2-formylpyrimidin-5-yl)carbamate (99 mg).

MSm/z(M+H):346.

0116-3

Morpholine (0.037 mL), sodium triacetoxyborohydride (150 mg), and acetic acid (0.024 mL) were added to a solution of (9H-fluoren-9-yl)methyl (2-formylpyrimidin-5-yl)carbamate (99 mg) in dichloromethane (2.8 mL), followed by stirring at room temperature for 1 hour. Ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining (9H-fluoren-9-yl)methyl (2-(morpholinomethyl)pyrimidin-5-yl)carbamate (89 mg).

MSm/z(M+H):417.

0116-4

Diethylamine (1 mL) was added to a solution of (9H-fluoren-9-yl)methyl (2-(morpholinomethyl)pyrimidin-5-yl)carbamate (89 mg) in dichloromethane (2 mL), followed by stirring at room temperature for 14 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 2-(morpholinomethyl)pyrimidine-5-amine (30 mg).

MSm/z(M+H):195.

0116-5 and 0116-6

The following compounds were obtained in the same manner as in Examples 0046-1 and 0046-2.

›Example 0117

0117-1

A mixture of 4-(3-chloropropyl)morpholine (648 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg), cesium carbonate (837 mg), and sodium iodide (77 mg) in acetonitrile (3 mL) and tetrahydrofuran (1 mL) was stirred at 80° C. for 18 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)morpholine (485 mg).

1 H-NMR(CDCl 3 )δ:7.78(1H,s),7.68(1H,s),4.19(2H,t,J=6.6 Hz),3.76-3.66(4H,m),3.70(2H,t,J=4.8 Hz),2.45-2.35(4H,m),2.10-1.98(2H,m),1.31(12H,s).

0117-2 and 0117-3

The following compounds were obtained in the same manner as in Examples 0001-4 and 0001-5.

Examples 0118 and 0119

The following compounds were obtained in the same manner as in Example 0001-5.

›Example 0120

0120-1

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (2.01 g), 5-isopropyl-1,3,4-thiadiazole-2-amine (1.18 g), and potassium carbonate (1.71 g) in dimethylsulfoxide (16 mL) was stirred at 130° C. for 2 hours. After the obtained reaction mixture was cooled to room temperature, the solid matter was collected by filtration, thereby obtaining N-(7-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-1,3,4-thiadiazole-2-amine (2.21 g).

MSm/z(M+H):351.

0120-2

(2-(Trimethylsilyl)ethoxy)methyl chloride (1.66 mL) was added to a solution of N-(7-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-1,3,4-thiadiazole-2-amine (2.21 g) in N-methylpyrrolidone (60 mL), followed by stirring for 15 minutes under ice-cooling, and 60% sodium hydride (505 mg) was added thereto, followed by stirring at the same temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed sequentially with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining N-(7-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (1.71 g).

MSm/z(M+H):480.

0120-3 and 0120-4

The following compounds were obtained in the same manner as in Examples 0110-3 and 0110-4.

Examples 0121 and 0122

The following compounds were obtained in the same manner as in Examples 0110-3 and 0110-4.

›Example 0123

0123-1

A mixture of 2-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine (14 mg), 5-isopropylthiazole-2-amine (10 mg), tris (dibenzylideneacetone)dipalladium(0) (5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7 mg), and cesium carbonate (48 mg) in 1,4-dioxane (1 mL) was stirred at 150° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 5-isopropyl-N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)thiazole-2-amine (3.8 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.85(1H,brs),8.29(1H,brs),8.14(1H,d,J=8.7 Hz),8.00(1H,s),7.98(1H,s),7.26(1H,d,J=8.7 Hz),7.08(1H,s),3.36(3H,s),3.25-3.15(1H,m),1.42(6H,d,J=6.6 Hz).

MSm/z(M+H):351.

›Example 0124

0124-1

60% sodium hydride (516 mg) was added to a solution of 4-bromo-3-phenyl-1H-pyrazole (1.44 g) and iodomethane (0.80 mL) in N-methylpyrrolidone (13 mL) under ice-cooling, followed by stirring at the same temperature for 1.5 hours. Ethyl acetate and water were added to the reaction mixture at the same temperature. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-bromo-1-methyl-3-phenyl-1H-pyrazole (811 mg).

MSm/z(M+H):237,239.

0124-2

A 1.6 mol/L n-butyllithium-hexane solution (1.2 mL) was added to a solution of 4-bromo-1-methyl-3-phenyl-1H-pyrazole (300 mg) in tetrahydrofuran (6 mL) at −80° C., followed by stirring at the same temperature for 30 minutes, and 2-isopropyloxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (470 mg) was added thereto at the same temperature, followed by stirring while heating to room temperature over a period of 4 hours. A saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (184 mg).

MSm/z(M+H):285.

0124-3

A mixture of N-(7-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (20 mg), 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15 mg), sodium carbonate (8 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (5 mg), and water (0.1 mL) in 1,4-dioxane (1 mL) was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane), thereby obtaining 5-isopropyl-N-(7-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (11 mg).

MSm/z(M+H):558.

0124-4

Water (0.1 mL) and trifluoroacetic acid (2 mL) were added to 5-isopropyl-N-(7-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (11 mg), followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 5-isopropyl-N-(7-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (5.2 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.59(1H,brs),8.18(1H,d,J=8.7 Hz),8.13(1H,brs),7.84(1H,s),7.56-7.24(6H,m),3.47-3.34(1H,m),3.36(3H,s),1.48(6H,d,J=7.2 Hz).

MSm/z(M+H):428.

›Example 0125

The following compounds were obtained in the same manner as in Examples 0110-1 to 0110-4.

›Example 0126

0126-1

A 6% sodium hypochlorite aqueous solution (7 mL) was added to a mixture of 2-cyclopentylethanol (1.4 g), sodium hydrogen carbonate (3.1 g), and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl free radical (19 mg) in toluene (20 mL), ethyl acetate (20 mL) and water (3.5 mL) under ice-cooling, followed by stirring at the same temperature for 10 minutes. A 3 mol/L potassium hydrogen sulfate aqueous solution (10 mL), potassium iodide (120 mg), and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 2-cyclopentyl acetaldehyde (2.5 g).

1 H-NMR(CDCl 3 )δ:9.75(1H,t,J=1.8 Hz),2.44(2H,dd,J=7.2 Hz,1.8 Hz),2.34-2.19(1H,m),1.92-1.46(6H,m),1.22-1.05(2H,m).

0126-2

Trimethylphenylammonium tribromide (4.7 g) was added to a solution of 2-cyclopentyl acetaldehyde (2.5 g) in tetrahydrofuran (60 mL) under ice-cooling, followed by stirring while slowly heating to room temperature for 1 day. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed sequentially with a 10% sodium hydrogen sulfite aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 2-bromo-2-cyclopentyl acetaldehyde (2.4 g).

1 H-NMR(CDCl 3 ):9.39(1H,d,J=3.9 Hz),3.73-3.64(1H,m),2.03-1.46(7H,m),1.22-1.05(2H,m).

0126-3

Thiourea (936 mg) was added to a solution of 2-bromo-2-cyclopentyl acetaldehyde (2.4 g) in ethanol (12 mL), followed by stirring for 4 hours under heating to reflux. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed sequentially with a 4 mol/L sodium hydroxide aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 5-cyclopentylthiazole-2-amine (412 mg).

MSm/z(M+H):169.

0126-4

5-cyclopentyl-N-(7-(1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)thiazole-2-amine was obtained in the same manner as in Example 0001-5.

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.86(1H,brs),8.28(1H,brs),8.14(1H,d,J=9.0 Hz),8.04(1H,s),8.01(1H,s),7.25(1H,d,J=9.0 Hz),7.09(1H,s),4.33-4.25(2H,m),3.30-3.19(1H,m),2.61-2.46(6H,m),2.24-2.11(4H,m),1.94-1.67(10H,m).

MSm/z(M+H):474.

Examples 0127 and 0128

The following compounds were obtained in the same manner as in Example 0015-4.

›Example 0129

0129-1

A mixture of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (10 mg), 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8 mg), sodium carbonate (5 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2 mg), and water (0.07 mL) in 1,4-dioxane (0.7 mL) was stirred at 100° C. for 6 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 5-cyclopentyl-N-(7-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (4.7 mg).

MSm/z(M+H):584.

0129-2

Water (0.1 mL) and trifluoroacetic acid (2 mL) were added to 5-cyclopentyl-N-(7-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (4.7 mg), followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 5-cyclopentyl-N-(7-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (2.6 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.59(1H,brs),8.18(1H,d,J=8.7 Hz),8.13(1H,brs),7.84(1H,s),7.56-7.24(6H,m),3.56-3.3.43(1H,m),3.36(3H,s),2.32-2.20(2H,m),1.96-1.74(6H,m).

MSm/z(M+H):454.

Examples 0130 and 0131

The following compounds were obtained in the same manner as in Examples 0110-3 and 0110-4.

›Example 0132

0132-1

A solution of methylhydrazine (0.18 mL) and ethyl formate (0.45 mL) in ethanol (2 mL) was stirred for 4 hours under heating to reflux, and ethyl 3-cyclopropyl-3-oxopropanoate (1.0 g) was added thereto, followed by stirring at the same temperature for 4 hours. The reaction mixture was cooled to room temperature, and a 20% sodium ethoxide-ethanol solution (2 mL) was added thereto, followed by stirring for 1.5 hours under heating to reflux. The reaction mixture was cooled to room temperature, and ethyl acetate and a 3 mol/L potassium hydrogen sulfate aqueous solution were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining ethyl 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylate (167 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1):7.74(1H,s),4.29(2H,q,J=6.6 Hz),3.79(3H,s),2.56-2.46(1H,m),1.34(3H,t,J=6.6 Hz),1.00-0.87(4H,m).

0132-2 to 0132-5

The following compounds were obtained in the same manner as in Examples 0110-1 to 0110-4.

›Example 0133

The following compounds were obtained in the same manner as in Examples 0110-3 and 0110-4.

›Example 0134

0134-1

60% sodium hydride (412 mg) was added to a solution of 3-(4-bromo-1H-pyrazol-3-yl)pyridine (1.90 g) in N-methylpyrrolidone (7 mL) under ice-cooling, followed by stirring at the same temperature for 10 minutes, and iodomethane (0.64 mL) was added thereto, followed by stirring at the same temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyridine (284 mg).

MSm/z(M+H):238,240.

0134-2 and 0134-3

The following compounds were obtained in the same manner as in Examples 0110-3 and 0110-4.

›Example 0135

0135-1

60% sodium hydride (412 mg) was added to a solution of 4-(4-bromo-1H-pyrazol-3-yl)pyridine (2.77 g) in N-methylpyrrolidone (7 mL) under ice-cooling, followed by stirring at the same temperature for 10 minutes, and iodomethane (0.64 mL) was added thereto, followed by stirring at the same temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyridine (177 mg).

MSm/z(M+H):238,240.

0135-2 and 0135-3

The following compounds were obtained in the same manner as in Examples 0110-3 and 0110-4.

›Example 0136

0136-1

60% sodium hydride (412 mg) was added to a solution of 2-(4-bromo-1H-pyrazol-3-yl)pyridine (1.59 g) in N-methylpyrrolidone (7 mL) under ice-cooling, followed by stirring at the same temperature for 10 minutes, and iodomethane (0.64 mL) was added thereto, followed by stirring at the same temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 2-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyridine (770 mg).

MSm/z(M+H):238,240.

0136-2

A 1.6 mol/L n-butyllithium-hexane solution (1.45 mL) was added to a solution of 2-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyridine (370 mg) in tetrahydrofuran (8 mL) at −80° C., followed by stirring at the same temperature for 30 minutes, and 2-isopropyloxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (576 mg) was added thereto at the same temperature, followed by stirring while slowly heating to room temperature over a period of 2.5 hours. A saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl)pyridine (20 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1):8.54-8.51(1H,m),8.34-8.23(1H,m),7.84-7.78(1H,m),7.79(1H,s),7.30-7.25(1H,m),3.97(3H,s),1.56(12H,s).

0136-3

A mixture of N-(7-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (20 mg), 2-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl)pyridine (15 mg), sodium carbonate (8 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (5 mg), and water (0.1 mL) in 1,4-dioxane (1 mL) was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane), thereby obtaining 5-isopropyl-N-(7-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (12 mg).

MSm/z(M+H):559.

0136-4

Water (0.1 mL) and trifluoroacetic acid (2 mL) were added to 5-isopropyl-N-(7-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (12 mg), followed by stirring at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 5-isopropyl-N-(7-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (6.4 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.67(1H,brs),8.54(1H,d,J=3.9 Hz),8.24(1H,brs),8.21(1H,d,J=8.7 Hz),7.85(1H,s),7.82-7.69(2H,m),7.35-7.27(1H,m),7.33(1H,d,J=8.7 Hz),3.47-3.36(1H,m),3.37(3H,s),1.47(6H,d,J=6.6 Hz).

MSm/z(M+H):429.

›Example 0137

0137-1

N-(pyridazin-3-yl)-7-(1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine was obtained in the same manner as in Example 0001-5.

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:9.12(1H,d,J=9.0 Hz),8.89(1H,s),8.81(1H,d,J=1.8 Hz),8.22(1H,s),8.21(1H,d,J=9.0 Hz),8.02(1H,s),7.98(1H,s),7.61(1H,dd,J=9.0 Hz,1.8 Hz),7.47(1H,d,J=9.0 Hz),4.33-4.25(2H,m),2.61-2.46(6H,m),2.23-2.15(2H,m),1.86-1.77(4H,m).

MSm/z(M+H):401.

›Example 0138

0138-1

A solution of methylhydrazine (0.29 mL) and ethyl formate (0.65 mL) in ethanol (3 mL) was stirred for 4 hours under heating to reflux, and ethyl 5-methyl-3-oxohexanoate (1.91 g) was added thereto, followed by stirring at the same temperature for 4 hours. The reaction mixture was cooled to room temperature, and a 20% sodium ethoxide-ethanol solution (3 mL) was added thereto, followed by stirring for 1.5 hours under heating to reflux. The reaction mixture was cooled to room temperature, and ethyl acetate and a 3 mol/L potassium hydrogen sulfate aqueous solution were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining ethyl 3-isobutyl-1-methyl-1H-pyrazole-4-carboxylate (280 mg).

MSm/z(M+H):211.

0138-2 to 0138-5

The following compounds were obtained in the same manner as in Examples 0110-1 to 0110-4.

›Example 0139 to 0141

The following compounds were obtained in the same manner as in Example 0015-4.

›Example 0142

0142-1

2,2′-Azobis(isobutyronitrile) (27 mg) was added to a solution of 4-bromo-1,3-dimethyl-1H-pyrazole (286 mg) and N-bromosuccinimide (320 mg) in chlorobenzene (6 mL), followed by stirring at 80° C. for 7 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole (465 mg) as a white solid.

MSm/z(M+H):253.

0142-2

A 28% sodium methoxide-methanol solution (2 mL) was added to a solution of 4-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole (84 mg) in methanol (2 mL), followed by stirring at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-bromo-3-(methoxymethyl)-1-methyl-1H-pyrazole (42 mg).

MSm/z(M+H):205.

0142-3 and 0142-4

The following compounds were obtained in the same manner as in Examples 0110-3 and 0110-4

›Example 0143

0143-1

Tetrapropylammonium perruthenate (171 mg) was added to a mixture of 4-methylpentan-1-ol (1.0 g), molecular sieve 4A (1.0 g), and N-methylmorpholine-N-oxide (1.26 g) in dichloromethane (30 mL) under ice-cooling, followed by stirring at the same temperature for 5 minutes. The reaction mixture was purified by silica gel column chromatography (dichloromethane), thereby obtaining 4-methylpentanal (2.79 g).

1 H-NMR(CDCl 3 )δ:9.77(1H,t,J=2.1 Hz),2.43(2H,td,J=5.1 Hz,2.1 Hz),1.66-1.48(1H,m),1.28-1.18(2H,m),0.91(6H,d,J=6.0 Hz).

0143-2

Trimethylphenylammonium tribromide (4.0 g) was added to a solution of 4-methylpentanal (2.79 g) in tetrahydrofuran (30 mL) under ice-cooling, followed by stirring while slowly heating to room temperature for 1 day. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed sequentially with a 10% sodium hydrogen sulfite aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 2-bromo-4-methylpentanal (2.84 g).

1 H-NMR(CDCl 3 )δ:9.13(1H,s),3.46(1H,t,J=6.6 Hz),1.80-1.46(3H,m),1.04(6H,d,J=6.6 Hz).

0143-3

Thiourea (744 mg) was added to a solution of 2-bromo-4-methylpentanal (2.84 g) in ethanol (10 mL), followed by stirring for 3 hours under heating to reflux. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed sequentially with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 5-isobutylthiazole-2-amine (449 mg).

MSm/z(M+H):157.

0143-4

5-isobutyl-N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)thiazole-2-amine was obtained in the same manner as in Example 0015-4.

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.85(1H,brs),8.26(1H,brs),8.15(1H,d,J=9.0 Hz),7.99(1H,s),7.93(1H,s),7.24(1H,d,J=9.0 Hz),7.07(1H,s),4.02(3H,s),2.68(2H,d,J=7.5 Hz),2.02-1.90(1H,m),1.01(6H,d,J=6.36 Hz).

MSm/z(M+H):365.

Examples 0144 and 0145

The following compounds were obtained in the same manner as in Example 0015-4.

›Example 0146

0146-1

60% sodium hydride (23 mg) was added to a mixture solution of 4-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole (72 mg) in 1,4-dioxane (0.5 mL) and 2-propanol (0.5 mL), followed by stirring at 120° C. for 5 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed sequentially with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-bromo-3-(isopropyloxymethyl)-1-methyl-1H-pyrazole (57 mg).

1 H-NMR(CDCl 3 )δ:7.34(1H,s),4.46(2H,s),3.85(3H,s),3.78-3.68(1H,m),1.22(6H,d,J=6.6 Hz).

0146-2 and 0146-3

The following compounds were obtained in the same manner as in Examples 0110-3 and 0110-4.

›Example 0147 · 1 of 2

0147-1

After a mixture of ethyl 3-amino-1H-pyrazole-4-carboxylate (2.00 g), trioctylmethylammonium chloride (0.31 mg), and potassium carbonate (3.25 g) in toluene (25 mL) was stirred for 15 minutes under heating to reflux, 3-bromopropanol (1.45 mL) was added to the mixture, followed by stirring at the same temperature for 7 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed sequentially with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining ethyl 3-amino-1-(3-hydroxypropyl)-1H-pyrazole-4-carboxylate (3.01 g).

MSm/z(M+H):214.

0147-2

tert-Butyl nitrite (2.12 mL) was added to a mixture of copper(II) bromide (3.71 g) in acetonitrile (30 mL) under ice-cooling, followed by stirring at the same temperature for 5 minutes, and ethyl 3-amino-1-(3-hydroxypropyl)-1H-pyrazole-4-carboxylate (3.01 g) was added thereto, followed by stirring at room temperature for 5 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed sequentially with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining ethyl 3-bromo-1-(3-hydroxypropyl)-1H-pyrazole-4-carboxylate (1.58 g).

MSm/z(M+H):277.

0147-3

A mixture of ethyl 3-bromo-1-(3-hydroxypropyl)-1H-pyrazole-4-carboxylate (383 mg), (E)-4,4,5,5-tetramethyl-2-(prop-1-en-1-yl)-1,3,2-dioxaborolane (278 mg), sodium carbonate (366 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (97 mg), and water (1 mL) in 1,4-dioxane (10 mL) was stirred for 2 hours under heating to reflux. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining (E)-ethyl 1-(3-hydroxypropyl)-3-(prop-1-en-1-yl)-1H-pyrazole-4-carboxylate (236 mg).

MSm/z(M+H):239.

0147-4

(E)-ethyl 1-(3-hydroxypropyl)-3-(prop-1-en-1-yl)-1H-pyrazole-4-carboxylate (236 mg) was added to a mixture of 10% palladium-carbon (50 mg) in methanol (10 mL), followed by stirring for 1.5 hours in a hydrogen atmosphere. The insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure, thereby obtaining ethyl 1-(3-hydroxypropyl)-3-propyl-1H-pyrazole-4-carboxylate (206 mg).

MSm/z(M+H):241.

0147-5

A 4 mol/L sodium hydroxide aqueous solution (2 mL) was added to a solution of ethyl 1-(3-hydroxypropyl)-3-propyl-1H-pyrazole-4-carboxylate (206 mg) in ethanol (2 mL), followed by stirring at 70° C. for 1 hour. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, the resultant product was adjusted to pH 2 by the addition of a 3 mol/L potassium hydrogen sulfate aqueous solution, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 1-(3-hydroxypropyl)-3-propyl-1H-pyrazole-4-carboxylic acid (171 mg).

MSm/z(M+H):213.

0147-6

N-bromosuccinimide (158 mg) was added to a mixture of 1-(3-hydroxypropyl)-3-propyl-1H-pyrazole-4-carboxylic acid (206 mg), and sodium hydrogen carbonate (291 mg) in N,N-dimethylformamide (4 mL), followed by stirring at room temperature for 2.5 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(4-bromo-3-propyl-1H-pyrazol-1-yl)propan-1-ol (146 mg).

1 H-NMR(CDCl 3 )δ:7.34(1H,s),4.20(2H,t,J=6.6 Hz),2.56(2H,t,J=6.6 Hz),3.67-3.56(2H,m),2.06-1.96(2H,m),1.75-1.61(2H,m),0.95(3H,t,J=7.2 Hz).

0147-7

Methanesulfonyl chloride (0.043 mL) was added to a solution of 3-(4-bromo-3-propyl-1H-pyrazol-1-yl)propan-1-ol (90 mg) and triethylamine (0.10 mL) in dichloromethane (3 mL) under ice-cooling, followed by stirring at the same temperature for 30 minutes. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(4-bromo-3-propyl-1H-pyrazol-1-yl)propyl methanesulfonate (136 mg).

1 H-NMR(CDCl 3 )δ:7.35(1H,s),4.27-4.08(4H,m),3.03(3H,s),2.56(2H,t,J=7.2 Hz),2.34-2.23(2H,m),1.74-1.59(2H,m),0.95(3H,t,J=7.2 Hz).

0147-8

Pyrrolidine (0.037 mL) was added to a mixture of 3-(4-bromo-3-propyl-1H-pyrazol-1-yl)propyl methanesulfonate (136 mg), and potassium carbonate (127 mg) in acetonitrile (2 mL), followed by stirring at 50° C. for 10 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-bromo-3-propyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazole (63 mg).

1 H-NMR(CDCl 3 )δ:7.33(1H,s),4.10(2H,t,J=6.6 Hz),2.56(2H,t,J=7.2 Hz),2.50-2.43(4H,m),2.40(2H,t,J=7.5 Hz),2.06-1.96(2H,m),1.82-1.73(4H,m),1.72-1.60(2H,m),0.95(3H,t,J=7.2 Hz).

0147-9 and 0147-10

The following compounds were obtained in the same manner as in Examples 0110-3 and 0110-4.

›Example 0147 · 2 of 2

Examples 0148 and 0149

The following compounds were obtained in the same manner as in Example 0001-5.

›Example 0150

The following compounds were obtained in the same manner as in Examples 0110-1 to 0110-4.

Examples 0151 and 0152

The following compounds were obtained in the same manner as in Example 0001-5.

›Example 0153

The following compounds were obtained in the same manner as in Examples 0001-4 and 0001-5.

›Example 0154

The following compounds were obtained in the same manner as in Example 0001-5.

›Example 0155

0155-1

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (50 mg), 5-methoxypyridine-3-amine (25 mg), tris(dibenzylideneacetone)dipalladium(0) (19 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (24 mg), and cesium carbonate (33 mg) in 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining N 2 ,N 7 -bis(5-methoxypyridin-3-yl)-1,5-naphthyridine-2,7-diamine (15 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.44(1H,d,J=2.7 Hz),8.37(2H,brs),8.07(1H,d,J=2.7 Hz),7.99(1H,d,J=9.0 Hz),7.88(2H,brs),7.21(2H,brs),7.02(1H,d,J=9.0 Hz),3.91(3H,s),3.89(3H,s).

MSm/z(M+H):375.

›Example 0156 · 1 of 2

0156-1

A solution of ((3-bromopropyloxy)methyl)benzene (5.0 g) in ethanol (5 mL) was added to hydrazine monohydrate (6.4 mL) at 65° C., followed by stirring at the same temperature for 1 hour. The reaction mixture was cooled to room temperature, and filtered through DOWEX MONOSPHERE 550A (OH) (product name, manufactured by Wako Pure Chemical Industries, Ltd.). The solvent was distilled off under reduced pressure, thereby obtaining (3-(benzyloxy)propyl)hydrazine (3.7 g).

MSm/z(M+H):181.

0156-2

Ethyl 3-oxobutanoate (0.254 mL) was added to a solution of (3-(benzyloxy)propyl)hydrazine (500 mg) in ethanol (5 mL), followed by stirring for 3 hours under heating to reflux. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 1-(3-(benzyloxy)propyl)-3-methyl-1H-pyrazol-5(4H)-one (261 mg).

MSm/z(M+H):247.

0156-3

Trifluoromethanesulfonic acid anhydride (0.260 mL) was added to a solution of 1-(3-(benzyloxy)propyl)-3-methyl-1H-pyrazol-5(4H)-one (261 mg) and pyridine (0.154 mL) in dichloromethane (10 mL) under ice-cooling, followed by stirring at the same temperature for 30 minutes. A saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane), thereby obtaining (1-(3-(benzyloxy)propyl)-3-methyl-1H-pyrazol-5-yl) trifluoromethanesulfonate (237 mg).

MSm/z(M+H):379.

0156-4

(1-(3-(Benzyloxy)propyl)-3-methyl-1H-pyrazol-5-yl) trifluoromethanesulfonate (237 mg) was added to a mixture of 20%-palladium hydroxide-carbon (50 mg) in methanol (10 mL), followed by stirring for 5 hours in a hydrogen atmosphere. The insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(3-methyl-1H-pyrazol-1-yl)propan-1-ol (177 mg).

1 H-NMR(CDCl 3 )δ:7.73(1H,d,J=2.7 Hz),6.40(1H,d,J=2.7 Hz),4.58(2H,t,J=6.6 Hz),3.73(2H,5.1 Hz),2.52(3H,s),2.26-2.15(2H,m).

0156-5

Iodine (95 mg) and ammonium cerium nitrate (206 mg) were added to a solution of 3-(3-methyl-1H-pyrazol-1-yl)propan-1-ol (177 mg) in acetonitrile (6 mL), followed by stirring at room temperature for 9 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed sequentially with a 10% sodium hydrogen sulfite aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(4-iodo-3-methyl-1H-pyrazol-1-yl)propan-1-ol (134 mg).

MSm/z(M+H):267.

0156-6

Methanesulfonyl chloride (0.059 mL) was added to a solution of 3-(4-iodo-3-methyl-1H-pyrazol-1-yl)propan-1-ol (134 mg) and triethylamine (0.14 mL) in dichloromethane (5 mL) under ice-cooling, followed by stirring at the same temperature for 30 minutes. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(4-iodo-3-methyl-1H-pyrazol-1-yl)propyl methanesulfonate (165 mg).

MSm/z(M+H):345.

0156-7

Pyrrolidine (0.048 mL) was added to a mixture of 3-(4-iodo-3-methyl-1H-pyrazol-1-yl)propyl methanesulfonate (165 mg), and potassium carbonate (100 mg) in acetonitrile (2.4 mL), followed by stirring at 50° C. for 10 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-iodo-3-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazole (73 mg).

MSm/z(M+H):320.

0156-8

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (56 mg), bis(pinacolato)diboron (87 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (19 mg), and potassium acetate (45 mg) in 1,4-dioxane (2 mL) was stirred at 100° C. for 2 hours in a nitrogen atmosphere. 4-Iodo-3-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazole (73 mg), sodium carbonate (49 mg), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (16 mg) were added to the reaction mixture, followed by stirring at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 2-chloro-7-(3-methyl-1-(3-(pyrrolidin-1-yl)-1H-pyrazol-4-yl)-1,5-naphthyridine (13 mg).

MSm/z(M+H):356.

0156-9

A mixture of 2-chloro-7-(3-methyl-1-(3-(pyrrolidin-1-yl)-1H-pyrazol-4-yl)-1,5-naphthyridine (13 mg), 5-isopropylpyridazine-3-amine (8 mg), tris(dibenzylideneacetone)dipalladium(0) (4 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5 mg), and cesium carbonate (30 mg) in 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining N-(5-isopropylpyridazin-3-yl)-7-(3-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine (4.4 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.92(1H,brs),8.79(1H,d,J=1.8 Hz),8.72(1H,brs),8.22(1H,d,J=9.0 Hz),8.10(1H,d,J=1.8 Hz),7.81(1H,s),7.52(1H,d,J=9.0 Hz),4.25-4.18(2H,m),3.38-3.35(2H,m),3.10-2.99(1H,m),2.61-2.49(4H,m),2.50(3H,s),2.20-2.07(2H,m),1.89-1.79(4H,m),1.40(6H,d,J=6.6 Hz).

›Example 0156 · 2 of 2

MSm/z(M+H):457.

›Example 0157

0157-1

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (50 mg), 5-methoxypyridine-3-amine (25 mg), tris(dibenzylideneacetone)dipalladium(0) (19 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (24 mg), and cesium carbonate (33 mg) in 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 6-chloro-N-(5-methoxypyridin-3-yl)-1,5-naphthyridine-3-amine (5.4 mg).

MSm/z(M+H):287.

0157-2

A mixture of 6-chloro-N-(5-methoxypyridin-3-yl)-1,5-naphthyridine-3-amine (5 mg), 5-methylpyridazine-3-amine (3 mg), tris(dibenzylideneacetone)dipalladium(0) (5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), and cesium carbonate (20 mg) in 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining N 7 -(5-methoxypyridin-3-yl)-N 2 -(5-methylpyridazin-3-yl)-1,5-naphthyridine-2,7-diamine (15 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.69(1H,brs),8.63(1H,brs),8.50(1H,d,J=2.7 Hz),8.13(1H,d,J=2.7 Hz),8.10(1H,d,J=9.3 Hz),7.92(1H,d,J=2.7 Hz),7.78(1H,brs),7.35(1H,d,J=9.0 Hz),7.22(1H,d,J=2.7 Hz),3.90(3H,s),2.43(3H,s).

MSm/z(M+H):360.

›Example 0158

0158-1

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (100 mg), 5-(2-morpholinoethoxyl)pyridine-3-amine (92 mg), tris(dibenzylideneacetone)dipalladium(0) (37 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (47 mg), and cesium carbonate (267 mg) in 1,4-dioxane (2 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 6-chloro-N-(5-(2-morpholinoethoxyl)pyridin-3-yl)-1,5-naphthyridine-3-amine (5.4 mg).

MSm/z(M+H):386.

0158-2

A mixture of 6-chloro-N-(5-(2-morpholinoethoxyl)pyridin-3-yl)-1,5-naphthyridine-3-amine (10 mg), 5-methylpyridazine-3-amine (4 mg), tris(dibenzylideneacetone)dipalladium(0) (5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), and cesium carbonate (20 mg) in 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining N 2 -(5-methylpyridazin-3-yl)-N 7 -(5-(2-morpholinoethoxyl)pyridin-3-yl)-1,5-naphthyridine-2,7-diamine (1.9 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.67(1H,brs),8.63(1H,brs),8.50(1H,brs),8.14(1H,brs),8.11(1H,d,J=9.0 Hz),7.91(1H,brs),7.78(1H,brs),7.24(1H,d,J=9.0 Hz),7.21(1H,brs),4.20(2H,t,J=5.4 Hz),3.79-3.71(4H,m),2.85(2H,t,J=5.4 Hz),2.66-2.56(4H,m),2.43(3H,s).

MSm/z(M+H):459.

›Example 0159

0159-1

A mixture of 6-chloro-N-(5-(2-morpholinoethoxyl)pyridin-3-yl)-1,5-naphthyridine-3-amine (10 mg), 5-isopropylpyridazine-3-amine (5 mg), tris(dibenzylideneacetone)dipalladium(0) (5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), and cesium carbonate (20 mg) in 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining N 2 -(5-isopropylpyridazin-3-yl)-N 7 -(5-(2-morpholinoethoxyl)pyridin-3-yl)-1,5-naphthyridine-2,7-diamine (3.8 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.75(1H,brs),8.69(1H,brs),8.52(1H,d,J=2.7 Hz),8.12(1H,brs),8.11(1H,d,J=8.7 Hz),7.91(1H,brs),7.73(1H,brs),7.40(1H,d,J=8.7 Hz),7.22(1H,brs),4.18(2H,t,J=5.4 Hz),3.77-3.72(4H,m),3.06-2.95(1H,m),2.84(2H,t,J=5.4 Hz),2.63-2.57(4H,m),1.37(6H,d,J=7.4 Hz).

MSm/z(M+H):487.

›Example 0160

0160-1

A 2.6 mol/L n-butyllithium-hexane solution (0.52 mL) was added to a solution of 4-bromo-3-(methoxymethyl)-1-methyl-1H-pyrazole (185 mg) in tetrahydrofuran (4.5 mL) at −80° C., followed by stirring at the same temperature for 30 minutes, and 2-isopropyloxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (369 mg) was added thereto at the same temperature, followed by stirring while slowly heating to room temperature over a period of 2.5 hours. A saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(methoxymethyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (304 mg).

1 H-NMR(CDCl 3 )δ:7.59(1H,s),4.60(2H,s),3.87(3H,s),3.43(3H,s),1.24(12H,s).

0160-2 and 0160-3

The following compounds were obtained in the same manner as in Examples 0001-4 and 0001-5.

Examples 0161 to 0164

The following compounds were obtained in the same manner as in Example 0001-5.

›Example 0165

0165-1

MSm/z(M+H):224,226.

0165-2

1-Methylpyrazole-4-boronic acid pinacol ester (460 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (70 mg), sodium carbonate (440 mg), 1,4-dioxane (1 mL), and water (200 μL) were added to a solution of 7-bromo-1,5-naphthyridine-2-amine (500 mg) in 1,4-dioxane (2 mL), followed by stirring at 100° C. for 2 hours in a nitrogen atmosphere. The reaction liquid was cooled to room temperature, a solution of chloroform-methanol was added thereto, and the resultant product was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine (180 mg).

MSm/z(M+H):226.

0165-3

Pyridine (5 mL) was added to a mixture of 7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine (100 mg) and phenyl chlorothioformate (200 mg), followed by stirring at room temperature for 1 hour. The solvent was distilled off at 60° C. under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining 2-isothiocyanate-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine (105 mg).

1 H-NMR(CDCl 3 )δ:9.11(1H,d,J=2.3 Hz),8.37(1H,d,J=8.6 Hz),8.26(1H,t,J=1.0 Hz),7.96(1H,s),7.84(1H,s),7.38(1H,d,J=8.9 Hz),4.02(3H,s).

0165-4

A solution of 2-isothiocyanate-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine (10 mg) and benzeneacetic acid hydrazide (10 mg) in 1,4-dioxane (1 mL) was stirred at 120° C. for 30 minutes using a microwave reaction apparatus. The solvent was distilled off under reduced pressure, and sulfuric acid (0.6 mL) was added thereto under ice-coolong, followed by stirring at room temperature for 30 minutes. The reaction mixture was added dropwise to ice water, and the resultant product was neutralized with a sodium hydroxide aqueous solution. The solid matter was collected by filtration, thereby obtaining 5-benzyl-N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (10 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.10(1H,s),9.06(1H,d,J=2.0 Hz),8.49(1H,s),8.27-8.23(2H,m),8.18(1H,s),7.42-7.34(5H,m),7.31-7.25(1H,m),4.40(2H,s),3.92(3H,s).

MSm/z(M+H):400.

›Example 0166

0166-1

5-((Dimethylamino)methyl)-N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a yellow solid in the same manner as in Example 0165-4.

1 H-NMR(CDCl 3 )δ:8.96(1H,s),8.36-8.28(2H,m),8.02(1H,s),7.90(1H,s),7.63-7.59(1H,m),4.04(3H,s),3.96(2H,s),2.45(6H,s).

MSm/z(M+H):367.

›Example 0167

0167-1

5-Isopropyl-N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a white solid in the same manner as in Example 0165-4.

1 H-NMR(DMSO-d 6 )δ:12.04(1H,s),9.05(1H,d,J=2.0 Hz),8.52(1H,s),8.31(1H,d,J=1.7 Hz),8.24-8.21(2H,m),7.38(1H,d,J=9.2 Hz),3.93(3H,s),3.41-3.35(1H,m),1.42(6H,d,J=6.9 Hz).

MSm/z(M+H):352.

›Example 0168

0168-1

5-((7-(1-Methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazole-2-carboxamide was obtained as a pale yellow solid in the same manner as in Example 0165-4.

1 H-NMR(DMSO-d 6 )δ:12.56(1H,s),9.12(1H,d,J=2.3 Hz),8.59(1H,s),8.37-8.35(2H,m),8.32(1H,d,J=9.2 Hz),8.25(1H,s),7.91(1H,s),7.45(1H,d,J=8.9 Hz),3.92(3H,s).

MSm/z(M+H):353.

›Example 0169

0169-1

N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-propyl-1,3,4-thiadiazole-2-amine was obtained as a white solid in the same manner as in Example 0165-4.

1 H-NMR(CDCl 3 )δ:12.04(1H,s),9.07(1H,d,J=2.0 Hz),8.53(1H,s),8.32(1H,d,J=1.7 Hz),8.25(1H,d,J=8.9 Hz),8.21(1H,s),7.39(1H,d,J=8.9 Hz),3.93(3H,s),2.99(2H,t,J=7.4 Hz),1.87-1.75(2H,m),1.00(3H,t,J=7.4 Hz).

MSm/z(M+H):352.

›Example 0170

0170-1

5-(Methoxymethyl)-N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine) was obtained as a white solid in the same manner as in Example 0165-4.

1 H-NMR(CDCl 3 )δ:12.20(1H,s),9.09(1H,d,J=2.3 Hz),8.55(1H,s),8.34(1H,d,J=1.7 Hz),8.28(1H,d,J=8.9 Hz),8.23(1H,s),7.42(1H,d,J=8.9 Hz),4.79(2H,s),3.92(3H,s),3.39(3H,s).

MSm/z(M+H):354.

›Example 0171

171-1

Pyridine (5 mL) was added to a mixture of 7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine (150 mg) and phenyl chlorothioformate (200 μL), followed by stirring at room temperature for 1 hour. Phenyl chlorothioformate (200 μL) was added thereto, followed by stirring at room temperature for 1 hour. The solvent was distilled off at 40° C. under reduced pressure. A solution of ethanol-chloroform was added to the obtained residue, and the resultant product was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining (7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)thiocarbamic acid phenyl (100 mg).

MSm/z(M+H):362.

0171-2

N,N-diisopropylethylamine (400 μL) was added to a solution of 3-phenylpropionyl chloride (170 mg) and tert-butyl carbazate (150 mg) in 1,4-dioxane (2 mL), followed by stirring at room temperature for 2 hours. A 4 mol/L hydrogen chloride/1,4-dioxane solution (2 mL) was added to the reaction mixture, followed by allowing to stand at room temperature overnight. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the obtained residue. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 3-phenylpropanoic acid hydrazide.

(7-(1-Methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)thiocarbamic acid phenyl (10 mg) and 1,4-dioxane (1 mL) were added to 3-phenylpropanoic acid hydrazide, followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was washed with ethyl acetate, thereby obtaining N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-2-(3-phenylpropanoyl)hydrazine carbothioamide.

Sulfuric acid (0.6 mL) was added to N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-2-(3-phenylpropanoyl)hydrazine carbothioamide under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction mixture was added dropwise to ice water, and the resultant product was neutralized with a sodium hydroxide aqueous solution. The solid matter was collected by filtration, and washed with a solution of chloroform-methanol, thereby obtaining N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-phenethyl-1,3,4-thiadiazole-2-amine (6 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:12.05(1H,s),9.07(1H,d,J=2.0 Hz),8.51(1H,s),8.27-8.23(2H,m),8.20(1H,s),7.39(1H,d,J=9.2 Hz),7.34-7.32(4H,m),7.26-7.19(1H,m),3.94(3H,s),3.38-3.34(2H,m),3.12(2H,t,J=7.8 Hz).

MSm/z(M+H):414.

›Example 0172

0172-1

A solution of cyclopentanecarboxylic acid methyl (20 μL) and hydrazine monohydrate (20 μL) in methanol (1 mL) was stirred at 100° C. for 1 hour using a microwave reaction apparatus. The solvent was distilled off under reduced pressure, and (7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)thiocarbamic acid phenyl (10 mg) and 1,4-dioxane (1 mL) were added to the obtained residue, followed by stirring at 140° C. for 30 minutes using a microwave reaction apparatus. The solvent was distilled off under reduced pressure, and ethanol (1 mL) and sulfuric acid (10 μL) were added to the obtained residue, followed by stirring at 100° C. for 30 minutes using a microwave reaction apparatus. Water was added to the reaction mixture, and the resultant product was neutralized with a sodium hydroxide aqueous solution. The solid matter was collected by filtration, and washed with a solution of chloroform-methanol, thereby obtaining 5-cyclopentyl-N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (2 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.03(1H,s),9.06(1H,d,J=2.0 Hz),8.53(1H,s),8.31(1H,d,J=1.7 Hz),8.26-8.20(2H,m),7.38(1H,d,J=8.9 Hz),3.93(3H,s),3.52-3.43(1H,m),2.21-2.13(2H,m),1.93-1.65(6H,m).

MSm/z(M+H):378.

›Example 0173

0173-1

A solution of 5-bromo-1,3,4-thiadiazole-2-amine (20 mg), potassium carbonate (20 mg), and pyrrolidine (20 μL) in 1,4-dioxane (1 mL) was stirred at 100° C. for 30 minutes using a microwave reaction apparatus. Water was added to the reaction mixture, the solid matter was collected by filtration, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 2-amino-5-(1-pyrrolidinyl)-1,3,4-thiadiazole (10 mg).

1 H-NMR(DMSO-d 6 )δ:6.27(2H,s),3.30-3.23(4H,m),1.93-1.88(4H,m).

0173-2

N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-(pyrrolidin-1-yl)-1,3,4-thiadiazole-2-amine was obtained as a yellow solid in the same manner as in Example 0001-5.

1 H-NMR(DMSO-d 6 )δ:11.55(1H,s),9.01(1H,d,J=2.3 Hz),8.50(1H,s),8.22(1H,d,J=1.3 Hz),8.20(1H,s),8.16(1H,d,J=8.9 Hz),7.29(1H,d,J=9.2 Hz),3.92(3H,s),3.47(4H,t,J=6.6 Hz),2.01(4H,t,J=6.4 Hz).

MSm/z(M+H):379.

›Example 0174

0174-1

N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-(methylthio)-1,3,4-thiadiazole-2-amine was obtained as a yellow solid in the same manner as in Example 0001-5.

1 H-NMR(DMSO-d 6 )δ:9.08(1H,d,J=2.3 Hz),8.54(1H,s),8.39(1H,d,J=1.7 Hz),8.26(1H,d,J=9.2 Hz),8.23(1H,s),7.38(1H,d,J=8.9 Hz),3.92(3H,s),2.76(3H,s).

MSm/z(M+H):356.

›Example 0175

0175-1

Cyclopentanecarbonyl chloride (3 mL) was added to a solution of thiosemicarbazide (2.0 g) in hydrochloric acid (10 mL), followed by stirring for 60 hours under heating to reflux. The reaction mixture was cooled to room temperature, and neutralized by the addition of a sodium hydroxide aqueous solution under ice-cooling. The solid matter was collected by filtration, and dissolved by the addition of ethyl acetate and methanol. The resultant product was dried over anhydrous sodium sulfate, and passed through silica gel column chromatography (NH silica). The solvent was distilled off under reduced pressure, and the obtained residue was washed with a solution of ethyl acetate-hexane, thereby obtaining 2-amino-5-cyclopentyl-1,3,4-thiadiazole (2.83 g).

1 H-NMR(DMSO-d 6 )δ:6.98(2H,s),3.30-3.20(1H,m),2.07-1.95(2H,m),1.69-1.59(6H,m).

0175-2

A mixture of 2-amino-5-cyclopentyl-1,3,4-thiadiazole (1.73 g), 7-bromo-2-chloro-1,5-naphthyridine (2.40 g), and potassium carbonate (1.99 g) in dimethylsulfoxide (20 mL) was stirred at 150° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and water (300 mL) was added thereto. The solid matter was collected by filtration, thereby obtaining N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-1,3,4-thiadiazole-2-amine (1.55 g).

60% sodium hydride (150 mg) was added to a solution of the obtained N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-1,3,4-thiadiazole-2-amine in N,N-dimethylformamide (25 mL) under ice-cooling, followed by stirring at 0° C. for 15 minutes. 2-(Chloromethoxy)ethyltrimethylsilane (700 μL) was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture at 0° C., and a saturated sodium chloride aqueous solution and ethyl acetate were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate, NH silica), thereby obtaining N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (1.82 g) as brown oily substance.

1 H-NMR(DMSO-d 6 )δ:8.92(1H,d,J=2.0 Hz),8.70(1H,d,J=2.0 Hz),8.34(1H,d,J=8.9 Hz),7.55(1H,d,J=9.2 Hz),5.73(2H,s),3.81(2H,td,J=7.9,3.2 Hz),3.58(1H,t,J=7.9 Hz),2.28-2.16(2H,m),2.01-1.76(8H,m),0.03(9H,s).

0175-3

tert-Butyl=4-amino-1H-pyrazole-1-carboxylate (25 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7 mg), cesium carbonate (65 mg), and tris(dibenzylideneacetone)dipalladium(0) (6 mg) were added to a solution of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (50 mg) in 1,4-dioxane (1 mL), followed by stirring at 100° C. for 8 hours in a nitrogen atmosphere. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (5 mg) and tris(dibenzylideneacetone)dipalladium(0) (5 mg) were added thereto, followed by stirring at 100° C. for 3 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water was added thereto. The solid matter was collected by filtration, thereby obtaining tert-butyl 4-((6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)amino)-1H-pyrazole-1-carboxylate.

Hydrochloric acid (1 mL) was added to the obtained tert-butyl 4-((6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)amino)-1H-pyrazole-1-carboxylate, followed by stirring at 90° C. for 1 hour. The reaction mixture was cooled to room temperature, and the resultant product was neutralized with a sodium hydroxide aqueous solution. The solid matter was collected by filtration, and purified by preparative reversed phase HPLC (a 0.1% formic acid aqueous solution-a 0.1% formic acid acetonitrile solution), thereby obtaining N 2 -(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-N 7 -(1H-pyrazol-4-yl)-1,5-naphthyridine-2,7-diamine (4.5 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.82(1H,s),11.79(1H,s),8.42(1H,d,J=2.6 Hz),8.36(1H,s),8.05(1H,d,J=8.9 Hz),7.90(1H,s),7.56(1H,s),7.12(1H,d,J=2.3 Hz),7.09(1H,d,J=8.9 Hz),3.52-3.40(1H,m),2.16-2.07(2H,m),1.88-1.62(6H,m).

MSm/z(M+H):379.

›Example 0176

0176-1

A sodium hypochlorite solution (13 mL) was added dropwise to a mixture solution of dichloromethane (25 mL) and 2 mol/L hydrochloric acid (15 mL) at −10° C., and a solution of 5-acetamide-2-mercapto-1,3,4-thiadiazole (300 mg) in dichloromethane (5 mL) was added dropwise thereto. Then, sodium hydrogen sulfite aqueous solution was added thereto until potassium iodide starch paper was decolorized. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and aniline (400 μL) was added thereto under ice-cooling. A saturated ammonium chloride aqueous solution was added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining N-(5-(N-phenylsulfamoyl)-1,3,4-thiadiazol-2-yl)acetamide (161 mg).

1 H-NMR(DMSO-d 6 )δ:13.10(1H,s),11.16(1H,s),7.35-7.29(2H,m),7.20-7.12(3H,m),2.21(3H,s).

0176-2

Hydrochloric acid (2 mL) was added to a solution of N-(5-(N-phenylsulfamoyl)-1,3,4-thiadiazol-2-yl)acetamide (155 mg) in ethanol (2 mL), followed by stirring at 90° C. for 30 minutes. The reaction mixture was cooled to room temperature, and neutralized with a sodium hydroxide aqueous solution under ice-cooling. Liquid-liquid separation was performed by the addition of chloroform thereto, and the water of the aqueous layer was distilled off under reduced pressure. A solution of chloroform-methanol was added to the residue, the solid was separated by filtration, and the filtrate was purified by silica gel column chromatography (ethyl acetate, NH silica), thereby obtaining 5-amino-N-phenyl-1,3,4-thiadiazole-2-sulfonamide (98 mg).

1 H-NMR(DMSO-d 6 )δ:10.91(1H,s),7.95(2H,s),7.35-7.28(2H,m),7.19-7.10(3H,m).

0176-3

5-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-N-phenyl-1,3,4-thiadiazole-2-sulfonamide was obtained as a pale yellow solid in the same manner as in Example 0015-4.

1 H-NMR(DMSO-d 6 )δ:12.81(1H,s),11.15(1H,s),9.14(1H,d,J=2.3 Hz),8.56(1H,s),8.33-8.32(2H,m),8.24(1H,s),7.46(1H,d,J=8.9 Hz),7.36-7.29(2H,m),7.27-7.23(2H,m),7.11(1H,t,J=7.1 Hz),3.94(3H,s).

MSm/z(M+H):465.

›Example 0177

0177-1

Benzenesulfonyl chloride (300 μL) was added dropwise to a solution of 2-amino-1,3,4-thiadiazole (202 mg) in pyridine (4 mL) over a period of 5 minutes under ice-cooling, followed by stirring at 0° C. for 30 minutes. Benzenesulfonyl chloride (150 μL) was added dropwise thereto over a period of 5 minutes, followed by stirring at 80° C. for 30 minutes. The solvent was distilled off under reduced pressure, and the resultant product was neutralized by the addition of hydrochloric acid. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining N-(1,3,4-thiadiazol-2-yl)benzene sulfonamide (240 mg).

1 H-NMR(DMSO-d 6 )δ:8.76(1H,s),7.83-7.77(2H,m),7.63-7.53(3H,m).

0177-2

A mixture of N-(1,3,4-thiadiazol-2-yl)benzene sulfonamide (120 mg), and sodium acetate (80 mg) in acetic acid (3 mL) was stirred at 80° C. for 5 minutes. Bromine (30 μL) was added dropwise thereto, followed by stirring at 80° C. for 30 minutes. Bromine (10 μL) was added dropwise thereto, followed by stirring at 80° C. for 30 minutes. After the reaction mixture was cooled to room temperature, a sodium hydrogen sulfite aqueous solution was added thereto until potassium iodide starch paper was decolorized, and the resultant product was neutralized by the addition of a sodium hydroxide aqueous solution. The solid matter was collected by filtration, thereby obtaining N-(5-bromo-1,3,4-thiadiazol-2-yl)benzene sulfonamide (190 mg).

1 H-NMR(DMSO-d 6 )δ:7.84-7.77(2H,m),7.67-7.54(3H,m).

0177-3

4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), potassium tert-butoxide (60 mg), and tris(dibenzylideneacetone)dipalladium(0) (10 mg) were added to a solution of 7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine (20 mg) and N-(5-bromo-1,3,4-thiadiazol-2-yl)benzene sulfonamide (30 mg) in 1,4-dioxane (1 mL), followed by stirring at 170° C. for 2 hours using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. Liquid-liquid separation was performed, and the water of the aqueous layer was distilled off under reduced pressure. The obtained residue was purified by preparative reversed phase HPLC (a 0.1% formic acid aqueous solution-a 0.1% formic acid acetonitrile solution), thereby obtaining N-(5-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazol-2-yl)benzene sulfonamide (5 mg).

A solution (1 mL) of 4 mol/L hydrogen chloride/1,4-dioxane was added to the obtained N-(5-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazol-2-yl)benzene sulfonamide, and the solvent was distilled off under reduced pressure, thereby obtaining N-(5-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazol-2-yl)benzene sulfonamide hydrochloride (3 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:9.09(1H,d,J=2.0 Hz),8.51(1H,s),8.28(1H,d,J=9.6 Hz),8.18(1H,s),8.09(1H,d,J=1.7 Hz),7.90-7.87(2H,m),7.79-7.42(4H,m),7.32(1H,d,J=8.9 Hz),3.94(3H,s).

MSm/z(M+H):465.

›Example 0178

0178-1

N-(5-ethylpyridazin-3-yl)-7-(1-(3-morpholinopropyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine was obtained as a white solid in the same manner as in Example 0001-5.

1 H-NMR(CDCl 3 )δ:9.07(1H,brs),8.93(1H,d,J=2.1 Hz),8.84(1H,m),8.79(1H,d,J=1.5 Hz),8.24(1H,d,J=9.3 Hz),8.13(1H,d,J=1.5 Hz),7.97(1H,s),7.88(1H,s),7.58(1H,d,J=9.3 Hz),4.31(2H,m),3.73(4H,m),2.81(2H,m),2.50-2.34(6H,m),2.13(2H,m),1.42(3H,t,J=8.1 Hz).

MSm/z(M+H):445.

›Example 0179

0179-1

N-(5-((7-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazol-2-yl)benzene sulfonamide was obtained as a yellow solid in the same manner as in Example 0177-3.

1 H-NMR(DMSO-d 6 )δ:11.86(1H,s),9.09(1H,d,J=2.0 Hz),8.55(1H,s),8.27(1H,d,J=9.2 Hz),8.18(1H,s),8.08(1H,d,J=1.7 Hz),7.90-7.87(2H,m),7.79-7.42(4H,m),7.32(1H,d,J=8.9 Hz),4.33(2H,t,J=6.4 Hz),3.56(4H,t,J=4.6 Hz),2.80(2H,t,J=6.6 Hz),2.50-2.42(4H,m).

MSm/z(M+H):564.

›Example 0180

0180-1

tert-Butyl 4-(2-(4-(6-((5-(N-phenyl sulfamoyl)-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate was obtained as a pale yellow solid in the same manner as in Example 0015-4.

1 H-NMR(DMSO-d 6 )δ:9.06(1H,d,J=2.0 Hz),8.62(1H,s),8.37-8.32(2H,m),8.24(1H,s),7.37(1H,d,J=9.2 Hz),7.03-6.94(5H,m),4.34-4.27(2H,m),3.33-3.25(4H,m),2.86-2.78(2H,m),2.44-2.38(4H,m)1.38(9H,s).

MSm/z(M+H):663.

›Example 0181

0181-1

A solution (2 mL) of 4 mol/L hydrogen chloride/1,4-dioxane was added to tert-butyl 4-(2-(4-(6-((5-(N-phenylsulfamoyl)-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate (52 mg), followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was washed with a solution of ethyl acetate-methanol-chloroform, thereby obtaining N-phenyl-5-((7-(1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazole-2-sulfonamide hydrochloride (41 mg) as a pale yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.90(1H,s),11.21(1H,s),9.17(1H,d,J=2.0 Hz),8.69(1H,s),8.37-8.32(2H,m),8.24(1H,s),7.52(1H,d,J=8.9 Hz),7.36-7.29(2H,m),7.27-7.23(2H,m),7.11(1H,t,J=7.1 Hz),4.66-4.56(2H,m),3.57-3.56(4H,m),3.39-3.27(6H,m).

MSm/z(M+H):563.

›Example 0182

0182-1

N-(7-bromo-1,5-naphthyridin-2-yl)-5-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine was obtained as brown oily substance in the same manner as in Example 0175-2.

MSm/z(M+H):452.

0182-2 and 0182-3

The following compounds were obtained in the same manner as in Example 0175-3.

›Example 0183

0183-1

60% sodium hydride (3 mg) was added to a solution of tert-butyl 4-((6-((5-methyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)amino)-1H-pyrazole-1-carboxylate (10 mg) in N,N-dimethylformamide (1 mL) under ice-cooling, and iodomethane (10 μL) was added thereto, followed by stirring at room temperature for 30 minutes. Methanol (1 drop) was added to the reaction mixture, and water and ethyl acetate were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate, NH silica), thereby obtaining tert-butyl 4-(methyl (6-((5-methyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)amino)-1H-pyrazole-1-carboxylate.

Methanol (500 μL) and a 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) were added to the obtained tert-butyl 4-(methyl (6-((5-methyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)amino)-1H-pyrazole-1-carboxylate, followed by stirring at 60° C. for 1.5 hours. The solvent was distilled off under reduced pressure, the obtained residue was neutralized by the addition of a saturated sodium hydrogen carbonate aqueous solution, and a solution of methanol-chloroform was added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate, NH silica), thereby obtaining N 7 -methyl-N 2 -(5-methyl-1,3,4-thiadiazol-2-yl)-N 7 -(1H-pyrazol-4-yl)-1,5-naphthyridine-2,7-diamine (8.5 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.54(1H,s),11.86(1H,s),8.66(1H,d,J=2.6 Hz),8.12(1H,d,J=8.9 Hz),7.77(1H,d,J=2.3 Hz),7.52(1H,d,J=2.3 Hz),7.19(1H,d,J=8.9 Hz),6.19(1H,d,J=2.3 Hz),3.43(3H,s),2.64(3H,s).

MSm/z(M+H):339.

›Example 0184

The following compounds were obtained in the same manner as in Example 0175-3.

›Example 0185

0185-1

N 7 -methyl-N 2 -(5-methyl-1,3,4-thiadiazol-2-yl)-N 7 -(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2,7-diamine was obtained as a yellow solid in the same manner as in Example 0183.

1 H-NMR(DMSO-d 6 )δ:11.87(1H,s),8.68(1H,d,J=2.6 Hz),8.12(1H,d,J=8.9 Hz),7.71(1H,d,J=2.0 Hz),7.49(1H,d,J=2.6 Hz),7.20(1H,d,J=8.9 Hz),6.14(1H,d,J=2.3 Hz),3.81(3H,s),3.41(3H,s),2.64(3H,s).

MSm/z(M+H):353.

›Example 0186

0186-1

N-(7-bromo-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine was obtained in the same manner as in Example 0175-2.

MSm/z(M+H):438,440.

0186-2

N 7 -(1H-pyrazol-4-yl)-N 2 -(1,3,4-thiadiazol-2-yl)-1,5-naphthyridine-2,7-diamine was obtained as a yellow solid in the same manner as in Example 0175-3.

1 H-NMR(DMSO-d 6 )δ:12.32(1H,s),12.03(1H,s),9.32(1H,s),9.10(1H,s),8.60(1H,d,J=2.6 Hz),8.40(1H,d,J=2.3 Hz),8.12(1H,d,J=8.9 Hz),7.69(1H,t,J=2.0 Hz),7.19(1H,d,J=8.9 Hz),5.96(1H,t,J=2.1 Hz).

MSm/z(M+H):311.

›Example 0187

0187-1

N-(1,3,4-thiadiazol-2-yl)methane sulfonamide was obtained in the same manner as in Example 0177-1.

MSm/z(M+H):180.

0187-2

N-(5-bromo-1,3,4-thiadiazol-2-yl)methane sulfonamide was obtained in the same manner as in Example 0177-2.

MSm/z(M+H):258,260.

0187-3

60% sodium hydride (15 mg) was added to a solution of N-(5-bromo-1,3,4-thiadiazol-2-yl)methane sulfonamide (100 mg) in N,N-dimethylformamide (10 mL) under ice-cooling, followed by stirring at 0° C. for 15 minutes. 2-(Chloromethoxy)ethyltrimethylsilane (60 μL) was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. After the reaction mixture was cooled to 0° C., methanol (2 drops) was added thereto, and a saturated sodium chloride aqueous solution and ethyl acetate were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining N-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methane sulfonamide (100 mg) as oily substance.

MSm/z(M+H):388,390.

187-4

4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), potassium tert-butoxide (20 mg), and tris(dibenzylideneacetone)dipalladium(0) (10 mg) were added to a solution of 7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine (25 mg) and N-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methane sulfonamide (45 mg) in 1,4-dioxane (1 mL), followed by stirring at 150° C. for 2 hour using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and chloroform and water were added thereto. The organic layer was collected by separation, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol), thereby obtaining N-(5-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazol-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methane sulfonamide (20 mg).

A 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) was added to a solution of the obtained N-(5-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazol-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methane sulfonamide in ethanol (1 mL), followed by stirring at 65° C. for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. A saturated sodium hydrogen carbonate aqueous solution was added to the obtained residue, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative reversed phase HPLC (a 0.1% formic acid aqueous solution-a 0.1% formic acid acetonitrile solution), thereby obtaining N-(5-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazol-2-yl)methane sulfonamide (0.5 mg) as a pale yellow solid.

1 H-NMR(DMSO-d 6 )δ:11.10(1H,s),8.96(1H,d,J=2.3 Hz),8.47(1H,s),8.13-8.09(2H,m),8.02(1H,d,J=1.7 Hz),7.30(1H,d,J=9.2 Hz),3.92(3H,s),2.74(3H,s).

MSm/z(M+H):403.

›Example 0188

0188-1

A 5-((7-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-N-phenyl-1,3,4-thiadiazole-2-sulfonamide sodium salt was obtained as a pale yellow solid in the same manner as in Example 0015-4.

1 H-NMR(DMSO-d 6 )δ:12.18(1H,s),9.07(1H,d,J=1.7 Hz),8.61(1H,s),8.25-8.20(3H,m),7.38(1H,d,J=8.9 Hz),7.07-6.98(4H,m),6.70-6.63(1H,m),4.30(2H,t,J=6.6 Hz),3.57(4H,t,J=4.5 Hz),2.80(2H,t,J=6.6 Hz),2.45(4H,t,J=4.6 Hz).

MSm/z(M+H):564.

›Example 0189

0189-1

A solution of 5-acetamide-2-mercapto-1,3,4-thiadiazole (1.0 g) in dichloromethane (20 mL) was added dropwise to a mixture of dichloromethane (15 mL),2 mol/L hydrochloric acid (15 mL), and a sodium hypochlorite solution (10 mL) at −10° C. A sodium hydrogen sulfite aqueous solution was added thereto until potassium iodide starch paper was decolorized. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, then, pentafluorophenol (1.0 g) and triethylamine (2.0 mL) were added thereto under ice-cooling, followed by stirring for 5 minutes, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining pentafluorophenyl 5-acetamide-1,3,4-thiadiazole-2-sulfonate (210 mg).

1 H-NMR(CDCl 3 )δ:11.61(1H,s),2.52(3H,s).

0189-2

Methylamine hydrochloride (20 mg) and triethylamine (100 μL) were added to a solution of pentafluorophenyl 5-acetamide-1,3,4-thiadiazole-2-sulfonate (70 mg) in acetonitrile (1 mL), followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining N-(5-(N-methylsulfamoyl)-1,3,4-thiadiazol-2-yl)acetamide.

Hydrochloric acid (1 mL) was added to the obtained N-(5-(N-methylsulfamoyl)-1,3,4-thiadiazol-2-yl)acetamide, followed by stirring at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, and neutralized with a sodium hydroxide aqueous solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining 5-amino-N-methyl-1,3,4-thiadiazole-2-sulfonamide (37 mg).

1 H-NMR(CDCl 3 )δ:1.25(3H,s).

MSm/z(M+H):195.

0189-3

4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (7 mg), potassium tert-butoxide (30 mg), and tris(dibenzylideneacetone)dipalladium(0) (7 mg) were added to a solution of 2-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine (35 mg) and 5-amino-N-methyl-1,3,4-thiadiazole-2-sulfonamide (35 mg) in 1,4-dioxane (1 mL), followed by stirring at 150° C. for 1 hour using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and chloroform and water were added thereto. Liquid-liquid separation was performed, and the water of the aqueous layer was distilled off under reduced pressure. The obtained residue was purified by preparative reversed phase HPLC (a 0.1% formic acid aqueous solution-a 0.1% formic acid acetonitrile solution), and purified by reversed silica gel chromatography (methanol-sodium hydrogen carbonate aqueous solution), thereby obtaining methyl ((5-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazol-2-yl)sulfonyl)amide sodium salt (3.2 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:8.83(1H,d,J=1.7 Hz),8.46(1H,s),8.12(1H,s),8.06(1H,s),7.92(1H,d,J=8.9 Hz),7.81(1H,s),7.15(1H,d,J=8.9 Hz),3.91(3H,s),2.62(3H,s).

MSm/z(M+H):403.

›Example 0190

The following compounds were obtained in the same manner as in Examples 0177-1 to 0177-3.

›Example 0191

0191-1

A ((5-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazol-2-yl)sulfonyl)amide sodium salt was obtained as a white solid in the same manner as in Example 0189-3.

1 H-NMR(DMSO-d 6 )δ:8.73(1H,d,J=2.0 Hz),8.42(1H,s),8.07(1H,s),7.96(1H,d,J=1.7 Hz),7.80(1H,d,J=8.9 Hz),7.53(2H,s),7.05(1H,d,J=8.9 Hz),3.91(3H,s).

MSm/z(M+H):389.

›Example 0192

0192-1

5-Amino-N-benzyl-1,3,4-thiadiazole-2-sulfonamide was obtained in the same manner as in Example 0189-2.

MSm/z(M+H):271.

0192-2

An N-benzyl-5-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazole-2-sulfonamide sodium salt was obtained as a yellow solid in the same manner as in Example 0189-3.

1 H-NMR(DMSO-d 6 )δ:8.75(1H,d,J=2.3 Hz),8.43(1H,s),8.08(1H,d,J=4.6 Hz),7.99(1H,d,J=1.7 Hz),7.82(1H,d,J=8.9 Hz),7.36-7.23(5H,m),7.08(1H,d,J=8.9 Hz),4.19(2H,s),3.90(3H,s).

MSm/z(M+H):479.

›Example 0193

0193-1

5-Amino-N,N-dimethyl-1,3,4-thiadiazole-2-sulfonamide was obtained in the same manner as in Example 0189-2.

1 H-NMR(DMSO-d 6 )δ:8.03(2H,s),2.83(6H,s).

0193-2

N,N-dimethyl-5-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazole-2-sulfonamide was obtained as a pale yellow solid in the same manner as in Example 0015-4.

1 H-NMR(DMSO-d 6 )δ:12.88(1H,s),9.14(1H,d,J=2.3 Hz),8.58(1H,s),8.42(1H,d,J=1.3 Hz),8.36(1H,d,J=8.9 Hz),8.26(1H,s),7.49(1H,d,J=8.9 Hz),3.93(3H,s),2.93(6H,s).

MSm/z(M+H):417.

›Example 0194

The following compounds were obtained in the same manner as in Example 0175-3.

›Example 0195

0195-1

N 2 -(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-N 7 -methyl-N 7 -(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2,7-diamine was obtained as a yellow solid in the same manner as in Example 0183-1.

1 H-NMR(DMSO-d 6 )δ:11.89(1H,s),8.68(1H,d,J=2.6 Hz),8.12(1H,d,J=8.9 Hz),7.70(1H,d,J=2.3 Hz),7.55(1H,d,J=2.3 Hz),7.20(1H,d,J=8.9 Hz),6.14(1H,d,J=2.3 Hz),3.81(3H,s),3.42(3H,s),2.21-2.06(2H,m),1.92-1.62(7H,m).

MSm/z(M+H):407.

›Example 0196

0196-1

tert-Butyl 4-amino-1H-pyrazole-1-carboxylate (25 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5 mg), cesium carbonate (45 mg), and tris(dibenzylideneacetone)dipalladium(0) (5 mg) were added to a solution of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (40 mg) in 1,4-dioxane (1 mL), followed by stirring at 100° C. for 8 hours in a nitrogen atmosphere. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (5 mg) and tris(dibenzylideneacetone)dipalladium(0) (5 mg) were added thereto, followed by stirring at 100° C. for 3 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate, NH silica), thereby obtaining tert-butyl 4-((6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)amino)-1H-pyrazole-1-carboxylate (40 mg).

MSm/z(M+H):609.

0196-2

N 2 -(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-N 7 -methyl-N 7 -(1H-pyrazol-4-yl)-1,5-naphthyridine-2,7-diamine was obtained as a yellow solid in the same manner as in Example 0183-1.

1 H-NMR(DMSO-d 6 )δ:12.04(1H,s),9.08(1H,d,J=2.0 Hz),8.56(1H,s),8.32(1H,d,J=1.7 Hz),8.24(2H,d,J=10.9 Hz),7.39(1H,d,J=8.9 Hz),2.14(3H,s),2.04-1.68(9H,m).

MSm/z(M+H):393.

›Example 0197

0197-1

tert-Butyl 4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (30 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5 mg), sodium carbonate (12 mg), and water (100 μL) were added to a solution of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (50 mg) in 1,4-dioxane (1 mL), followed by stirring at 80° C. for 2 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The solid matter was collected by filtration, and hydrochloric acid (1 mL) was added thereto, followed by stirring at 90° C. for 1 hour. The reaction mixture was cooled to room temperature, and the resultant product was neutralized with a sodium hydroxide aqueous solution. The solid matter was collected by filtration, and purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining tert-butyl 4-(3-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (27 mg) as a yellow solid.

MSm/z(M+H):720.

0197-2

Methanol (1 mL) and hydrochloric acid (1 mL) were added to tert-butyl 4-(3-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (27 mg), followed by stirring at 60° C. for 1 hour. The solvent was distilled off under reduced pressure, the resultant product was neutralized with a saturated sodium hydrogen carbonate aqueous solution, and a solution of methanol-chloroform was added thereto.

The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 5-cyclopentyl-N-(7-(1-(3-(piperazin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine.

A 20% formaldehyde solution (5 μL) and sodium triacetoxyborohydride (12 mg) were added to a solution of the obtained 5-cyclopentyl-N-(7-(1-(3-(piperazin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine in methanol (600 μL) and chloroform (600 μL), followed by stirring at room temperature for 2 hours. A saturated sodium chloride aqueous solution and chloroform were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 5-cyclopentyl-N-(7-(1-(3-(4-methylpiperazin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (4 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.04(1H,s),9.07(1H,d,J=2.0 Hz),8.56(1H,s),8.32(1H,d,J=1.3 Hz),8.26-8.22(2H,m),7.39(1H,d,J=8.9 Hz),4.19(2H,t,J=7.1 Hz),3.51-3.44(1H,m),2.74-2.71(1H,m),2.42-2.24(11H,m),2.14(3H,s),2.02-1.72(8H,m).

MSm/z(M+H):504.

›Example 0198

0198-1

Cyclobutanecarboxylic acid (600 μL) was added to a solution of thiosemicarbazide (500 mg) in hydrochloric acid (2 mL), followed by stirring for 60 hours under heating to reflux. The reaction mixture was cooled to room temperature, and neutralized by the addition of a sodium hydroxide aqueous solution under ice-cooling. The solid matter was collected by filtration, thereby obtaining 2-amino-5-cyclobutyl-1,3,4-thiadiazole (650 mg).

MSm/z(M+H):156.

0198-2

5-Cyclobutyl-N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a pale yellow solid in the same manner as in Example 0001-5.

1 H-NMR(DMSO-d 6 )δ:12.06(1H,s),9.07(1H,d,J=2.0 Hz),8.53(1H,s),8.34(1H,d,J=1.7 Hz),8.25(1H,d,J=9.2 Hz),8.22(1H,s),7.39(1H,d,J=8.9 Hz),3.93(3H,s),2.45-2.27(5H,m),2.17-1.92(2H,m).

MSm/z(M+H):364.

›Example 0199

0199-1

5-Aminothiazole (15 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5 mg), cesium carbonate (45 mg), and tris(dibenzylideneacetone)dipalladium(0) (5 mg) were added to a solution of 2-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine (25 mg) in 1,4-dioxane (2 mL), followed by stirring at 100° C. in a nitrogen atmosphere overnight. The reaction mixture was cooled to room temperature, and a mixed solvent of chloroform-methanol was added thereto. The obtained solution was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)thiazole-5-amine (2 mg) as a brown solid.

1 H-NMR(DMSO-d 6 )δ:10.99(1H,s),8.97(1H,d,J=2.3 Hz),8.56(1H,s),8.49(1H,s),8.21-8.11(3H,m),7.74(1H,d,J=0.7 Hz),7.21(1H,d,J=8.9 Hz),3.91(3H,d,J=6.3 Hz).

MSm/z(M+H):309.

›Example 0200

0200-1

N 2 -(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-N 7 -phenyl-1,5-naphthyridine-2,7-diamine was obtained as a yellow solid in the same manner as in Example 0175-3.

1 H-NMR(DMSO-d 6 )δ:11.88(1H,s),8.90(1H,s),8.56(1H,d,J=2.6 Hz),8.11(1H,d,J=8.9 Hz),7.59(1H,d,J=2.3 Hz),7.39(2H,t,J=7.9 Hz),7.28(2H,dd,J=8.4,1.2 Hz),7.18(1H,d,J=9.2 Hz),7.03(1H,t,J=7.3 Hz),3.52-3.41(1H,m),2.17-2.05(2H,m),1.87-1.60(6H,m).

MSm/z(M+H):389.

Examples 0201 to 0204

The following compounds were obtained in the same manner as in Examples 0197-1 and 0197-2.

Examples 0205 to 0210

The following compounds were obtained in the same manner as in Example 0175-3.

Examples 0211 to 0216

The following compounds were obtained in the same manner as in Examples 0197-1 and 0197-2.

›Example 0217

0217-1

2-Amino-5-cyclohexyl-1,3,4-thiadiazole was obtained in the same manner as in Example 0198-1.

MSm/z(M+H):184.

0217-2

5-Cyclohexyl-N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a yellow solid in the same manner as in Example 0001-5.

1 H-NMR(DMSO-d 6 )δ:12.03(1H,s),9.07(1H,d,J=2.3 Hz),8.53(1H,s),8.33(1H,d,J=1.7 Hz),8.26-8.22(2H,m),7.39(1H,d,J=9.2 Hz),3.93(3H,s),3.13-3.02(1H,m),2.17-2.08(2H,m),1.85-1.15(8H,m).

MSm/z(M+H):392.

›Example 0218

0218-1

5-Cyclopentyl-N-(7-phenyl-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a pale yellow solid in the same manner as in Examples 0197-1 and 0197-2.

1 H-NMR(DMSO-d 6 )δ:12.10(1H,s),9.12(1H,d,J=2.0 Hz),8.44(1H,d,J=1.7 Hz),8.33(1H,d,J=9.2 Hz),7.97-7.92(2H,m),7.61-7.55(2H,m),7.53-7.47(2H,m),3.57-3.44(1H,m),2.21-2.08(2H,m),1.92-1.64(6H,m).

MSm/z(M+H):374.

›Example 0219

0219-1

N 2 -(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-N 7 -(2-methoxyphenyl)-1,5-naphthyridine-2,7-diamine was obtained as a yellow solid in the same manner as in Example 0175-3.

1 H-NMR(DMSO-d 6 )δ:11.84(1H,s),8.57(1H,d,J=2.3 Hz),8.29(1H,s),8.09(1H,d,J=8.6 Hz),7.38(1H,t,J=4.3 Hz),7.33(1H,d,J=2.3 Hz),7.16-7.09(3H,m),7.03-6.97(1H,m),3.84(3H,s),3.51-3.40(1H,m),2.16-2.07(2H,m),1.85-1.67(6H,m).

MSm/z(M+H):419.

›Example 0220

220-1

N 2 -(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-N 7 -(3-methoxyphenyl)-1,5-naphthyridine-2,7-diamine was obtained as a yellow solid in the same manner as in Example 0175-3.

1 H-NMR(DMSO-d 6 )δ:11.89(1H,s),8.91(1H,s),8.55(1H,d,J=2.6 Hz),8.11(1H,d,J=8.9 Hz),7.64(1H,d,J=2.3 Hz),7.29(1H,t,J=8.1 Hz),7.18(1H,d,J=8.9 Hz),6.84(2H,dt,J=12.1,3.4 Hz),6.61(1H,dd,J=8.1,2.1 Hz),3.78(3H,s),3.54-3.42(1H,m),2.17-2.08(2H,m),1.86-1.66(6H,m).

MSm/z(M+H):419.

›Example 0221

0221-1

N 2 -(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-N 7 -(4-(morpholinomethyl)phenyl)-1,5-naphthyridine-2,7-diamine was obtained as a yellow solid in the same manner as in Example 0175-3.

1 H-NMR(DMSO-d 6 )δ:11.87(1H,s),8.87(1H,s),8.55(1H,d,J=2.6 Hz),8.10(1H,d,J=8.9 Hz),7.56(1H,d,J=2.3 Hz),7.31(2H,d,J=8.6 Hz),7.23(2H,d,J=8.6 Hz),7.17(1H,d,J=8.9 Hz),3.61-3.56(4H,m),3.49-3.41(3H,m),2.40-2.35(4H,m),2.15-2.08(2H,m),1.84-1.64(6H,m).

MSm/z(M+H):488.

›Example 0222

0222-1

N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclobutyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine was obtained as brown oily substance in the same manner as in Example 0175-2.

MSm/z(M+H):492,494.

0222-2

N 2 -(5-cyclobutyl-1,3,4-thiadiazol-2-yl)-N 7 -(1H-pyrazol-4-yl)-1,5-naphthyridine-2,7-diamine was obtained as a yellow solid in the same manner as in Example 0175-3.

1 H-NMR(DMSO-d 6 )δ:12.30(1H,s),11.85(1H,s),9.28(1H,s),8.62(1H,d,J=2.3 Hz),8.32(1H,d,J=2.0 Hz),8.09(1H,d,J=8.9 Hz),7.69(1H,t,J=2.0 Hz),7.15(1H,d,J=8.9 Hz),5.95(1H,t,J=2.1 Hz),4.04-3.87(1H,m),2.45-2.27(4H,m),2.16-1.90(2H,m).

MSm/z(M+H):365.

›Example 0223

0223-1

N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclohexyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine was obtained as brown oily substance in the same manner as in Example 0175-2.

MSm/z(M+H):520,522.

0223-2

N 2 -(5-cyclohexyl-1,3,4-thiadiazol-2-yl)-N 7 -((1H-pyrazol-4-yl)-1,5-naphthyridine-2,7-diamine was obtained as a yellow solid in the same manner as in Example 0175-3.

1 H-NMR(DMSO-d 6 )δ:12.29(1H,s),11.83(1H,s),9.27(1H,s),8.62(1H,d,J=2.6 Hz),8.31(1H,d,J=2.0 Hz),8.08(1H,d,J=8.9 Hz),7.69(1H,t,J=2.0 Hz),7.15(1H,d,J=8.9 Hz),5.94(1H,t,J=2.3 Hz),3.11-3.03(1H,m),2.16-2.04(2H,m),1.84-1.27(8H,m).

MSm/z(M+H):393.

›Example 0224

0224-1

N 2 -(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-N 7 -(pyridazin-3-yl)-1,5-naphthyridine-2,7-diamine was obtained as a yellow solid in the same manner as in Example 0175-3.

1 H-NMR(DMSO-d 6 )δ:11.70(1H,s),9.02(1H,d,J=2.0 Hz),8.49(1H,s),8.29(1H,d,J=1.7 Hz),8.19(2H,dd,J=4.8,4.1 Hz),7.31(1H,d,J=8.9 Hz),3.92(3H,s),3.80-3.76(4H,m),3.48-3.42(4H,m).

MSm/z(M+H):391.

›Example 0225

0225-1

5-Morpholino-1,3,4-thiadiazole-2-amine was obtained in the same manner as in Example 0173-1.

1 H-NMR(DMSO-d 6 )δ:6.52(2H,s),3.67(4H,t,J=5.0 Hz),3.20(4H,t,J=4.8 Hz).

0225-2

N-(7-bromo-1,5-naphthyridin-2-yl)-5-morpholino-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine was obtained as brown oily substance in the same manner as in Example 0175-2.

MSm/z(M+H):523,525.

0225-3

N 2 -(5-morpholino-1,3,4-thiadiazol-2-yl)-N 7 -(1H-pyrazol-4-yl)-1,5-naphthyridine-2,7-diamine was obtained as a yellow solid in the same manner as in Example 0175-3.

1 H-NMR(DMSO-d 6 )δ:12.25(1H,s),11.48(1H,s),9.22(1H,s),8.61(1H,d,J=2.3 Hz),8.22(1H,s),8.03(1H,d,J=8.9 Hz),7.67(1H,s),7.07(1H,d,J=8.9 Hz),5.94(1H,s),3.79-3.75(4H,m),3.43-3.39(4H,m).

MSm/z(M+H):396.

›Example 0226

0226-1

1-Methylpyrazole-4-boronic acid pinacol ester (10 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5 mg), and 2 mol/L sodium carbonate aqueous solution (50 μL) were added to a solution of N-(7-bromo-1,5-naphthyridin-2-yl)-5-morpholino-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (20 mg) in 1,4-dioxane (1 mL), followed by stirring at 130° C. for 0.5 hours using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The solid matter was collected by filtration, thereby obtaining N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-morpholino-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine.

A 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) was added to the obtained N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-morpholino-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine, followed by allowing to stand at room temperature overnight. The solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative thin layer silica gel chromatography (chloroform-methanol, NH silica), thereby obtaining N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-morpholino-1,3,4-thiadiazole-2-amine (9 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:11.70(1H,s),9.02(1H,d,J=2.0 Hz),8.49(1H,s),8.29(1H,d,J=1.7 Hz),8.19(2H,dd,J=4.8,4.1 Hz),7.31(1H,d,J=8.9 Hz),3.92(3H,s),3.80-3.76(4H,m),3.48-3.42(4H,m).

MSm/z(M+H):395.

›Example 0227

The following compounds were obtained in the same manner as in Examples 0198-1 and 0001-5.

›Example 0228

The following compounds were obtained in the same manner as in Examples 0175-2 and 0175-3.

Examples 0229 to 0238

Example 0198-1, The following compounds were obtained in the same manner as in Examples 0001-4 and 0001-5

›Example 0239

0239-1

A solution of ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (340 mg) in tetrahydrofuran (10 mL) was cooled by ice, and lithium aluminum hydride (a 10% tetrahydrofuran solution, about 2.5 mol/L, 1 mL) was added dropwise thereto, followed by stirring at room temperature for 1 hour. After the reaction mixture was cooled by ice, ethyl acetate (2 mL) was added thereto, followed by stirring for 15 minutes under ice-cooling, and methanol (1 mL) was added thereto, followed by stirring for 5 minutes under ice-cooling. Anhydrous sodium sulfate aqueous solution (anhydrous sodium sulfate: 100 mg, water: 2 mL) was added to the reaction mixture, followed by neutralizing with 2 mol/L hydrochloric acid. The solid matter was separated by filtration, ethyl acetate was added thereto, and liquid-liquid separation was performed. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining (5-amino-1,3,4-thiadiazol-2-yl)methanol (75 mg).

1 H-NMR(DMSO-d 6 )δ:7.07(2H,s),5.74(1H,t,J=6.1 Hz),4.55(2H,d,J=5.9 Hz).

0239-2

(5-((7-(1-(3-(Pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazol-2-yl)methanol was obtained as a yellow solid in the same manner as in Example 0001-5.

1 H-NMR(DMSO-d 6 )δ:12.09(1H,s),9.09(1H,d,J=2.0 Hz),8.60(1H,s),8.32-8.25(2H,m),8.23(1H,s),7.41(1H,d,J=8.9 Hz),5.98(1H,t,J=5.8 Hz),4.82(2H,d,J=5.9 Hz),4.21(2H,t,J=6.9 Hz),2.47-2.40(6H,m),2.09-1.99(2H,m),1.70(4H,s).

MSm/z(M+H):437.

Examples 0240 and 0241

The following compounds were obtained in the same manner as in Examples 0198-1, 0001-4 and 0001-5.

›Example 0242

0242-1

Ethyl (5-amino-1,3,4-thiadiazol-2-yl)acetate (15 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (10 mg), cesium carbonate (90 mg), and tris(dibenzylideneacetone)dipalladium(0) (10 mg) were added to a solution of 2-chloro-7-(1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (25 mg) in 1,4-dioxane (1 mL), followed by stirring at 150° C. for 1 hour using a microwave reaction apparatus. After the reaction mixture was cooled to room temperature, a mixed solvent of chloroform-methanol was added thereto, and the resultant product was purified by silica gel column chromatography (chloroform-methanol, NH silica), and purified by preparative thin layer silica gel chromatography (chloroform-methanol, NH silica), thereby obtaining ethyl (5-((7-(1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazol-2-yl)acetate (17 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.17(1H,s),9.09(1H,d,J=2.3 Hz),8.58(1H,s),8.32-8.26(2H,m),8.21(1H,s),7.42(1H,d,J=8.9 Hz),4.25-4.15(4H,m),3.71(3H,s),2.46-2.37(6H,m),2.06-1.96(2H,m),1.71-1.67(4H,m).

MSm/z(M+H):479.

›Example 0243

0243-1

N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-(tetrahydrofuran-3-yl)-1,3,4-thiadiazole-2-amine was obtained as a white solid in the same manner as in Example 0001-5.

1 H-NMR(DMSO-d 6 )δ:12.12(1H,s),9.07(1H,d,J=2.0 Hz),8.52(1H,s),8.32(1H,d,J=1.3 Hz),8.26(1H,d,J=8.9 Hz),8.21(1H,s),7.40(1H,d,J=8.9 Hz),4.15-4.08(1H,m),4.02-3.82(7H,m),2.48-2.39(1H,m),2.31-2.19(1H,m).

MSm/z(M+H):380.

›Example 0244

0244-1

0.5 mol/L sodium hydroxide aqueous solution (20 mL) was added to tetrahydropyran-2-methanol (1.16 g), followed by stirring at room temperature for 5 minutes. Potassium permanganate (3.30 g) was added to the reaction mixture, followed by stirring at 90° C. for 1 hour. Potassium permanganate (1.58 g) was added thereto, followed by stirring at 90° C. for 30 minutes. After the reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and ethyl acetate was added thereto. After the aqueous layer was collected by separation, the aqueous layer was neutralized by the addition of hydrochloric acid under ice-cooling, and the water was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining tetrahydro-2H-pyran-2-carboxylic acid (150 mg) as colorless oily substance.

1 H-NMR(CDCl 3 )δ:4.16-4.08(1H,m),4.02-3.94(1H,m),3.60-3.42(2H,m),2.11-2.04(1H,m),1.97-1.90(1H,m),1.61-1.54(3H,m).

0244-2

5-(Tetrahydro-2H-pyran-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a white solid in the same manner as in Example 0198-1.

MSm/z(M+H):186.

0244-3

N-(7-(1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-(tetrahydro-2H-pyran-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a yellow solid in the same manner as in Example 0001-5.

1 H-NMR(DMSO-d 6 )δ:12.09(1H,s),9.02(1H,s),8.58(1H,s),8.29-8.15(3H,m),7.34(1H,d,J=8.9 Hz),4.77(1H,t,J=5.0 Hz),4.21(2H,t,J=6.9 Hz),4.04(1H,d,J=11.6 Hz),3.64(1H,dd,J=14.4,10.4 Hz),2.40(6H,t,J=7.1 Hz),2.18-1.82(4H,m),1.81-1.55(8H,m).

MSm/z(M+H):491.

›Example 0245

The following compounds were obtained in the same manner as in Examples 0198-1, 0001-4 and 0001-5.

›Example 0246

0246-1

Water (5 mL) was added to pyrrolidine-2-carboxylic acid (230 mg) and sodium carbonate (500 mg), followed by stirring at room temperature for 5 minutes. A tetrahydrofuran solution (5 mL) of (9-fluorenylmethyl)succinimidyl carbonate (720 mg) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture. The aqueous layer was neutralized by the addition of hydrochloric acid, extracted three times with ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (620 mg).

1 H-NMR(DMSO-d 6 )δ:12.62(1H,s),7.93-7.87(2H,m),7.70-7.62(2H,m),7.45-7.29(4H,m),4.35-4.27(1H,m),4.21-4.13(2H,m),3.47-3.36(2H,m),2.59(1H,s),2.40-2.11(1H,m),1.92-1.80(3H,m).

0246-2

Phosphorus oxychloride (5 mL) was added to 1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (505 mg) and thiosemicarbazide (175 mg), followed by stirring at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and added dropwise to water. The resultant product was neutralized by the addition of a sodium hydroxide aqueous solution under ice-cooling, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate, NH silica), thereby obtaining (9H-fluoren-9-yl)methyl 2-(5-amino-1,3,4-thiadiazol-2-yl)pyrrolidine-1-carboxylate (238 mg).

MSm/z(M+H):393.

0246-3

(9H-fluoren-9-yl)methyl 2-(5-amino-1,3,4-thiadiazol-2-yl)pyrrolidine-1-carboxylate (115 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (20 mg), cesium carbonate (150 mg), and tris(dibenzylideneacetone)dipalladium(0) (20 mg) were added to a solution of 2-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine (75 mg) in 1,4-dioxane (1 mL), followed by stirring at 100° C. for 3 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and chloroform and methanol were added thereto. The obtained solution was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-(pyrrolidin-2-yl)-1,3,4-thiadiazole-2-amine (64 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:11.93(1H,s),9.06(1H,d,J=2.0 Hz),8.54(1H,s),8.23(3H,dd,J=8.3,5.9 Hz),7.40(1H,d,J=8.9 Hz),4.54-4.47(1H,m),3.92(3H,s),3.02-2.90(2H,m),2.28-2.13(1H,m),2.01-1.90(1H,m),1.86-1.72(2H,m).

MSm/z(M+H):379.

›Example 0247

0247-1

A 20% formaldehyde solution (10 μL) and sodium triacetoxyborohydride (10 mg) were added to a solution of N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-(pyrrolidin-2-yl)-1,3,4-thiadiazole-2-amine (17 mg) in methanol (1 mL), followed by stirring at room temperature for 30 minutes. A 20% formaldehyde solution (10 μL) and sodium triacetoxyborohydride (5 mg) were added thereto, followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and water and ethyl acetate were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-(1-methylpyrrolidin-2-yl)-1,3,4-thiadiazole-2-amine (5 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.06(1H,s),9.07(1H,d,J=2.0 Hz),8.56(1H,s),8.25(3H,t,J=5.8 Hz),7.41(1H,d,J=8.9 Hz),3.93(3H,s),3.67(1H,t,J=7.6 Hz),2.38-2.25(5H,m),1.99-1.81(4H,m).

MSm/z(M+H):393.

›Example 0248

0248-1

Pyridine (40 μL) and acetyl chloride (7 μL) were added to a solution of N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-(pyrrolidin-2-yl)-1,3,4-thiadiazole-2-amine (15 mg) in dichloromethane (3 mL), followed by stirring at room temperature for 5 minutes. The reaction mixture was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 1-(2-(5-((7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazol-2-yl)pyrrolidin-1-yl)ethanone (10 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.11(1H,s),9.06(1H,d,J=2.0 Hz),8.50(1H,s),8.26-8.19(3H,m),7.40(1H,d,J=8.9 Hz),5.50-5.31(1H,m),3.93(3H,s),3.78-3.46(2H,m),2.32-1.95(7H,m).

MSm/z(M+H):421.

›Example 0249

0249-1

A mixture of 7-bromo-1,5-naphthyridine-2-amine (50 mg), sodium carbonate (47 mg), 1-(2-morpholinoethyl)-1H-pyrazole-4-boronic acid pinacol ester (137 mg), bis(tri-tert-butylphosphine)palladium(0) (11 mg), 1,4-dioxane (1 mL), and water (0.1 mL) was stirred at 140° C. for 1 hour using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 7-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine (49 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:8.78(1H,d,J=2.0 Hz),8.41(1H,s),8.08(1H,s),7.89(2H,dd,J=7.1,5.8 Hz),6.90(1H,d,J=8.9 Hz),6.65(2H,s),4.27(2H,t,J=6.6 Hz),3.59-3.51(4H,m),2.75(2H,t,J=6.6 Hz),2.43(4H,t,J=4.5 Hz).

0249-2

Phenyl chlorocarbonate (60 μL) was added to a solution of 7-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine (168 mg) in pyridine (10 mL), and candy-like lumps were dissolved using an ultrasonic cleaning machine. The reaction liquid was stirred at room temperature for 1 hour, and phenyl chlorocarbonate (20 μL) was added thereto, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining phenyl (7-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)carbamate (84 mg).

1 H-NMR(DMSO-d 6 )δ:11.21(1H,s),9.18(1H,d,J=2.0 Hz),8.57(1H,s),8.38(1H,d,J=9.2 Hz),8.27(1H,d,J=1.7 Hz),8.23-8.18(2H,m),7.49-7.42(2H,m),7.33-7.25(3H,m),4.30(2H,t,J=6.4 Hz),3.56(4H,t,J=4.6 Hz),2.78(2H,t,J=6.6 Hz),2.44(4H,t,J=4.5 Hz).

0249-3

4-Methylthiosemicarbazide (7 mg) was added to a solution of phenyl (7-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)carbamate (20 mg) in 1,4-dioxane (1.2 mL), followed by stirring at 70° C. for 1 hour. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, thereby obtaining 2-(methylcarbamothioyl)-N-(7-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)hydrazinecarboxamide (20 mg).

MSm/z(M+H):456.

0249-4

Phosphorus oxychloride (500 μL) was added to 2-(methylcarbamothioyl)-N-(7-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)hydrazinecarboxamide (7 mg), followed by stirring at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, and added dropwise to water. The resultant product was neutralized by the addition of a sodium hydroxide aqueous solution under ice-cooling, and chloroform was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining N 2 -methyl-N 5 -(7-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2,5-diamine (1.4 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:11.52(1H,s),8.97(1H,s),8.51(1H,s),8.11(3H,t,J=7.3 Hz),7.26(1H,d,J=9.2 Hz),7.06(1H,s),4.29(2H,t,J=6.6 Hz),3.56(4H,t,J=4.6 Hz),2.87(3H,d,J=4.6 Hz),2.78(2H,t,J=6.6 Hz),2.44(4H,t,J=4.5 Hz).

MSm/z(M+H):438.

›Example 0250

0250-1

N-(7-bromo-1,5-naphthyridin-2-yl)-5-((tetrahydrofuran-2-yl)methyl)-N-((2-(trimethylsilyl)methoxy)methyl)-1,3,4-thiadiazole-2-amine was obtained as brown oily substance in the same manner as in Example 0175-2.

MSm/z(M+H):522,524.

0250-2

3-Amino-5-methoxypyridine (14 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (5 mg), cesium carbonate (45 mg), and tris(dibenzylideneacetone)dipalladium(0) (5 mg) were added to a solution of N-(7-bromo-1,5-naphthyridin-2-yl)-5-((tetrahydrofuran-2-yl)methyl)-N-((2-(trimethylsilyl)methoxy)methyl)-1,3,4-thiadiazole-2-amine (58 mg) in 1,4-dioxane (2 mL), followed by stirring at 100° C. in a nitrogen atmosphere overnight. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure, thereby obtaining N 7 -(5-methoxypyridin-3-yl)-N 2 -(5-((tetrahydrofuran-2-yl)methyl)-1,3,4-thiadiazol-2-yl)-N 2 -((2-(trimethylsilyl)ethoxy)methyl)-1,5-naphthyridine-2,7-diamine.

A 4 mol/L hydrogen chloride/1,4-dioxane solution (2 mL) was added to the obtained N 7 -(5-methoxypyridin-3-yl)-N 2 -(5-((tetrahydrofuran-2-yl)methyl)-1,3,4-thiadiazol-2-yl)-N 2 -((2-(trimethylsilyl)ethoxy)methyl)-1,5-naphthyridine-2,7-diamine, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, the resultant product was neutralized with a saturated sodium hydrogen carbonate aqueous solution, and a chloroform-methanol solution was added thereto. The organic layer was collected by separation, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol), thereby obtaining N 7 -(5-methoxypyridin-3-yl)-N 2 -(5-((tetrahydrofuran-2-yl)methyl)-1,3,4-thiadiazol-2-yl)-1,5-naphthyridine-2,7-diamine (7 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:11.92(1H,s),11.92-1.49(1H,m),9.11(1H,s),8.59(1H,d,J=2.6 Hz),8.17-8.13(2H,m),7.98(1H,d,J=2.6 Hz),7.64(1H,d,J=2.3 Hz),7.27(1H,t,J=2.3 Hz),7.22(1H,d,J=8.9 Hz),4.18-4.10(1H,m),3.85(3H,s),3.84-3.78(1H,m),3.72-3.64(1H,m),3.22-3.13(1H,m),2.06-1.94(1H,m),1.90-1.78(2H,m),1.62-1.49(1H,m).

MSm/z(M+H):436.

›Example 0251

The following compounds were obtained in the same manner as in Examples 0246-1 to 0246-3.

›Example 0252

0252-1

N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-(1-methylpyrrolidin-3-yl)-1,3,4-thiadiazole-2-amine was obtained as a yellow solid in the same manner as in Example 0247-1.

1 H-NMR(DMSO-d 6 )δ:12.01(1H,s),9.07(1H,d,J=2.0 Hz),8.52(1H,s),8.29-8.21(3H,m),7.40(1H,d,J=9.2 Hz),3.93(3H,s),3.86-3.76(2H,m),3.01-2.93(1H,m),2.81-2.58(2H,m),2.43-2.24(4H,m),2.23-2.09(1H,m).

MSm/z(M+H):393.

›Example 0253

0253-1

1-(3-(5-((7-(1-Methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazol-2-yl)pyrrolidin-1-yl)ethanone was obtained as a yellow solid in the same manner as in Example 0247-1.

1 H-NMR(DMSO-d 6 )δ:9.09-9.06(1H,m),8.52(1H,s),8.33-8.31(1H,m),8.26(1H,d,J=9.2 Hz),8.21(1H,s),7.40(1H,d,J=8.9 Hz),4.01-3.95(1H,m),3.93(3H,s),3.89-3.75(2H,m),3.73-3.50(2H,m),3.06-2.92(1H,m),2.47-2.09(2H,m),2.01(2H,d,J=5.0 Hz).

MSm/z(M+H):421.

›Example 0254

0254-1

Thiosemicarbazide (7 mg) was added to a solution of phenyl ((7-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)carbamate (43 mg) in 1,4-dioxane (1 mL), followed by stirring at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, thereby obtaining 2-carbamothioyl-N-(7-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)hydrazinecarboxamide. Phosphorus oxychloride (1 mL) was added to the obtained 2-carbamothioyl-N-(7-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)hydrazinecarboxamide, followed by stirring at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, and added dropwise to water. The resultant product was neutralized by the addition of a sodium hydroxide aqueous solution under ice-cooling, and chloroform was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining N 2 -(7-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2,5-diamine (2 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:11.42(1H,s),9.00(1H,d,J=1.7 Hz),8.51(1H,s),8.18-8.09(3H,m),7.31(1H,d,J=9.2 Hz),6.61(2H,s),4.33-4.26(2H,m),3.59-3.53(4H,m),2.82-2.75(2H,m),2.47-2.41(4H,m).

MSm/z(M+H):424.

›Example 0255

0255-1

Methanesulfonyl chloride (20 μL) was added to a solution of (5-((7-(1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)amino)-1,3,4-thiadiazol-2-yl)methanol and pyridine (200 μL) in N,N-dimethylformamide (500 μL) under ice-cooling, followed by stirring at 0° C. for 30 minutes. Morpholine (50 μL) was added to the reaction mixture, followed by stirring at 0° C. for 1 hour. Morpholine (50 μL) was added thereto, followed by stirring at room temperature for 30 minutes. Ethyl acetate and water were added to the reaction mixture, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 5-(morpholinomethyl)-N-(7-(1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (4.5 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.12(1H,s),9.09(1H,d,J=2.0 Hz),8.59(1H,s),8.31(1H,d,J=2.0 Hz),8.27(1H,d,J=9.2 Hz),8.23(1H,s),7.41(1H,d,J=8.9 Hz),4.22(2H,t,J=6.9 Hz),3.89(2H,s),3.66-3.58(4H,m),3.44-3.38(2H,m),2.46-2.39(8H,m),2.07-1.98(2H,m),1.70(4H,s).

MSm/z(M+H):506.

›Example 0256

0256-1

A solution of cyclopropylacetonitrile (486 mg) and thiosemicarbazide (455 mg) in trifluoroacetic acid (5 mL) was stirred at 65° C. for 2 hours. The reaction mixture was cooled to room temperature, neutralized by the addition of a sodium hydroxide aqueous solution, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with a hexane-ethyl acetate solution, thereby obtaining 5-(cyclopropylmethyl)-1,3,4-thiadiazole-2-amine (536 mg).

MSm/z(M+H):156.

0256-2

5-(Cyclopropylmethyl)-N-(7-(1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a yellow solid in the same manner as in Example 0001-5.

1 H-NMR(DMSO-d 6 )δ:12.07(1H,s),9.08(1H,d,J=2.0 Hz),8.56(1H,s),8.30(1H,d,J=1.7 Hz),8.26(1H,d,J=9.2 Hz),8.22(1H,s),7.40(1H,d,J=8.9 Hz),4.22(2H,t,J=6.9 Hz),2.93(2H,d,J=6.9 Hz),2.48-2.40(5H,m),2.09-1.97(2H,m),1.75-1.66(4H,m),1.25-1.12(1H,m),1.24-1.12(1H,m),0.64-0.59(2H,m),0.40-0.33(2H,m).

MSm/z(M+H):461.

›Example 0257

0257-1

5-((Methylsulfonyl)methyl)-1,3,4-thiadiazole-2-amine was obtained in the same manner as in Example 0256-1.

MSm/z(M+H):194.

0257-2

N-(7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-((methylsulfonyl)methyl)-1,3,4-thiadiazole-2-amine was obtained as a yellow solid in the same manner as in Example 0246-3.

1 H-NMR(DMSO-d 6 )δ:9.09(1H,d,J=2.0 Hz),8.51(1H,s),8.37(1H,s),8.30(1H,d,J=8.9 Hz),8.25(1H,d,J=1.7 Hz),8.18(1H,s),7.45(1H,d,J=8.9 Hz),5.08(2H,s),3.93(3H,s),3.13(3H,s).

MSm/z(M+H):402.

Examples 0258 to 0263

The following compounds were obtained in the same manner as in Examples 0256-1 and 0001-5.

›Example 0264

0264-1

Phenylboronic acid (40 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (10 mg), sodium carbonate (45 mg), and water (200 μL) were added to a solution of 8-bromo-2-methoxy-1,5-naphthyridine (60 mg) in 1,4-dioxane (1 mL), followed by stirring at 120° C. for 1 hour using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and ethyl acetate and a saturated sodium chloride aqueous solution were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining 2-methoxy-8-phenyl-1,5-naphthyridine (50 mg).

1 H-NMR(DMSO-d 6 )δ:8.85(1H,d,J=4.3 Hz),8.33(1H,d,J=9.2 Hz),7.94-7.91(2H,m),7.75(1H,d,J=4.6 Hz),7.57-7.48(3H,m),7.30(1H,d,J=9.2 Hz),3.91(3H,s).

0264-2

Hydrochloric acid (2 mL) was added to 2-methoxy-8-phenyl-1,5-naphthyridine (49 mg), followed by stirring at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, neutralized with a sodium hydroxide aqueous solution, and ethyl acetate was added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 8-phenyl-1,5-naphthyridin-2-ol (45 mg).

1 H-NMR(DMSO-d 6 )δ:10.40(1H,s),8.54(1H,d,J=4.6 Hz),8.02(1H,d,J=9.9 Hz),7.57-7.51(5H,m),7.43(1H,d,J=5.0 Hz),6.81(1H,d,J=9.6 Hz).

0264-3

Phosphorus oxychloride (500 μL) and N,N-dimethylformamide (2 mL) were added to 8-phenyl-1,5-naphthyridin-2-ol (39 mg), followed by stirring at 80° C. for 30 minutes. Phosphorus oxychloride (400 μL) was added thereto, followed by stirring at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and added dropwise to water. The resultant product was neutralized by the addition of a sodium hydroxide aqueous solution, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining 2-chloro-8-phenyl-1,5-naphthyridine (25 mg).

1 H-NMR(DMSO-d 6 )δ:9.08(1H,d,J=4.6 Hz),8.55(1H,d,J=8.9 Hz),7.92-7.86(2H,m),7.80-7.75(2H,m),7.60-7.52(3H,m).

0264-4

2-Amino-5-isopropyl-1,3,4-thiadiazole (8 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (5 mg), cesium carbonate (15 mg), and tris(dibenzylideneacetone)dipalladium(0) (5 mg) were added to a solution of 2-chloro-8-phenyl-1,5-naphthyridine (10 mg) in 1,4-dioxane (1 mL), followed by stirring at 150° C. for 45 minutes using a microwave reaction apparatus. After the reaction mixture was cooled to room temperature, a mixed solvent of chloroform-methanol was added thereto, and the obtained solution was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 5-isopropyl-N-(8-phenyl-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (3 mg) as a pale yellow solid.

1 H-NMR(DMSO-d 6 )δ:11.99(1H,s),8.80(1H,d,J=4.6 Hz),8.35(1H,d,J=8.9 Hz),7.66-7.48(7H,m),3.21-3.10(1H,m),1.21(6H,d,J=7.2 Hz).

MSm/z(M+H):348.

Examples 0265 and 0266

The following compounds were obtained in the same manner as in Examples 0256-1 and 0001-5.

›Example 0267

0267-1

Triethylamine (800 μL) was added to a solution of (tetrahydrofuran-3-yl)methanol (410 mg) in dichloromethane (4 mL), and methanesulfonyl chloride (350 μL) was added dropwise thereto under ice-cooling, followed by stirring at 0° C. for 30 minutes. Methanesulfonyl chloride (50 μL) was added thereto, followed by stirring at 0° C. for 30 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining (tetrahydrofuran-3-yl)methyl methanesulfonate (540 mg).

1 H-NMR(CDCl 3 )δ:4.21-4.10(2H,m),3.88-3.63(4H,m),3.05(3H,s),2.75-2.64(1H,m),2.18-2.04(1H,m),1.76-1.62(1H,m).

0267-2

Sodium cyanide (70 mg) was added to a solution of (tetrahydrofuran-3-yl)methyl methanesulfonate (200 mg) in dimethylsulfoxide (3 mL), followed by stirring at 80° C. overnight. The reaction mixture was cooled to room temperature, and ethyl acetate and a saturated sodium chloride aqueous solution were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining 2-(tetrahydrofuran-3-yl)acetonitrile (80 mg).

1 H-NMR(CDCl 3 )δ:3.98-3.87(2H,m),3.84-3.77(1H,m),3.60-3.52(1H,m),2.65-2.56(1H,m),2.50-2.37(2H,m),2.25-2.14(1H,m),1.78-1.66(1H,m).

0267-3 and 0267-4

The following compounds were obtained in the same manner as in Examples 0256-1 and 0001-5.

›Example 0268

0268-1

3-Pyridylboronic acid (35 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5 mg), and a 2 mol/L sodium carbonate aqueous solution (100 μL) were added to a solution of 8-bromo-1,5-naphthyridin-2-ol (50 mg) in 1,4-dioxane (1.5 mL), followed by stirring at 130° C. for 1 hour using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and ethyl acetate was added thereto. The obtained solution was purified by silica gel column chromatography (ethyl acetate-methanol, NH silica), thereby obtaining 8-(pyridin-3-yl)-1,5-naphthyridin-2-ol (33 mg).

1 H-NMR(DMSO-d 6 )δ:11.12(1H,s),8.68(2H,dd,J=5.0,1.7 Hz),8.55(1H,d,J=4.3 Hz),8.02(1H,d,J=10.2 Hz),7.93(1H,d,J=7.6 Hz),7.55(1H,ddd,J=7.8,4.9,0.7 Hz),7.46(1H,d,J=4.3 Hz),6.81(1H,d,J=9.2 Hz).

0268-2

Triethylamine (50 μL) was added to a solution of 8-(pyridin-3-yl)-1,5-naphthyridin-2-ol (25 mg) in dichloromethane (2 mL), and trifluoromethanesulfonic acid anhydride (20 μL) was added dropwise thereto under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate, NH silica), thereby obtaining (8-(pyridin-3-yl)-1,5-naphthyridin-2-yl) trifluoromethanesulfonate.

2-Amino-5-isopropyl-1,3,4-thiadiazole (14 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (5 mg), cesium carbonate (20 mg), and tris(dibenzylideneacetone)dipalladium(0) (5 mg) were added to a solution of the obtained (8-(pyridin-3-yl)-1,5-naphthyridin-2-yl) trifluoromethanesulfonate in 1,4-dioxane (1.5 mL), followed by stirring at 150° C. for 45 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and a mixed solvent of chloroform-methanol was added thereto. The obtained solution was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 5-isopropyl-N-(8-(pyridin-3-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (6 mg) as a pale yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.06(1H,s),8.87(1H,d,J=1.3 Hz),8.84(1H,d,J=4.3 Hz),8.73(1H,dd,J=5.0,1.7 Hz),8.38(1H,d,J=8.9 Hz),8.10-8.04(1H,m),7.71(1H,d,J=4.6 Hz),7.65-7.58(1H,m),7.52(1H,d,J=9.2 Hz),3.22-3.12(1H,m),1.24(6H,d,J=7.2 Hz).

MSm/z(M+H):349.

›Example 0269

0269-1

2-Methoxy-8-(pyridin-4-yl)-1,5-naphthyridine was obtained in the same manner as in Example 0264-1.

1 H-NMR(DMSO-d 6 )δ:8.91(1H,d,J=4.3 Hz),8.75-8.72(2H,m),8.37(1H,d,J=8.9 Hz),7.93-7.91(2H,m),7.86-7.83(1H,m),7.34(1H,d,J=8.9 Hz),3.93(3H,s).

0269-2

Hydrochloric acid (3 mL) was added to 2-methoxy-8-(pyridin-4-yl)-1,5-naphthyridine (90 mg), followed by stirring at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, neutralized with a sodium hydroxide aqueous solution, and the solvent was distilled off under reduced pressure, thereby obtaining 8-(pyridin-4-yl)-1,5-naphthyridine-2-ol. Triethylamine (300 μL) was added to a solution of the obtained 8-(pyridin-4-yl)-1,5-naphthyridin-2-ol in dichloromethane (3 mL), and trifluoromethanesulfonic acid anhydride (150 μL) was added dropwise thereto under ice-cooling, followed by stirring at room temperature for 30 minutes. Water was added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, then, the solvent was distilled off under reduced pressure, and the resultant product was purified by silica gel column chromatography (hexane-ethyl acetate, NH silica), thereby obtaining (8-(pyridin-4-yl)-1,5-naphthyridin-2-yl) trifluoromethanesulfonate. 2-Amino-5-isopropyl-1,3,4-thiadiazole (30 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (10 mg), cesium carbonate (70 mg), and tris(dibenzylideneacetone)dipalladium(0) (10 mg) were added to a solution of the obtained (8-(pyridin-4-yl)-1,5-naphthyridin-2-yl) trifluoromethanesulfonate in 1,4-dioxane (2 mL), followed by stirring at 150° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and purified by silica gel column chromatography (ethyl acetate-methanol, NH silica), thereby obtaining 5-isopropyl-N-(8-(pyridin-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (23 mg) as a pale yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.07(1H,s),8.84(1H,d,J=4.6 Hz),8.77(2H,dd,J=4.5,1.5 Hz),8.38(1H,d,J=8.9 Hz),7.68-7.65(3H,m),7.51(1H,d,J=9.2 Hz),3.24-3.09(1H,m),1.22(6H,d,J=7.2 Hz).

MSm/z(M+H):349.

Examples 0270 to 0276

The following compounds were obtained in the same manner as in Examples 0268-1 and 0268-2.

›Example 0277

0277-1

N-(5-methyl-1H-pyrazol-3-yl)-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine was obtained as a white solid in the same manner as in Example 0246-3.

1 H-NMR(CD 3 OD)δ:7.62(1H,d,J=1.7 Hz),7.03(1H,s),6.91(1H,d,J=9.6 Hz),6.84(1H,s),6.62(1H,s),5.90(1H,d,J=9.2 Hz),4.57(1H,s),2.48(3H,s),0.88(3H,s).

MSm/z(M+H):306.

›Example 0278

0278-1

5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (5 mg), bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3 mg), and a 2 mol/L sodium carbonate aqueous solution (50 μL) were added to a solution of N-(8-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-N-((2-trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (10 mg) in 1,4-dioxane (1 mL), followed by stirring at 130° C. for 45 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained solution was purified by silica gel column chromatography (hexane-ethyl acetate, NH silica), thereby obtaining 5-isopropyl-N-(8-(pyrimidin-5-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine.

Trifluoroacetic acid (1 mL) and water (50 μL) were added to the obtained 5-isopropyl-N-(8-(pyrimidin-5-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine, followed by stirring at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, triethylamine (2 drops) was added thereto, and the resultant product was purified by silica gel column chromatography (ethyl acetate-methanol, NH silica), thereby obtaining 5-isopropyl-N-(8-(pyrimidin-5-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (0.58 mg).

1 H-NMR(DMSO-d 6 )δ:12.14(1H,s),9.37(1H,s),9.15(2H,s),8.88(1H,d,J=4.6 Hz),8.40(1H,d,J=8.9 Hz),7.82(1H,d,J=4.3 Hz),7.54(1H,d,J=9.2 Hz),3.26-3.15(1H,m),1.27(6H,d,J=6.9 Hz).

MSm/z(M+H):350.

Examples 0279 and 0280

The following compounds were obtained in the same manner as in Example 0278-1.

›Example 0281

0281-1

2-(Tributyltin)pyridine (15 μL), tetrakis(triphenylphosphine)palladium(0) (5 mg), and cesium carbonate (20 mg) were added to a solution of N-(8-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-N-((2-trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (10 mg) in 1,4-dioxane (1 mL), followed by stirring at 100° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 5-isopropyl-N-(8-(pyridin-2-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine.

Trifluoroacetic acid (1 mL) and water (50 μL) were added to the obtained 5-isopropyl-N-(8-(pyridin-2-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine, followed by allowing to stand at room temperature overnight. The solvent was distilled off under reduced pressure, and ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol, NH silica), thereby obtaining 5-isopropyl-N-(8-(pyridin-2-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (2.5 mg).

1 H-NMR(DMSO-d 6 )δ:12.05(1H,s),8.85(1H,d,J=4.3 Hz),8.81(1H,d,J=5.0 Hz),8.38(1H,d,J=8.9 Hz),8.03-7.93(2H,m),7.77(1H,d,J=4.6 Hz),7.58-7.55(1H,m),7.52(1H,d,J=9.2 Hz),3.24-3.16(1H,m),1.23(6H,d,J=6.9 Hz).

MSm/z(M+H):349.

Examples 0282 and 0283

The following compounds were obtained in the same manner as in Example 0278-1.

Examples 0284 and 0285

The following compounds were obtained in the same manner as in Example 0278-1.

›Example 0286

0286-1

Morpholine (50 μL), tris(dibenzylideneacetone)palladium(0) (3.1 mg), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (5 mg), and cesium carbonate (30 mg) were added to a solution of N-(8-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (15 mg) in 1,4-dioxane (1 mL), followed by stirring at 150° C. for 30 minutes using a microwave reaction apparatus. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 5-isopropyl-N-(8-morpholino-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine.

Trifluoroacetic acid (1 mL) was added to the obtained 5-isopropyl-N-(8-morpholino-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine, followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 5-isopropyl-N-(8-morpholino-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (10 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:8.54(1H,d,J=5.0 Hz),8.22(1H,d,J=8.9 Hz),7.45(1H,d,J=9.2 Hz),7.09(1H,d,J=5.3 Hz),4.01-3.92(4H,m),3.47-3.38(5H,m),1.41(6H,d,J=6.9 Hz).

MSm/z(M+H):357.

Examples 0287 and 0288

The following compounds were obtained in the same manner as in Example 0278-1.

›Example 0289

0289-1

2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5 mg), and a 2 mol/L sodium carbonate aqueous solution (100 μL) were added to a solution of N-(8-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-N-((2-trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (10 mg) in 1,4-dioxane (1 mL), followed by stirring at 130° C. for 45 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 5-isopropyl-N-(8-(2-methoxypyridin-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine.

Hydrobromic acid (1 mL) was added to the obtained 5-isopropyl-N-(8-(2-methoxypyridin-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine, followed by stirring at 80° C. for 3 hours. The solvent was distilled off under reduced pressure, the resultant product was neutralized by the addition of a saturated sodium hydrogen carbonate aqueous solution, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol, NH silica), thereby obtaining 4-(6-((5-isopropyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-4-yl)pyridin-2(1H)-one (0.7 mg) as a pale yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.08(1H,s),8.81(1H,d,J=4.3 Hz),8.36(1H,dd,J=9.2,2.0 Hz),7.84(1H,d,J=6.9 Hz),7.65(1H,d,J=4.6 Hz),7.51(2H,dd,J=9.2,2.3 Hz),6.67(1H,d,J=1.3 Hz),6.46(1H,dd,J=6.9,2.0 Hz),3.25-3.19(1H,m),1.26(6H,d,J=6.9 Hz).

MSm/z(M+H):365.

Examples 0290 to 0294

The following compounds were obtained in the same manner as in Examples 0015-1 to 0015-4.

›Example 0295

0295-1 and 0295-2

The following compounds were obtained in the same manner as in Examples 0015-1 and 0015-2.

0295-3

Ammonium formate (120 mg), triethylamine (200 μL), and tetrakis(triphenylphosphine)palladium(0) (50 mg) were added to a solution of 6-chloro-5-cyclopropyl-N-(2,4-dimethoxybenzyl)pyridazine-3-amine (300 mg) in 1,4-dioxane (1.2 mL), followed by stirring at 100° C. for 3 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol, NH silica), thereby obtaining 5-cyclopropyl-N-(2,4-dimethoxybenzyl)pyridazine-3-amine (235 mg).

MSm/z(M+H):286.

0295-4

Trifluoroacetic acid (3 mL) was added to 5-cyclopropyl-N-(2,4-dimethoxybenzyl)pyridazine-3-amine (235 mg), followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, the resultant product was neutralized with a saturated sodium hydrogen carbonate aqueous solution, and chloroform was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 5-cyclopropylpyridazine-3-amine (105 mg).

MSm/z(M+H):136.

0295-5

N-(5-cyclopropylpyridazin-3-yl)-7-(1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine was obtained in the same manner as in Examples 0015-1 and 0015-2.

1 H-NMR(DMSO-d 6 )δ:10.63(1H,s),9.04(1H,d,J=2.3 Hz),8.64(1H,d,J=2.0 Hz),8.60(1H,d,J=2.0 Hz),8.51(1H,s),8.25(1H,d,J=1.7 Hz),8.20(2H,d,J=9.2 Hz),7.66(1H,d,J=9.2 Hz),4.22(2H,t,J=6.9 Hz),2.47-2.38(6H,m),2.13-1.97(3H,m),1.73-1.64(4H,m),1.23-1.17(2H,m),1.04-0.96(2H,m).

MSm/z(M+H):441.

›Example 0296

The following compounds were obtained in the same manner as in Examples 0015-1 to 0015-4.

›Example 0297

0297-1

Phenylboronic acid (60 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5 mg), and a 2 mol/L sodium carbonate aqueous solution (50 μL) were added to a solution of 5-chloropyridazin-3(2H)-one (50 mg) in 1,4-dioxane (1 mL), followed by stirring at 130° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol, NH silica), thereby obtaining 5-phenylpyridazin-3(2H)-one (25 mg).

1 H-NMR(DMSO-d 6 )δ:13.12(1H,s),8.31(1H,d,J=2.3 Hz),7.85-7.79(2H,m),7.56-7.51(3H,m),7.14(1H,s).

0297-2

A mixture of 5-phenylpyridazin-3(2H)-one (25 mg) and phosphorous oxybromide (1 g) was stirred at 120° C. for 30 minutes. The reaction mixture was added dropwise to a mixture solution of methanol-water (1:10), the resultant product was neutralized by the addition of a sodium hydroxide aqueous solution, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining 3-bromo-5-phenylpyridazine (25 mg).

1 H-NMR(CDCl 3 )δ:9.40(1H,d,J=2.0 Hz),7.85(1H,d,J=2.0 Hz),7.69-7.64(2H,m),7.61-7.53(3H,m).

0297-3

25% ammonia water (1 mL) and copper(I) oxide (10 mg) were added to a solution of 3-bromo-5-phenylpyridazine (60 mg) in ethylene glycol (1 mL), followed by stirring at 150° C. for 45 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, neutralized with 2 mol/L hydrochloric acid, and the resultant product was extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol, NH silica), thereby obtaining 5-phenylpyridazine-3-amine (45 mg).

MSm/z(M+H):172.

0297-4

N-(5-phenylpyridazin-3-yl)-7-(1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine was obtained in the same manner as in Example 0015-4.

1 H-NMR(DMSO-d 6 )δ:10.87(1H,s),9.28(1H,d,J=2.0 Hz),9.06(2H,d,J=2.0 Hz),8.52(1H,s),8.24(3H,dd,J=9.9,8.3 Hz),7.97(2H,dd,J=8.3,1.3 Hz),7.74(1H,d,J=9.2 Hz),7.68-7.58(3H,m),4.21(2H,t,J=6.9 Hz),2.45-2.36(6H,m),2.05-1.95(2H,m),1.70-1.66(4H,m).

MSm/z(M+H):477.

›Example 0298

0298-1

N-(5-cyclopropylpyridazin-3-yl)-7-(1-(3-morpholinopropyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine was obtained as a white solid in the same manner as in Example 0015-4.

1 H-NMR(CDCl 3 )δ:8.93(1H,d,J=1.8 Hz),8.88(1H,brs),8.68-8.62(2H,m),8.23(1H,d,J=9.3 Hz),8.09(1H,m),7.97(1H,s),7.87(1H,s),7.51(1H,d,J=9.3 Hz),4.31(2H,m),3.73(4H,m),2.50-2.34(6H,m),2.13(2H,m),2.01(1H,m),1.27(2H,m),1.03(2H,m).

MSm/z(M+H):457.

›Example 0299

0299-1

A mixture of 2-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine (45 mg), 5-pentyl-4H-1,2,4-triazole-3-amine (56.7 mg), tris(dibenzylideneacetone)dipalladium(0) (21.2 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (35.1 mg), cesium carbonate (120 mg), and 1,4-dioxane (1 mL) was stirred at 100° C. for 2 hours in a nitrogen atmosphere in a sealed tube. The reaction mixture was cooled to room temperature, purified by silica gel column chromatography (chloroform-methanol, NH silica), and purified by preparative thin layer silica gel chromatography (chloroform-methanol), thereby obtaining 7-(1-methyl-1H-pyrazol-4-yl)-N-(5-pentyl-4H-1,2,4-triazol-3-yl)-1,5-naphthyridine-2-amine (4.5 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:13.16(1H,s),11.19(1H,s),9.00(1H,d,J=1.7 Hz),8.79(1H,d,J=1.7 Hz),8.36(1H,s),8.18(1H,d,J=9.2 Hz),8.04(1H,s),7.28(1H,d,J=9.2 Hz),3.94(3H,s),2.58(2H,t,J=7.6 Hz),1.78-1.60(2H,m),1.42-1.25(4H,m),0.97-0.80(3H,m).

MSm/z(M+H):363.

›Example 0300

0300-1

7-(1-Methyl-1H-pyrazol-4-yl)-N-(4H-1,2,4-triazol-3-yl)-1,5-naphthyridine-2-amine was obtained as a yellow solid in the same manner as in Example 0299-1.

1 H-NMR(DMSO-d 6 )δ:13.56(1H,s),11.28(1H,s),9.02(1H,d,J=2.0 Hz),8.83(1H,d,J=2.0 Hz),8.36(1H,s),8.20(1H,d,J=8.6 Hz),8.05(1H,s),7.78(1H,d,J=1.3 Hz),7.32(1H,d,J=8.6 Hz),3.94(3H,s).

MSm/z(M+H):293.

Examples 0301 and 0302

The following compounds were obtained in the same manner as in Examples 0001-4 and 0001-5.

›Example 0303

0303-1

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.473 g), tert-butyl 4-(3-bromopropyl)piperazine-1-carboxylate (0.818 g), potassium carbonate (0.61 g), and N,N-dimethylformamide (5 mL) was stirred at 80° C. for 3 hours in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, diisopropyl ether was added thereto, the solid matter was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining tert-butyl 4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (0.78 g) as yellow oily substance.

1 H-NMR(CDCl 3 )δ:7.56(1H,s),7.45(1H,s),4.19(2H,t,J=6.9 Hz),3.49-3.33(4H,m),2.44-2.26(6H,m),2.13-1.93(2H,m),1.51-1.37(21H,m).

0303-2

60% sodium hydride (40 mg) was added to a solution of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-1,3,4-thiadiazole-2-amine (0.25 g) and 2-(chloromethoxy)ethyltrimethylsilane (125 mg) in N-methylpyrrolidone (32 mL) under ice-cooling, followed by stirring at the same temperature for 1 hour, and stirring at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (601 mg) and (Z)-7-bromo-N-(5-cyclopentyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazol-2(3H)-ylidene)-1,5-naphthyridine-2-amine (255 mg).

MSm/z(M+H):506,508, 506,508.

0303-3

A 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) was added to a solution of the obtained mixture (29.8 mg) in methanol (1 mL) at room temperature, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, methanol and a saturated sodium hydrogen carbonate aqueous solution were added to the obtained residue in order to neutralize, and the water was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 5-cyclopentyl-N-(7-(1-(3-(piperazin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (5.9 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:9.07(1H,d,J=2.3 Hz),8.57(1H,s),8.32(1H,d,J=2.3 Hz),8.28-8.20(2H,m),7.39(1H,d,J=9.2 Hz),4.20(2H,t,J=6.9 Hz),3.60-3.35(1H,m),2.69(4H,t,J=4.6 Hz),2.38-1.61(16H,m).

MSm/z(M+H):490.

›Example 0304

0304-1

5-Cyclopentyl-N-(7-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a yellow solid in the same manner as in Example 0303-3.

1 H-NMR(DMSO-d 6 )δ:12.05(1H,s),9.07(1H,d,J=2.0 Hz),8.57(1H,s),8.32(1H,d,J=2.0 Hz),8.29-8.19(2H,m),7.39(1H,d,J=9.2 Hz),4.26(2H,t,J=6.3 Hz),3.55-3.40(1H,m),2.72(2H,t,J=6.6 Hz),2.31-2.06(8H,m),1.98-1.59(6H,m).

MSm/z(M+H):435.

›Example 0305 and 0305-2

The following compounds were obtained in the same manner as in Examples 0001-4 and 0001-5.

0305-3

A 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) was added to a solution of tert-butyl 4-(3-(4-(6-((1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (59.8 mg) in methanol (1 mL) at room temperature, followed by stirring for 2 hours. The solid matter was collected by filtration, and washed with methanol, thereby obtaining N-(7-(1-(3-(piperazin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine hydrochloride (38.4 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:9.46(2H,brs),9.20(1H,s),9.14(1H,d,J=2.0 Hz),8.63(1H,s),8.40(1H,d,J=2.0 Hz),8.35-8.25(2H,m),7.48(1H,d,=8.6 Hz),4.32(2H,t,J=6.6 Hz),3.84-3.09(10H,m),2.43-2.22(2H,m).

MSm/z(M+H):422.

›Example 0306

0306-1

70% meta-chloroperoxybenzoic acid (200 mg) was added to a solution of 2-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine (200 mg) in dichloromethane (4 mL) at room temperature, followed by stirring at room temperature for 30 minutes. 70% meta-chloroperoxybenzoic acid (200 mg) was added thereto, followed by stirring at room temperature for 30 minutes. 70% meta-chloroperoxybenzoic acid (200 mg) was added thereto, followed by stirring at room temperature for 30 minutes, and 70% meta-chloroperoxybenzoic acid (400 mg) was added thereto, followed by stirring at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution and sodium sulfite were added to the reaction mixture, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine 1-oxide (240 mg) as a yellow solid.

MSm/z(M+H):261,263.

0306-2

Phosphorus oxychloride (2 mL) was added to 6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine 1-oxide (240 mg), followed by stirring at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature, and added dropwise to water. The resultant product was neutralized by the addition of sodium carbonate, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining a mixture (210 mg) of 2,6-dichloro-3-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine and 2,8-dichloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine as a yellow solid.

MSm/z(M+H):279,281.

0306-3

A mixture of a mixture (200 mg) of 2,6-dichloro-3-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine and 2,8-dichloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine,1,4-dioxane (5 mL) and a 25% ammonia aqueous solution (5 mL) was stirred at 120° C. for 2 hours, and stirred at 140° C. for 2 hours using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine (46.9 mg) as a white solid.

MSm/z(M+H):260,262.

0306-4

7-(1-methyl-1H-pyrazol-4-yl)-N 2 -(1,3,4-thiadiazol-2-yl)-1,5-naphthyridine-2,6-diamine was obtained as a yellow solid in the same manner as in Example 0001-5.

1 H-NMR(DMSO-d 6 )δ:11.82(1H,s),9.03(1H,s),8.20(1H,s),7.94-7.79(3H,m),7.30(1H,d,J=9.2 Hz),6.13(2H,brs),3.92(3H,s).

MSm/z(M+H):325.

Examples 0307 to 0310

The following compounds were obtained in the same manner as in Examples 0053-1 and 0053-2.

›Example 0311

0311-1

A mixture of a mixture (20 mg) of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine and (Z)-7-bromo-N-(5-cyclopentyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazol-2(3H)-ylidene)-1,5-naphthyridine-2-amine, morpholine (6.9 μL), tris(dibenzylideneacetone)dipalladium(0) (2.3 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (3.8 mg), sodium tert-butoxide (7.6 mg), and 1,4-dioxane (1 mL) was stirred at 100° C. for 4.5 hours in a nitrogen atmosphere in a sealed tube. The reaction mixture was cooled to room temperature, and methanol (1 mL) and a 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) were added thereto, followed by stirring at 40° C. for 15 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Methanol and triethylamine were added to the obtained residue, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 5-cyclopentyl-N-(7-morpholino-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (9.0 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:11.88(1H,brs),8.72(1H,d,J=2.6 Hz),8.13(1H,d,J=9.2 Hz),7.38(1H,d,J=2.6 Hz),7.20(1H,d,J=9.2 Hz),3.87-3.75(4H,m),3.52-3.28(5H,m),2.22-2.06(2H,m),1.94-1.61(6H,m).

MSm/z(M+H):383.

Examples 0312 to 0314

The following compounds were obtained in the same manner as in Example 0311-1.

›Example 0315

0315-1

A mixture of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (30 mg), isoxazole-3-amine (9.9 mg), tris(dibenzylideneacetone)dipalladium(0) (3.4 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (5.6 mg), cesium carbonate (38.4 mg), and 1,4-dioxane (1 mL) was stirred at 100° C. for 14.5 hours in a nitrogen atmosphere in a sealed tube. The reaction mixture was cooled to room temperature, and methanol and a 4 mol/L hydrogen chloride/1,4-dioxane solution were added thereto, followed by stirring at room temperature for 2 hours, and stirring at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Methanol and triethylamine were added to the obtained residue, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining N 2 -(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-N 7 -(isoxazol-3-yl)-1,5-naphthyridine-2,7-diamine (4.4 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:11.95(1H,brs),10.00(1H,s),8.74(1H,d,J=1.3 Hz),8.69(1H,d,J=2.6 Hz),8.37(1H,d,J=2.6 Hz),8.18(1H,d,J=9.2 Hz),7.27(1H,d,J=9.2 Hz),6.36(1H,d,J=1.3 Hz),3.57-3.39(1H,m),2.24-2.06(2H,m),1.96-1.60(6H,m).

MSm/z(M+H):380.

›Example 0316

0316-1

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.867 g), 3-bromopropyl acetate (0.970 g), potassium carbonate (1.85 g), and acetonitrile (4 mL) was stirred at 65° C. for 16.5 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, the solid matter was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl acetate (1.24 g) as yellow oily substance.

1 H-NMR(CDCl 3 )δ:7.79(1H,s),7.69(1H,s),4.23(2H,t,J=6.6 Hz),4.05(2H,t,J=5.9 Hz),2.26-2.14(2H,m),2.05(3H,s),1.32(12H,s).

0316-2

A mixture of a mixture (100 mg) of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine and (Z)-7-bromo-N-(5-cyclopentyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazol-2(3H)-ylidene)-1,5-naphthyridine-2-amine, 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl acetate (87.1 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (13.9 mg), sodium carbonate (41.8 mg), 1,4-dioxane (1 mL), and water (0.1 mL) was stirred at 150° C. for 30 minutes in a nitrogen atmosphere using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and methanol (1 mL) and a 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) were added thereto, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure, methanol and triethylamine were added to the obtained residue, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 3-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)propan-1-ol (20.1 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:12.03(1H,s),9.08(1H,d,J=2.0 Hz),8.57(1H,s),8.33(1H,d,J=2.0 Hz),8.28-8.21(2H,m),7.39(1H,d,J=9.2 Hz),4.64(1H,t,J=5.0 Hz),4.24(2H,t,J=7.3 Hz),3.56-3.36(3H,m),2.25-1.62(10H,m).

MSm/z(M+H):422.

›Example 0317

0317-1

Methanesulfonyl chloride (0.326 mL) was added to a solution of 3-(dimethylamino)-2,2-dimethylpropan-1-ol (0.50 g) in pyridine (3.8 mL) in an ice bath, followed by stirring at room temperature for 30 minutes. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by stirring at room temperature for 20 minutes, and after sodium chloride was added thereto, ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The obtained solid matter was washed with ethyl acetate, thereby obtaining 3-(dimethylamino)-2,2-dimethylpropyl methanesulfonate (0.327 g) as a white solid.

1 H-NMR(CDCl 3 )δ:4.32(4H,s),3.49(6H,s),2.74(3H,s),1.46(6H,s).

0317-2

N,N,2,2-tetramethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propane-1-amine was obtained as colorless oily substance in the same manner as in Example 0316-1.

1 H-NMR(CDCl 3 )δ:7.76(1H,s),7.65(1H,s),4.02(2H,s),2.31(6H,s),2.16(2H,s),1.32(12H,s),0.90(6H,s).

0317-3

5-Cyclopentyl-N-(7-(1-(3-(dimethylamino)-2,2-dimethylpropyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a white solid in the same manner as in Example 0303-3.

1 H-NMR(DMSO-d 6 )δ:12.04(1H,brs),9.09(1H,d,J=1.7 Hz),8.52(1H,s),8.34(1H,d,J=1.7 Hz),8.28-8.20(2H,m),7.39(1H,d,J=9.2 Hz),4.06(2H,s),3.54-3.37(1H,m),2.30(6H,s),2.25-2.05(4H,m),1.98-1.63(6H,m),0.89(6H,s).

MSm/z(M+H):477.

›Example 0318

0318-1

A mixture of a mixture (30 mg) of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine and (Z)-7-bromo-N-(5-cyclopentyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazol-2(3H)-ylidene)-1,5-naphthyridine-2-amine, bis(pinacolato)diboron (22.5 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (4.8 mg), potassium acetate (11.6 mg), and 1,4-dioxane (1 mL) was stirred at 80° C. for 6 hours in a nitrogen atmosphere in a sealed tube. Bis(pinacolato)diboron (22.5 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (4.8 mg), and potassium acetate (11.6 mg) were added to the reaction mixture, followed by stirring at 80° C. for 14 hours. The reaction mixture was cooled to room temperature, and sodium carbonate (31.4 mg), tert-butyl 4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate (33.5 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.2 mg), and water (0.1 mL) were added thereto, followed by stirring at 100° C. for 23 hours. The reaction mixture was cooled to room temperature, and methanol (1 mL) and a 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) were added thereto, followed by stirring at room temperature for 2 hours, and stirring at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Methanol and triethylamine were added to the obtained residue, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 5-cyclopentyl-N-(7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine.

The obtained 5-cyclopentyl-N-(7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine was dissolved in a mixture of methanol (0.5 mL) and dichloromethane (0.5 mL), and a 36 to 38% formaldehyde aqueous solution (0.5 mL) and sodium triacetoxyborohydride (20 mg) were added thereto at room temperature, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 5-cyclopentyl-N-(7-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (3.5 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.04(1H,brs),9.09(1H,d,J=1.7 Hz),8.65(1H,s),8.34(1H,d,J=1.7 Hz),8.28-8.18(2H,m),7.38(1H,d,J=9.2 Hz),4.27-4.07(1H,m),3.57-3.38(1H,m),2.98-2.80(2H,m),2.31-1.60(17H,m).

MSm/z(M+H):461.

›Example 0319

0319-1

A mixture of a mixture (20 mg) of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine and (Z)-7-bromo-N-(5-cyclopentyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazol-2(3H)-ylidene)-1,5-naphthyridine-2-amine, tetrahydrofuran-3-amine (6.9 mg), tris(dibenzylideneacetone)dipalladium(0) (3.6 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (3.8 mg), cesium carbonate (25.7 mg), and 1,4-dioxane (1 mL) was stirred at 100° C. for 14 hours in a nitrogen atmosphere in a sealed tube. The reaction mixture was cooled to room temperature, and methanol (1 mL) and a 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) were added thereto, followed by stirring at room temperature for 2 days. The solvent was distilled off under reduced pressure, triethylamine was added to the obtained residue, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining N 2 -(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-N 7 -(tetrahydrofuran-3-yl)-1,5-naphthyridine-2,7-diamine (2.0 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:11.76(1H,brs),8.31(1H,d,J=2.3 Hz),8.01(1H,d,J=8.9 Hz),7.05(1H,d,J=8.9 Hz),6.94(1H,d,J=2.3 Hz),6.84(1H,d,J=6.6 Hz),4.27-4.14(1H,m),3.96(1H,dd,J=8.9,5.6 Hz),3.92-3.83(1H,m),3.78(1H,td,J=8.3,5.5 Hz),3.63(1H,dd,J=8.9,3.6 Hz),3.52-3.38(1H,m),2.36-2.21(1H,m),2.20-2.04(2H,m),1.93-1.60(7H,m).

MSm/z(M+H):383.

›Example 0320

0320-1

Pyridine (2.1 mL) and methanesulfonyl chloride (1.0 mL) were added to a solution of 3-(pyrrolidin-1-yl)propan-1-ol (1.14 g) in dichloromethane (18 mL) in an ice bath, followed by stirring for 30 minutes in an ice bath. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol, NH silica), thereby obtaining 3-(pyrrolidin-1-yl)propyl methanesulfonate (1.60 g) as yellow oily substance.

1 H-NMR(CDCl 3 )δ:4.32(2H,t,J=6.6 Hz),3.02(3H,s),2.56(2H,t,J=7.3 Hz),2.53-2.44(4H,m),2.03-1.88(2H,m),1.86-1.71(4H,m).

0320-2 and 0320-3

The following compounds were obtained in the same manner as in Examples 0316-1 and 0303-3.

›Example 0321

0321-1

A mixture of 3-methyl-1-(3-(pyrrolidin-1-yl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-methyl-1-(3-(pyrrolidin-1-yl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was obtained as colorless oily substance in the same manner as in Example 0316-1.

A mixture of the obtained mixture (59.8 mg) of 3-methyl-1-(3-(pyrrolidin-1-yl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-methyl-1-(3-(pyrrolidin-1-yl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 7-bromo-2-chloro-1,5-naphthyridine (38.0 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11.1 mg), sodium carbonate (33.1 mg), 1,4-dioxane (1 mL), and water (0.1 mL) was stirred at 100° C. for 64 hours in a nitrogen atmosphere in a sealed tube. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. After the obtained residue was purified by silica gel column chromatography (chloroform-methanol), the obtained residue was purified by preparative thin layer silica gel chromatography (chloroform-methanol, NH silica), thereby obtaining 2-chloro-7-(3-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (12.2 mg) as colorless oily substance and 2-chloro-7-(5-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (9.4 mg) as colorless oily substance.

2-Chloro-7-(3-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine

MSm/z(M+H):356,358.

2-Chloro-7-(5-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine

MSm/z(M+H):356,358.

0321-3

A mixture of 2-chloro-7-(3-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (12.2 mg), 5-isopropyl-1,3,4-thiadiazole-2-amine (9.8 mg), tris(dibenzylideneacetone)dipalladium(0) (3.1 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (4.0 mg), cesium carbonate (22.4 mg), and 1,4-dioxane (0.5 mL) was stirred at 100° C. for 13 hours in a nitrogen atmosphere in a sealed tube. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer silica gel chromatography (chloroform-methanol, NH silica), thereby obtaining 5-isopropyl-N-(7-(3-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (9.0 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.06(1H,brs),8.92(1H,d,J=2.0 Hz),8.31(1H,s),8.27(1H,d,J=9.2 Hz),8.16(1H,d,J=2.0 Hz),7.42(1H,d,J=9.2 Hz),4.13(2H,t,J=6.9 Hz),3.42-3.30(1H,m),2.47-2.35(9H,m),2.05-1.91(2H,m),1.75-1.63(4H,m),1.40(6H,d,J=7.3 Hz).

MSm/z(M+H):463.

Examples 0322 and 0323

The following compounds were obtained in the same manner as in Examples 0001-4 and 0001-5.

›Example 0324

0324-1

A solution of a mixture (30 mg) of N-(7-bromo-1,5-naphthyridin-2-yl)-5-(tetrahydrofuran-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine and (Z)-7-bromo-N-(5-(tetrahydrofuran-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazol-2(3H)-ylidene)-1,5-naphthyridine-2-amine, bis(pinacolato)diboron (22.5 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (4.8 mg), and potassium acetate (11.6 mg) in 1,4-dioxane (1 mL) was stirred at 100° C. for 12 hours in a nitrogen atmosphere in a sealed tube. The reaction mixture was cooled to room temperature, and tert-butyl 4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate (33.4 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.2 mg), sodium carbonate (31.3 mg), and water (0.1 mL) were added thereto, followed by stirring at 120° C. for 19 hours. The reaction mixture was cooled to room temperature, and purified by silica gel column chromatography (hexane-ethyl acetate, NH silica), thereby obtaining a mixture (61.2 mg) of tert-butyl 4-(4-(6-((5-(tetrahydrofuran-2-yl)-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and (Z)-tert-butyl 4-(4-(6-((5-(tetrahydrofuran-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazol-2(3H)-ylidene)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as brown oily substance.

A 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) was added to a solution of the obtained mixture (20 mg) in ethanol (1 mL) at room temperature, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, triethylamine was added to the obtained residue, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining N-(7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-(tetrahydrofuran-2-yl)-1,3,4-thiadiazole-2-amine (1.4 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:9.11(1H,d,J=2.0 Hz),8.65(1H,s),8.34(1H,d,J=2.0 Hz),8.30-8.21(2H,m),7.41(1H,d,J=9.2 Hz),5.24(1H,dd,J=7.3,5.9 Hz),4.36-4.20(1H,m),4.07-3.96(1H,m),3.95-3.83(1H,m),3.17-3.04(2H,m),2.75-2.60(2H,m),2.46-2.32(1H,m),2.30-2.13(1H,m),2.11-1.96(4H,m),1.96-1.79(2H,m).

MSm/z(M+H):449.

›Example 0325

0325-1

N-(7-(1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-(tetrahydrofuran-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a white solid in the same manner as in Example 0303-3.

1 H-NMR(DMSO-d 6 )δ:12.12(1H,brs),9.09(1H,d,J=1.7 Hz),8.59(1H,s),8.32(1H,d,J=1.7 Hz),8.27(1H,d,J=8.9 Hz),8.24(1H,s),7.41(1H,d,J=8.9 Hz),5.24(1H,dd,J=7.3,5.9 Hz),4.22(2H,t,J=6.9 Hz),4.07-3.96(1H,m),3.94-3.83(1H,m),2.61-2.32(7H,m),2.31-2.13(1H,m),2.12-1.95(4H,m),1.79-1.58(4H,m).

MSm/z(M+H):477.

›Example 0326

0326-1

A mixture of a mixture (20 mg) of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine and (Z)-7-bromo-N-(5-cyclopentyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazol-2(3H)-ylidene)-1,5-naphthyridine-2-amine, tetrahydrofuran-3-amine (6.9 mg), tris(dibenzylideneacetone)dipalladium(0) (3.6 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (3.8 mg), cesium carbonate (25.7 mg), and 1,4-dioxane (1 mL) was stirred at 100° C. for 12 hours in a sealed tube. The reaction mixture was cooled to room temperature, and purified by silica gel column chromatography (hexane-ethyl acetate, NH silica), thereby obtaining a mixture (13.7 mg) of N 2 -(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-N 7 -(tetrahydrofuran-3-yl)-N 2 -((2-(trimethylsilyl)ethoxy)methyl)-1,5-naphthyridine-2,7-diamine and (Z)-N 2 -(5-cyclopentyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazol-2(3H)-ylidene)-N 7 -(tetrahydrofuran-3-yl)-1,5-naphthyridine-2,7-diamine as yellow oily substance.

60% sodium hydride (1.6 mg) was added to a solution of the obtained mixture in tetrahydrofuran (1 mL) in an ice bath, followed by stirring at room temperature for 5 minutes, and iodomethane (6.6 mL) was added thereto in an ice bath. The reaction mixture was stirred at room temperature for 1 hour, and heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, and methanol (1 mL) and a 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) were added thereto, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure, triethylamine was added to the obtained residue, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining N 2 -(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-N 7 -methyl-N 7 -(tetrahydrofuran-3-yl)-1,5-naphthyridine-2,7-diamine (7.6 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:11.82(1H,s),8.66(1H,d,J=2.6 Hz),8.08(1H,d,J=8.6 Hz),7.22(1H,d,J=2.6 Hz),7.12(1H,d,J=8.6 Hz),4.95-4.78(1H,m),4.07-3.92(1H,m),3.89-3.75(2H,m),3.73-3.58(1H,m),3.55-3.38(1H,m),2.96(3H,s),2.39-2.23(1H,m),2.22-2.03(2H,m),2.01-1.56(7H,m).

MSm/z(M+H):397.

Examples 0327 to 0329

The following compounds were obtained in the same manner as in Examples 0001-4 and 0001-5.

›Example 0330

0330-1

A 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) was added to a solution of tert-butyl 4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (20 mg) in methanol (1 mL) at room temperature, followed by stirring for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was washed with ethyl acetate, thereby obtaining 5-cyclopentyl-N-(7-(1,2,3,6-tetrahydropyridin-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine hydrochloride (12 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:9.13(2H,brs),9.00(1H,d,J=2.0 Hz),8.30(1H,d,J=9.2 Hz),8.18(1H,d,J=2.0 Hz),7.47(1H,d,J=9.2 Hz),6.65-6.58(1H,m),3.55-3.43(3H,m),2.94-2.82(2H,m),2.23-2.08(2H,m),1.94-1.59(8H,m).

MSm/z(M+H):379.

›Example 0331

0331-1

A mixture of tert-butyl 4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (30 mg), methanol (3 mL), and tetrahydrofuran (1 mL) was reacted using a flow-type hydrogenation reaction apparatus (atmospheric pressure, 1.0 mL/min, room temperature, 10% Pd/C). The solvent was distilled off under reduced pressure, and the obtained residue was washed with ethyl acetate, thereby obtaining tert-butyl 4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)piperidine-1-carboxylate (8.3 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:12.02(1H,s),8.72(1H,d,J=2.3 Hz),8.26(1H,d,J=9.2 Hz),8.04(1H,d,J=2.3 Hz),7.42(1H,d,J=9.2 Hz),4.24-4.06(2H,m),3.56-3.38(1H,m),3.10-2.74(3H,m),2.22-2.01(2H,m),1.96-1.58(10H,m),1.44(9H,s).

MSm/z(M+H):481.

›Example 0332

0332-1

5-Cyclopentyl-N-(7-(piperidin-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine hydrochloride was obtained as a white solid in the same manner as in Example 0330-1.

1 H-NMR(DMSO-d 6 )δ:12.11(1H,brs),8.85-8.40(3H,m),8.29(1H,d,J=8.9 Hz),7.99(1H,d,J=2.0 Hz),7.46(1H,d,J=8.9 Hz),3.78-3.25(2H,m),3.24-2.96(3H,m),2.23-1.60(13H,m).

MSm/z(M+H):381.

›Example 0333

0333-1

A 36 to 38% formaldehyde aqueous solution (0.2 mL) and sodium triacetoxyborohydride (15.3 mg) were added to a solution of 5-cyclopentyl-N-(7-(1,2,3,6-tetrahydropyridin-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine hydrochloride (3.0 mg) in methanol (0.5 mL) and dichloromethane (0.5 mL) at room temperature, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 5-cyclopentyl-N-(7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (1.7 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:12.04(1H,brs),8.96(1H,d,J=2.3 Hz),8.26(1H,d,J=9.2 Hz),8.08(1H,d,J=2.3 Hz),7.41(1H,d,J=9.2 Hz),6.57(1H,bt,J=3.3 Hz),3.56-3.39(1H,m),3.10(2H,bd,J=3.3 Hz),2.71-2.59(4H,m),2.32(3H,s),2.24-2.06(2H,m),1.97-1.59(6H,m).

MSm/z(M+H):393.

›Example 0334

0334-1

Acetyl chloride (2 μL) was added to a solution of 5-cyclopentyl-N-(7-(1,2,3,6-tetrahydropyridin-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine hydrochloride (4.0 mg) in pyridine (0.5 mL) in an ice bath, followed by stirring at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 1-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-5,6-dihydropyridine-1(2H)-yl)ethanone (1.4 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:12.06(1H,brs),8.99-8.93(1H,m),8.27(1H,d,J=9.2 Hz),8.14-8.08(1H,m),7.43(1H,d,J=9.2 Hz),6.62-6.54(1H,m),4.27-4.15(2H,m),3.77-3.66(2H,m),3.57-3.40(1H,m),2.78-2.59(2H,m),2.22-2.04(5H,m),1.94-1.62(6H,m).

MSm/z(M+H):421.

›Example 0335

0335-1

1-(4-(6-((5-Cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)piperidin-1-yl)ethanone was obtained as a white solid in the same manner as in Example 0334-1.

1 H-NMR(DMSO-d 6 )δ:12.03(1H,brs),8.73(1H,d,J=2.0 Hz),8.26(1H,d,J=8.9 Hz),8.03(1H,d,J=2.0 Hz),7.42(1H,d,J=8.9 Hz),4.66-4.53(1H,m),4.04-3.93(1H,m),3.55-3.39(1H,m),3.25-3.00(2H,m),2.71-2.56(1H,m),2.23-2.03(6H,m),1.97-1.51(9H,m).

MSm/z(M+H):423.

›Example 0336

0336-1

A 4 mol/L hydrogen chloride/1,4-dioxane solution (1.5 mL) was added to a solution of tert-butyl 4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate (300 mg) in methanol (1.5 mL) at room temperature, followed by stirring for 1 hour. The solvent was distilled off under reduced pressure, hexane was added to the obtained residue, and the solid matter was collected by filtration, thereby obtaining 4-(4-iodo-1H-pyrazol-1-yl)piperidine hydrochloride (0.283 g) as a white solid.

60% sodium hydride (30.6 mg) was added to a solution of the obtained hydrochloride (100 mg) in N,N-dimethylformamide (1 mL) in an ice bath, followed by stirring at room temperature for 30 minutes. 2-Bromoethyl acetate (70 μL) was added to the reaction mixture at room temperature, followed by stirring at room temperature for 1 hour, and stirring at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was collected by separation, washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining 2-(4-(4-iodo-1H-pyrazol-1-yl)piperidin-1-yl)ethyl acetate (62.1 mg) as colorless oily substance.

1 H-NMR(CDCl 3 )δ:7.50(1H,s),7.46(1H,s),4.20(2H,t,J=5.9 Hz),3.11-2.99(2H,m),2.67(2H,t,J=5.9 Hz),2.23(2H,td,J=11.7,2.4 Hz),2.17-1.90(8H,m).

0336-2

2-(4-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanol (2.2 mg) was obtained as a white solid in the same manner as in Examples 0110-3 and 0110-4.

1 H-NMR(DMSO-d 6 )δ:12.04(1H,s),9.09(1H,d,J=2.0 Hz),8.66(1H,s),8.34(1H,d,J=2.0 Hz),8.28-8.20(2H,m),7.39(1H,d,J=8.6 Hz),4.43(1H,t,J=5.3 Hz),4.27-4.11(1H,m),3.61-3.21(5H,m),3.07-2.93(2H,m),2.45(2H,t,J=6.3 Hz),2.30-1.62(12H,m).

MSm/z(M+H):491.

›Example 0337

0337-1

1-(3-((tert-Butyldimethylsilyl)oxy)propyl)-4-(4-iodo-1H-pyrazol-1-yl)piperidine was obtained as a white solid in the same manner as in Example 0336-1.

1 H-NMR(CDCl 3 )δ:7.50(1H,s),7.47(1H,s),3.66(2H,t,J=6.3 Hz),3.08-2.96(2H,m),2.50-2.39(2H,m),2.19-1.88(5H,m),1.78-1.64(2H,m),0.95-0.78(11H,m),0.05(6H,s).

0337-2

3-(4-(4-(6-((5-Cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propan-1-ol was obtained as a white solid in the same manner as in Examples 0110-3 and 0110-4.

1 H-NMR(DMSO-d 6 )δ:9.09-8.92(1H,m),8.68-8.59(1H,m),8.35-8.02(3H,m),7.41-7.19(1H,m),4.56-4.38(1H,m),4.29-4.10(1H,m),3.55-3.11(5H,m),3.07-2.89(2H,m),2.39(2H,t,J=7.3 Hz),2.23-1.51(14H,m).

MSm/z(M+H):505.

›Example 0338

0338-1

60% sodium hydride (74.4 mg) was added to a solution of 4-iodo-1H-pyrazole (300 mg) in N,N-dimethylformamide (2 mL) at room temperature, followed by stirring for 30 minutes. 4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (0.439 mL) was added to the reaction mixture at room temperature, followed by stirring at room temperature for 1 hour, and stirring at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and a saturated ammonium chloride aqueous solution and ethyl acetate were added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-iodo-1H-pyrazole (304 mg) as a white solid.

1 H-NMR(CDCl 3 )δ:7.54(1H,s),7.51(1H,s),4.48-4.37(1H,m),4.33-4.17(2H,m),4.07(1H,dd,J=8.6,6.6 Hz),3.75(1H,dd,J=8.6,5.9 Hz),1.38(3H,s),1.35(3H,s).

0338-2

3-(4-(6-((5-Cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)propane-1,2-diol was obtained as a white solid in the same manner as in Examples 0110-3 and 0110-4.

1 H-NMR(DMSO-d 6 )δ:12.03(1H,s),9.09(1H,d,J=2.0 Hz),8.52(1H,s),8.34(1H,d,J=2.0 Hz),8.28-8.20(2H,m),7.39(1H,d,J=9.2 Hz),5.07(1H,d,J=5.3 Hz),4.79(1H,t,J=5.6 Hz),4.30(1H,dd,J=13.9,4.0 Hz),4.05(1H,dd,J=13.9,7.9 Hz),3.95-3.82(1H,m),3.57-3.21(3H,m),2.24-2.09(2H,m),1.97-1.62(6H,m).

MSm/z(M+H):438.

›Example 0339

0339-1

1-(3-Methoxypropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was obtained as colorless oily substance in the same manner as in Example 0316-1.

1 H-NMR(CDCl 3 )δ:7.84-7.76(1H,m),7.74-7.65(1H,m),4.30-4.19(2H,m),3.39-3.27(5H,m),2.20-2.06(2H,m),1.39-1.29(12H,m).

0339-2

A mixture of a mixture (10 mg) of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine and (Z)-7-bromo-N-(5-cyclopentyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazol-2(3H)-ylidene)-1,5-naphthyridine-2-amine, 1-(3-methoxypropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.9 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.4 mg), sodium carbonate (4.2 mg), 1,4-dioxane (1 mL), and water (0.1 mL) was stirred at 100° C. for 12.5 hours in a nitrogen atmosphere in a sealed tube. The reaction mixture was cooled to room temperature, and methanol (1 mL) and a 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) were added thereto, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure, triethylamine was added to the obtained residue, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining 5-cyclopentyl-N-(7-(1-(3-methoxypropyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (2.5 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:12.02(1H,brs),9.06(1H,s),8.57(1H,s),8.31(1H,s),8.27-8.15(2H,m),7.37(1H,d,J=8.6 Hz),4.22(2H,t,J=6.9 Hz),3.57-3.12(6H,m),2.24-2.02(4H,m),1.96-1.62(6H,m).

MSm/z(M+H):436.

›Example 0340

0340-1

Triethylamine (123 μL) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (102 mg) were added to a solution of 4-(4-iodo-1H-pyrazol-1-yl)piperidine hydrochloride (69 mg) in tetrahydrofuran (1 mL) at room temperature, followed by stirring at 80° C. for 13.5 hours in a sealed tube. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining 4-(4-iodo-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)piperidine (49.5 mg) as a white solid.

1 H-NMR(CDCl 3 )δ:7.67-7.41(2H,m),4.32-4.05(1H,m),3.35-2.95(4H,m),2.82-2.49(2H,m),2.40-1.91(4H,m).

0340-2

A mixture of a mixture (20 mg) of N-(7-bromo-1,5-naphthyridin-2-yl)-5-cyclopentyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine and (Z)-7-bromo-N-(5-cyclopentyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazol-2(3H)-ylidene)-1,5-naphthyridine-2-amine, bis(pinacolato)diboron (15.1 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (3.2 mg), potassium acetate (7.8 mg), and 1,4-dioxane (0.4 mL) was stirred at 80° C. for 4 hours in a nitrogen atmosphere in a sealed tube. The reaction mixture was cooled to room temperature, and sodium carbonate (21.0 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2.8 mg), 4-(4-iodo-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)piperidine (17.0 mg), 1,4-dioxane (1 mL), and water (0.14 mL) were added thereto, followed by stirring at 120° C. for 18 hours in a sealed tube. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure, thereby obtaining a mixture of 5-cyclopentyl-N-(7-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine and (Z)-N-(5-cyclopentyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazol-2(3H)-ylidene)-7-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine.

Methanol (1 mL) and a 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) were added to the obtained mixture at room temperature, followed by stirring for 1 hour. The solvent was distilled off under reduced pressure, triethylamine was added to the obtained residue, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining 5-cyclopentyl-N-(7-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (5.6 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:12.04(1H,brs),9.09(1H,d,J=2.0 Hz),8.69(1H,s),8.35(1H,d,J=2.0 Hz),8.28-8.20(2H,m),7.39(1H,d,J=8.6 Hz),4.32-4.16(1H,m),3.57-3.18(3H,m),3.11-2.98(2H,m),2.67-2.45(2H,m),2.23-1.62(12H,m).

MSm/z(M+H):529.

›Example 0341

0341-1

Methanol (1 mL) and a 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) were added to the obtained mixture at room temperature, followed by stirring for 1 hour. The solvent was distilled off under reduced pressure, ethanol was added to the obtained residue, and the resultant product was neutralized with a saturated sodium hydrogen carbonate aqueous solution. The solvent was distilled off under reduced pressure, thereby obtaining 3-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)propionic acid (48.3 mg) as a yellow solid.

MSm/z(M+H):436.

0341-2

1,1′-Carbonyldiimidazole (29.8 mg) was added to a solution of 3-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)propionic acid (20 mg) in N,N-dimethylformamide (0.5 mL) at room temperature, followed by stirring for 1 hour. Pyrrolidine (38 μL) was added to the reaction mixture at room temperature, followed by stirring for 30 minutes, and after methanol was added thereto, the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer silica gel chromatography (chloroform-methanol, NH silica), thereby obtaining 3-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)-1-(pyrrolidin-1-yl)propan-1-one (3.7 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:12.03(1H,brs),9.06(1H,d,J=2.0 Hz),8.56(1H,s),8.31(1H,d,J=2.0 Hz),8.27-8.19(2H,m),7.38(1H,d,J=9.2 Hz),4.41(2H,t,J=6.9 Hz),3.58-3.23(5H,m),2.89(2H,t,J=6.9 Hz),2.23-2.08(2H,m),1.96-1.62(10H,m).

MSm/z(M+H):489.

Examples 0342 and 0343

The following compounds were obtained in the same manner as in Example 0341-2.

›Example 0344

0344-1

Methanesulfonyl chloride (110 μL) was added to a solution of 3-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)propan-1-ol (200 mg) in pyridine (2.4 mL) in an ice bath, followed by stirring at room temperature for 1.5 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining 3-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)propyl methanesulfonate (173 mg) as a white solid.

MSm/z(M+H):500.

0344-2

Piperidine (15.8 μL) was added to a mixture of 3-(4-(6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)propyl methanesulfonate (30 mg), potassium carbonate (22.1 mg), and N,N-dimethylformamide (0.5 mL) at room temperature, followed by stirring at 80° C. for 18 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), and purified by preparative thin layer silica gel chromatography (chloroform-methanol, NH silica), thereby obtaining 5-cyclopentyl-N-(7-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (5.3 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:9.07(1H,d,J=2.0 Hz),8.56(1H,s),8.31(1H,d,J=2.0 Hz),8.28-8.20(2H,m),7.39(1H,d,J=9.2 Hz),4.19(2H,t,J=7.3 Hz),3.58-3.25(1H,m),2.39-2.08(8H,m),2.07-1.63(8H,m),1.59-1.32(6H,m).

MSm/z(M+H):489.

Examples 0345 and 0346

The following compounds were obtained in the same manner as in Example 0342-2.

Examples 0347 and 0348

The following compounds were obtained in the same manner as in Examples 0110-3 and 0110-4.

Examples 0349 and 0350

0349-1 and 350-1

A mixture of 6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine 1-oxide (230 mg), 5-cyclopentyl-1,3,4-thiadiazole-2-amine (223 mg), tris(dibenzylideneacetone)dipalladium(0) (80.8 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (102 mg), cesium carbonate (573 mg), and 1,4-dioxane (3 mL) was stirred at 120° C. for 17 hours in a nitrogen atmosphere in a sealed tube. The reaction mixture was cooled to room temperature, and water was added thereto. The solid matter was collected by filtration, and washed with water and ethyl acetate, thereby obtaining 6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine 1-oxide (415 mg) as a black solid.

MSm/z(M+H):394.

0349-2 and 0350-2

Phosphorus oxychloride (1 mL) was added to 6-((5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-3-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridine 1-oxide (415 mg), followed by stirring at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and added dropwise to water in an ice bath, followed by stirring at room temperature for 30 minutes. The resultant product was neutralized by the addition of sodium carbonate. The solid matter was collected by filtration, and washed with water and ethyl acetate, thereby obtaining a yellow solid (260 mg).

The obtained yellow solid (30 mg) was purified by preparative thin layer silica gel chromatography (chloroform-methanol), thereby obtaining N-(6-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-cyclopentyl-1,3,4-thiadiazole-2-amine (9.7 mg) as a white solid and N-(8-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-cyclopentyl-1,3,4-thiadiazole-2-amine (3.5 mg) as a white solid.

›Example 0349

N-(6-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-cyclopentyl-1,3,4-thiadiazole-2-amine

1 H-NMR(DMSO-d 6 )δ:12.14(1H,brs),8.42(1H,s),8.37(1H,s),8.23(1H,d,J=8.9 Hz),8.09(1H,s),7.47(1H,d,J=8.9 Hz),3.95(3H,s),3.53-3.31(1H,m),2.24-2.04(2H,m),1.95-1.58(6H,m).

MSm/z(M+H):412.

›Example 0350

N-(8-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-cyclopentyl-1,3,4-thiadiazole-2-amine

1 H-NMR(DMSO-d 6 )δ:12.30(1H,brs),9.02(1H,s),8.58(1H,s),8.34(1H,d,J=8.9 Hz),8.21(1H,s),7.50(1H,d,J=8.9 Hz),3.97(3H,s),3.63-3.24(1H,m),2.24-2.07(2H,m),1.94-1.62(6H,m).

MSm/z(M+H):412.

›Example 0351

0351-1

60% sodium hydride (96 mg) was added to a solution of (R)-3-fluoropyrrolidine hydrochloride (126 mg) in tetrahydrofuran (2 mL) in an ice bath, followed by stirring at room temperature for 30 minutes. (3-Bromopropoxy) (tert-butyl)dimethylsilane (348 μL) was added to the reaction mixture in an ice bath, followed by stirring at room temperature for 62 hours. A saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining (R)-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-fluoropyrrolidine (322 mg) as colorless oily substance.

1 H-NMR(CDCl 3 )δ:5.29-5.03(1H,m),3.67(2H,t,J=6.3 Hz),2.94-2.61(3H,m),2.58-2.50(2H,m),2.46-2.36(1H,m),2.26-1.92(2H,m),1.79-1.68(2H,m),0.89(9H,s),0.05(6H,s).

0351-2

A 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) was added to a solution of (R)-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-fluoropyrrolidine (0.322 g) in methanol (1 mL) at room temperature, followed by stirring for 30 minutes. The solvent was distilled off under reduced pressure, methanol (1 mL) and a saturated sodium hydrogen carbonate aqueous solution (1 mL) were added to the obtained residue, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining (R)-3-(3-fluoropyrrolidin-1-yl)propan-1-ol (0.101 mg) as colorless oily substance.

1 H-NMR(CDCl 3 )δ:5.29-5.02(1H,m),3.81(2H,t,J=5.3 Hz),3.02-2.69(5H,m),2.58-2.47(1H,m),2.23-1.93(2H,m),1.79-1.68(2H,m).

0351-3

Pyridine (136 μL) and methanesulfonyl chloride (65.2 μL) were added to a solution of (R)-3-(3-fluoropyrrolidin-1-yl)propan-1-ol (80.1 mg) in dichloromethane (2 mL) in an ice bath, followed by stirring for 30 minutes. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by stirring at room temperature for 30 minutes, and ethyl acetate was added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol, NH silica), thereby obtaining (R)-3-(3-fluoropyrrolidin-1-yl)propyl methanesulfonate (106 mg) as yellow oily substance.

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (60.9 mg), (R)-3-(3-fluoropyrrolidin-1-yl)propyl methanesulfonate (106 mg), potassium carbonate (86.8 mg), and acetonitrile (1 mL) was stirred at the external temperature of 80° C. for 14 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, the solid matter was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining (R)-1-(3-(3-fluoropyrrolidin-1-yl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (58.1 mg) as yellow oily substance.

1 H-NMR(CDCl 3 )δ:7.78(1H,s),7.69(1H,s),5.28-5.02(1H,m),4.21(2H,t,J=6.9 Hz),2.93-2.56(3H,m),2.50-2.31(3H,m),2.25-1.89(4H,m),1.32(12H,s).

0351-4

(R)-5-cyclopentyl-N-(7-(1-(3-(3-fluoropyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a white solid in the same manner as in Example 0339-2.

1 H-NMR(DMSO-d 6 )δ:12.05(1H,brs),9.08(1H,d,J=2.0 Hz),8.58(1H,s),8.33(1H,d,J=2.0 Hz),8.28-8.21(2H,m),7.39(1H,d,J=9.2 Hz),5.34-5.05(1H,m),4.22(2H,t,J=6.9 Hz),3.57-3.40(1H,m),2.94-2.38(6H,m),2.35-1.61(12H,m).

MSm/z(M+H):493.

Examples 0352 to 0354

The following compounds were obtained in the same manner as in Examples 0351-1, 0351-2, 0351-3, and 0339-2.

›Example 0355

0355-1

A 5 mol/L sodium methoxide/methanol solution (20 μL) was added to a solution of N-(8-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-cyclopentyl-1,3,4-thiadiazole-2-amine (2.0 mg) in methanol (1 mL), followed by stirring at 150° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and a 5 mol/L sodium methoxide/methanol solution (50 μL) was added thereto, followed by stirring at 150° C. for 1 hour. The reaction mixture was cooled to room temperature, and a saturated ammonium chloride aqueous solution was added thereto. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining 5-cyclopentyl-N-(8-methoxy-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (0.4 mg) as a yellow solid.

1 H-NMR(DMSO-d 6 )δ:12.10(1H,brs),9.08(1H,s),8.47(1H,s),8.27(1H,d,J=8.9 Hz),8.19(1H,s),7.42(1H,d,J=8.9 Hz),4.12(3H,s),3.95(3H,s),3.59-3.25(1H,m),2.26-2.10(2H,m),1.93-1.66(6H,m).

MSm/z(M+H):408.

›Example 0356

0356-1

A 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) was added to a solution of 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-iodo-1H-pyrazole (0.2 g) in methanol (1 mL) at room temperature, followed by stirring for 30 minutes. The solvent was distilled off under reduced pressure, thereby obtaining 3-(4-iodo-1H-pyrazol-1-yl)propane-1,2-diol (184 mg) as a white solid.

MSm/z(M+H):269.

0356-2

Toluenesulphonyl chloride (78.2 μL) was added to a solution of 3-(4-iodo-1H-pyrazol-1-yl)propane-1,2-diol (100 mg), and pyridine (60.3 μL) in dichloromethane (1.9 mL) in an ice bath, followed by stirring for 30 minutes, and stirring at room temperature for 30 minutes. Toluenesulphonyl chloride (78.2 μL) was added thereto, followed by stirring for 30 minutes. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by stirring at room temperature for 30 minutes, and ethyl acetate was added thereto. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining 2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)propyl 4-methylbenzenesulfonate (120 mg) as yellow oily substance.

MSm/z(M+H):423.

0356-3

Triethylsilyl trifluoromethanesulfonate (127 μL) was added to a solution of 2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)propyl 4-methylbenzenesulfonate (120 mg) and 2,6-lutidine (130 μL) in dichloromethane (1.9 mL) at room temperature, followed by stirring for 30 minutes. A saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining 3-(4-iodo-1H-pyrazol-1-yl)-2-((triethylsilyl)oxy)propyl 4-methylbenzenesulfonate (82.0 mg) as yellow oily substance.

MSm/z(M+H):537.

0356-4

A mixture of 3-(4-iodo-1H-pyrazol-1-yl)-2-((triethylsilyl)oxy)propyl 4-methylbenzenesulfonate (82.0 mg), pyrrolidine (37.1 μL), triethylamine (64 μL), and tetrahydrofuran (1 mL) was stirred at 70° C. for 2 hours, and stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining 4-iodo-1-(3-(pyrrolidin-1-yl)-2-((triethylsilyl)oxy)propyl)-1H-pyrazole (27.7 mg) as brown oily substance.

MSm/z(M+H):436.

0356-5

1-(4-(6-((5-Cyclopentyl-1,3,4-thiadiazol-2-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)-3-(pyrrolidin-1-yl)propan-2-ol was obtained as a yellow solid in the same manner as in Examples 0110-3 and 0110-4.

1 H-NMR(DMSO-d 6 )δ:12.03(1H,brs),9.09(1H,d,J=2.0 Hz),8.52(1H,s),8.34(1H,d,J=2.0 Hz),8.27-8.21(2H,m),7.39(1H,d,J=9.2 Hz),5.01(1H,d,J=4.6 Hz),4.30(1H,d,J=10.6 Hz),4.14-3.92(2H,m),3.56-3.42(1H,m),2.69-2.36(6H,m),2.24-2.09(2H,m),1.95-1.62(10H,m).

MSm/z(M+H):491.

Examples 0357 and 0358

0357-1 and 0358-1

An ethanol solution (0.1 mL) of 20% sodium ethoxide was added to a solution of a mixture (30 mg) of N-(6-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-cyclopentyl-1,3,4-thiadiazole-2-amine and N-(8-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-cyclopentyl-1,3,4-thiadiazole-2-amine in ethanol (1 ml), followed by stirring at 150° C. for 1.5 hours using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and a saturated ammonium chloride aqueous solution was added thereto. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform-methanol), and purified by preparative thin layer silica gel chromatography (chloroform-methanol), thereby obtaining 5-cyclopentyl-N-(6-ethoxy-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (2.0 mg) as a white solid and 5-cyclopentyl-N-(8-ethoxy-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (3.1 mg) as a white solid.

›Example 0357

5-Cyclopentyl-N-(6-ethoxy-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine

1 H-NMR(DMSO-d 6 )δ:11.82(1H,s),8.39(1H,s),8.36(1H,s),8.22(1H,s),8.06(1H,d,J=8.6 Hz),7.33(1H,d,J=8.6 Hz),4.55(2H,q,J=6.9 Hz),3.94(3H,s),3.53-3.26(1H,m),2.23-2.07(2H,m),1.95-1.64(6H,m),1.48(3H,t,J=6.9 Hz).

MSm/z(M+H):422.

›Example 0358

5-Cyclopentyl-N-(8-ethoxy-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine

1 H-NMR(DMSO-d 6 )δ:12.10(1H,s),9.05(1H,s),8.43(1H,s),8.27(1H,d,J=8.9 Hz),8.17(1H,s),7.41(1H,d,J=8.9 Hz), 4.34(2H,q,J=6.9 Hz),3.96(3H,s),3.59-3.44(1H,m),2.31-2.08(2H,m),1.96-1.63(6H,m),1.54(3H,t,J=6.9 Hz).

MSm/z(M+H):422.

›Example 0359

0359-1

60% sodium hydride (29.1 mg) was added to 2-propanol (1 mL) at room temperature, and a mixture (30 mg) of N-(6-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-cyclopentyl-1,3,4-thiadiazole-2-amine and N-(8-chloro-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-5-cyclopentyl-1,3,4-thiadiazole-2-amine was added thereto at room temperature, followed by stirring at 150° C. for 1.5 hours using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and a saturated ammonium chloride aqueous solution was added thereto. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform-methanol), and purified by preparative thin layer silica gel chromatography (chloroform-methanol), thereby obtaining 5-cyclopentyl-N-(8-isopropyloxy-7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (1.8 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:12.06(1H,s),9.02(1H,s),8.43(1H,s),8.26(1H,d,J=9.2 Hz),8.18(1H,s),7.41(1H,d,J=9.2 Hz), 5.52-5.39(1H,m),3.95(3H,s),3.58-3.43(1H,m),2.30-2.11(2H,m),1.93-1.64(6H,m),1.26(6H,d,J=6.6 Hz).

MSm/z(M+H):436.

›Example 0360

0360-1

5-Isopropyl-N-(7-(5-methyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine was obtained as a yellow solid in the same manner as in Example 0321-3.

1 H-NMR(DMSO-d 6 )δ:12.07(1H,brs),8.88(1H,d,J=2.0 Hz),8.28(1H,d,J=8.9 Hz),8.15(1H,d,J=2.0 Hz),7.92(1H,s),7.43(1H,d,J=8.9 Hz),4.18(2H,t,J=6.9),3.42-3.27(1H,m),2.58-2.34(9H,m),2.03-1.88(2H,m),1.76-1.62(4H,m),1.40(6H,d,J=6.6 Hz).

MSm/z(M+H):463.

Examples 0361 to 0363

The following compounds were obtained in the same manner as in Examples 0001-4 and 0001-5.

Examples 0364 to 0369

The following compounds were obtained in the same manner as in Examples 0198-1 and 0001-5.

›Example 0370

0370-1

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (300 mg), bis(pinacolato)diboron (469 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (100 mg), potassium acetate (241 mg), and 1,4-dioxane (12.3 mL) was stirred at 100° C. for 3 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and tert-butyl 4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate (557 mg), sodium carbonate (261 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (87 mg), and water (1.2 mL) were added thereto, followed by stirring at 110° C. for 1 hour. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane, chloroform-methanol), thereby obtaining tert-butyl 4-(4-(6-chloro-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (149 mg) as a white solid.

MSm/z(M+H):414.

0370-2

tert-Butyl 4-(4-(6-((5-isopropylpyridazin-3-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (56 mg) was obtained as a white solid in the same manner as in Example 0001-5.

MSm/z(M+H):515.

0370-3

A 4 mol/L hydrogen chloride/1,4-dioxane solution (1 mL) was added to a solution of tert-butyl 4-(4-(6-((5-isopropylpyridazin-3-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (50 mg) in methanol (1 mL) at room temperature, followed by stirring for 13 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the obtained residue, and the solid matter was collected by filtration, thereby obtaining N-(5-isopropylpyridazin-3-yl)-7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine hydrochloride (44.9 mg) as a yellow solid.

MSm/z(M+H):415.

0370-4

A 36 to 38% formaldehyde aqueous solution (0.33 mL) and sodium triacetoxyborohydride (103 mg) were added to a solution of N-(5-isopropylpyridazin-3-yl)-7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine hydrochloride (44.9 mg) in methanol (3.3 mL) and dichloromethane (3.3 mL) at room temperature, followed by stirring for 12 hours. Chloroform, a saturated sodium hydrogen carbonate aqueous solution, and a saturated sodium chloride aqueous solution were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol, NH silica), thereby obtaining N-(5-isopropylpyridazin-3-yl)-7-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine (10.0 mg) as a white solid.

1 H-NMR(DMSO-d 6 )δ:8.96(1H,d,J=2.7 Hz),8.85-8.78(2H,m),8.69(1H,brs),8.24(1H,d,J=8.7 Hz),8.10(1H,m),7.97(1H,s),7.89(1H,s),7.49(1H,d,J=9.3 Hz),4.23(1H,m),3.10-2.96(3H,m),2.37(3H,s),2.30-2.08(6H,m),1.42(6H,d,J=7.2 Hz).

MSm/z(M+H):429.

›Example 0371

0371-1

3-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol was obtained as brown oily substance in the same manner as in Example 0316-1.

MSm/z(M+H):253.

0371-2

Triethylamine (550 μL) and methanesulfonyl chloride (168 μL) were added to a solution of 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol (500 mg) in dichloromethane (19.8 mL) in an ice bath, followed by stirring at room temperature for 15 minutes. A saturated sodium hydrogen carbonate aqueous solution and chloroform were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl methanesulfonate (667 mg) as brown oily substance.

MSm/z(M+H):331.

0371-3

Azetidine (534 μL) was added to a mixture of 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl methanesulfonate (667 mg), cesium carbonate (1.29 g), sodium iodide (89 mg), and 1,4-dioxane (10 mL), followed by stirring at 80° C. for 11 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure, thereby obtaining 1-(3-(azetidin-1-yl)propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (188 mg) as brown oily substance.

MSm/z(M+H):292.

0371-4 and 0371-5

The following compounds were obtained in the same manner as in Examples 0001-4 and 0001-5.

›Example 0372

0372-1

3-Phenylpropyl bromide (0.12 mL) was added to a suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg) and potassium carbonate (144 mg) in acetonitrile (1 mL), followed by stirring at 80° C. overnight. The reaction mixture was cooled to room temperature, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 1-(3-phenylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (61 mg).

MSm/z(M+H):313.

0372-2 and 0372-3

The following compounds were obtained in the same manner as in Examples 0001-4 and 0001-5.

›Example 0373

0373-1

Piperidine (0.43 mL) was added to a solution of 1-bromo-3-chloropropane (0.32 mL) in toluene (1.6 mL), followed by stirring at 80° C. for 2.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added thereto, and 2 mol/L hydrochloric acid was added thereto. The aqueous layer was collected by separation, adjusted to pH 12 by the addition of a 2 mol/L sodium hydroxide aqueous solution, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 1-(3-chloropropyl)piperidine (451 mg) as pale yellow oily substance. A mixture of the obtained 1-(3-chloropropyl)piperidine (180 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (180 mg), cesium carbonate (610 mg), sodium iodide (28 mg), and 1,4-dioxane (1.9 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, the insolubles were filtered off, and the solvent was distilled off under reduced pressure, thereby obtaining 1-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)piperidine.

7-Bromo-2-chloro-1,5-naphthyridine (50 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (14.7 mg), and sodium carbonate (44.1 mg) were added to a mixture solution of the obtained 1-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)piperidine (80 mg) in 1,4-dioxane (2 mL)/water (0.2 mL), followed by stirring at 100° C. for 2 hours. After the reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the filter cake was washed with ethyl acetate. The filtrate and the washings were combined, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane, methanol-ethyl acetate, NH silica), thereby obtaining 2-chloro-7-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (45 mg)

MSm/z(M+H):356.

0373-2

N-(5-isopropylpyridazin-3-yl)-7-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine was obtained as a pale yellow solid in the same manner as in Example 0001-5.

1 H-NMR(CDCl 3 )δ:8.93(1H,d,J=2.0 Hz),8.89(1H,d,J=2.0 Hz),8.82(1H,d,J=2.0 Hz),8.24(1H,d,J=9.2 Hz),8.10(1H,d,J=2.0 Hz),7.96(1H,s),7.88(1H,s),7.58(1H,d,J=8.6 Hz),4.29(2H,t,J=6.9 Hz),3.11-3.02(1H,m),2.36-2.31(6H,m),2.14-2.10(2H,m),1.62-1.60(6H,m),1.43(6H,d,J=7.3 Hz).

MSm/z(M+H):457.

›Example 0374

0374-1

Diethylamine (0.62 mL) was added to a solution of 1-bromo-3-chloropropane (0.3 mL) in 1,4-dioxane (2 mL), followed by stirring at 50° C. for 4.5 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (194 mg), cesium carbonate (651 mg), and sodium iodide (30 mg) were added thereto, followed by stirring at 80° C. overnight. The reaction mixture was cooled to room temperature, the insolubles were filtered off, and the solvent was distilled off under reduced pressure, thereby obtaining N,N-diethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propane-1-amine.

7-Bromo-2-chloro-1,5-naphthyridine (50 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (14.7 mg), and sodium carbonate (44.1 mg) were added to a mixture solution of the obtained N,N-diethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propane-1-amine (80 mg) in 1,4-dioxane (2 mL)/water (0.2 mL), followed by stirring at 100° C. for 2 hours. After the reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the filter cake was washed with ethyl acetate. The filtrate and the washings were combined, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica), thereby obtaining 3-(4-(6-chloro-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)-N,N-diethylpropane-1-amine (15 mg).

MSm/z(M+H):344.

0374-2

7-(1-(3-(Diethylamino)propyl)-1H-pyrazol-4-yl)-N-(5-isopropylpyridazin-3-yl)-1,5-naphthyridine-2-amine was obtained as a pale yellow solid in the same manner as in Example 0001-5.

1 H-NMR(CDCl 3 )δ:8.93(1H,d,J=2.0 Hz),8.83-8.82(2H,m),8.24(1H,d,J=9.2 Hz),8.10(1H,d,J=1.3 Hz),7.97(1H,s),7.89(1H,s),7.50(1H,d,J=9.2 Hz),4.29(2H,t,J=6.9 Hz),3.07-3.05(1H,m),2.58-2.55(6H,m),2.15(2H,m),1.43-1.41(6H,m),1.04(6H,t,J=6.9 Hz).

MSm/z(M+H):445.

›Example 0375

0375-1

A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (195 mg), 2-(bromomethyl)pyridine hydrobromate (302 mg), and potassium carbonate (415 mg) in acetonitrile (2 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, the insolubles were filtered off, and the solvent was distilled off under reduced pressure, thereby obtaining 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine (284 mg) as brown oily substance.

MSm/z(M+H):286.

0375-2

1,4-Dioxane (2 mL)/water (0.2 mL) was added to a mixture of 7-bromo-2-chloro-1,5-naphthyridine (75 mg), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine (105 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (21 mg), and sodium carbonate (65 mg), followed by stirring at 100° C. for 2 hours. After the reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the filter cake was washed with ethyl acetate. The filtrate and the washings were combined, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane, methanol-ethyl acetate, NH silica), thereby obtaining 2-chloro-7-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (64 mg) as a yellow solid.

MSm/z(M+H):322.

0375-3

N-(5-isopropylpyridazin-3-yl)-7-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine was obtained as a yellow solid in the same manner as in Example 0001-5.

1 H-NMR(CDCl 3 )δ:8.94(1H,s),8.83-8.80(2H,m),8.63(2H,d,J=4.6 Hz),8.24(1H,d,J=9.9 Hz),8.13(1H,s),8.04(3H,m),7.72-7.70(1H,m),7.22(1H,d,J=7.9 Hz),5.56-5.52(2H,m),3.07-3.05(1H,m),1.42(6H,d,J=6.6 Hz).

MSm/z(M+H):423.

›Example 0376

The following compounds were obtained in the same manner as in Examples 0375-1, 0375-2, and 0001-5.

›Example 0377

0377-1

Triethylamine (1 mL) was added to a solution of 4-pyridineethanol (0.28 mL) in tetrahydrofuran (5.8 mL), and methanesulfonyl chloride (0.28 mL) was added thereto at 0° C., followed by stirring at room temperature for 1.5 hours. The insolubles were filtered off using celite, and the filter cake was washed with tetrahydrofuran. The filtrate and the washings were combined, and the solvent was distilled off under reduced pressure, thereby obtaining 2-(pyridin-4-yl)ethyl methanesulfonate (517 mg) as an orange solid.

MSm/z(M+H):202.

0377-2 to 0377-4

The following compounds were obtained in the same manner as in Examples 0375-1, 0375-2, and 0001-5.

›Example 0378

0378-1

Potassium carbonate (0.82 g) and 3-bromo-1-propanol (0.27 mL) were added to a suspension of 3-methoxypiperidine hydrochloride in acetonitrile (4 mL), followed by stirring at 80° C. for 15 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(3-methoxypiperidin-1-yl)propan-1-ol (400 mg) as brown oily substance.

Triethylamine (0.97 mL) was added to a suspension of the obtained 3-(3-methoxypiperidin-1-yl)propan-1-ol (400 mg) in tetrahydrofuran (5.5 mL), and methanesulfonyl chloride (0.27 mL) was added thereto at 0° C., followed by stirring at room temperature for 2 hours. The insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(3-methoxypiperidin-1-yl)propyl methanesulfonate (668 mg) as brown oily substance.

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (195 mg) and potassium carbonate (279 mg) were added to a solution of the obtained 3-(3-methoxypiperidin-1-yl)propyl methanesulfonate (375 mg) in acetonitrile (2 mL), followed by stirring at 80° C. for 17.5 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off, and the solvent was distilled off under reduced pressure, thereby obtaining 3-methoxy-1-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)piperidine (393 mg) as brown oily substance.

7-Bromo-2-chloro-1,5-naphthyridine (50 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (15 mg), and sodium carbonate (44 mg) were added to a mixture solution of the obtained 3-methoxy-1-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)piperidine (181 mg) in 1,4-dioxane (2.1 mL)/water (0.21 mL), followed by stirring at 100° C. for 2 hours. After the reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the filter cake was washed with ethyl acetate. The filtrate and the washings were combined, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane, methanol-ethyl acetate, NH silica), thereby obtaining 2-chloro-7-(1-(3-(3-methoxypiperidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (23 mg) as a white solid.

MSm/z(M+H):386.

0378-2

N-(5-isopropylpyridazin-3-yl)-7-(1-(3-(3-methoxypiperidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine was obtained as a pale yellow solid in the same manner as in Example 0001-5.

1 H-NMR(CDCl 3 )δ:9.48(1H,s),8.93(2H,s),8.83-8.83(1H,m),8.25(1H,d,J=9.2 Hz),8.11-8.10(1H,m),7.93(2H,d,J=20.5 Hz),7.67(1H,d,J=9.2 Hz),4.29(2H,t,J=6.9 Hz),3.37(3H,s),3.35-3.29(1H,m),3.12-3.03(1H,m),2.86-2.82(1H,m),2.59-2.57(1H,m),2.38(2H,t,J=6.9 Hz),2.25-1.74(8H,m),1.43(6H,d,J=7.3 Hz).

MSm/z(M+H):487.

›Example 0379

0379-1

1-(3-(4-(6-Chloro-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)propyl)piperidine-3-carbonitrile was obtained as colorless oily substance in the same manner as in Example 0378-1.

MSm/z(M+H):381.

0379-2

1-(3-(4-(6-((5-Isopropylpyridazin-3-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-1-yl)propyl)piperidine-3-carbonitrile was obtained as a pale yellow solid in the same manner as in Example 0001-5.

1 H-NMR(CDCl 3 )δ:8.97(1H,s),8.83-8.81(2H,m),8.26-8.23(1H,m),8.15(1H,s),8.04(1H,s),7.99(1H,s),7.45-7.42(1H,m),4.36-4.32(2H,m),3.07-3.05(1H,m),2.87-2.83(1H,m),2.67-1.64(12H,m),1.42(6H,d,J=6.6 Hz).

MSm/z(M+H):482.

›Example 0380

0380-1

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (194 mg) and potassium carbonate (276 mg) were added to a solution of 2-(1H-imidazol-1-yl)ethyl 4-methylbenzenesulfonate (430 mg) in acetonitrile (2 mL), followed by stirring at 80° C. for 17.5 hours. The reaction mixture was cooled to room temperature, and the insolubles were filtered off. The filtrate and the washings were combined, and the solvent was distilled off under reduced pressure, thereby obtaining 1-(2-(1H-imidazol-1-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (341 mg) as brown oily substance.

7-Bromo-2-chloro-1,5-naphthyridine (50 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (14 mg) and sodium carbonate (45 mg) were added to a mixture solution of the obtained 1-(2-(1H-imidazol-1-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (152 mg) in 1,4-dioxane (2.1 mL)/water (0.21 mL), followed by stirring at 100° C. for 2 hours. After the reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the filter cake was washed with ethyl acetate. The filtrate and the washings were combined, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane, methanol-ethyl acetate, NH silica), thereby obtaining 7-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-pyrazol-4-yl)-2-chloro-1,5-naphthyridine (20 mg) as a white solid.

MSm/z(M+H):325.

0380-2

7-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-pyrazol-4-yl)-N-(5-isopropylpyridazin-3-yl)-1,5-naphthyridine-2-amine was obtained as a brown solid in the same manner as in Example 0001-5.

1 H-NMR(CDCl 3 )δ:8.84-8.82(3H,m),8.24(1H,d,J=8.6 Hz),8.05-8.04(2H,m),7.55(1H,d,J=9.2 Hz), 7.49(1H,s),7.29(1H,s),7.04(1H,s),6.73(1H,s),4.55-4.49(4H,m),3.08-3.06(1H,m),1.44-1.42(6H,d).

MSm/z(M+H):426.

›Example 0381

0381-1

Triethylamine (0.15 mL) was added to a solution of 4-pyridinemethanol (102 mg) in tetrahydrofuran (2.2 mL), and methanesulfonyl chloride (0.08 mL) was added thereto at 0° C., followed by stirring at room temperature for 2 hours. The insolubles were filtered off using celite, and the filter cake was washed with tetrahydrofuran (5 mL). The filtrate and the washings were combined, thereby obtaining (pyridin-4-yl)methyl methanesulfonate as a yellow solution.

Acetonitrile (2 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (148 mg), and potassium carbonate (211 mg) were added to the obtained yellow solution, followed by stirring at 80° C. overnight. The reaction mixture was cooled to room temperature, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane, methanol-ethyl acetate), thereby obtaining 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine (29 mg).

MSm/z(M+H):286.

0381-2 and 0381-3

The following compounds were obtained in the same manner as in Examples 0375-2 and 0001-5.

›Example 0382

0382-1

N-(5-isopropylpyridazin-3-yl)-7-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine was obtained as a white solid in the same manner as in Example 0001-5.

1 H-NMR(CDCl 3 )δ:9.40(1H,brs),8.93(1H,d,J=2.1 Hz),8.91(1H,d,J=2.1 Hz),8.83(1H,d,J=1.8 Hz),8.25(1H,d,J=8.7 Hz),8.11(1H,d,J=2.4 Hz),7.96(2H,s),7.66(1H,d,J=8.7 Hz),4.35(2H,t,J=6.6 Hz),3.73(4H,m),3.07(1H,m),2.89(2H,t,J=6.6 Hz),2.54(4H,m),1.43(6H,d,J=6.6 Hz).

MSm/z(M+H):445.

›Example 0383

0383-1

60% sodium hydride (47 mg) was added to a solution of 4-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole (200 mg) and tert-butyl N-methylcarbamate (155 mg) in N-methylpyrrolidone (4 mL) under ice-cooling, followed by stirring at the same temperature for 1 hour, and stirring at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane), thereby obtaining tert-butyl ((4-bromo-1-methyl-1H-pyrazol-3-yl)methyl) (methyl)carbamate (60 mg).

MSm/z(M+H):304,306.

0383-2

A mixture of N-(7-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (20 mg), bis(pinacolato)diboron (157 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (3 mg), potassium acetate (8 mg), and 1,4-dioxane (1 mL) was stirred at 100° C. for 2 hours in a nitrogen atmosphere. tert-Butyl ((4-bromo-1-methyl-1H-pyrazol-3-yl)methyl) (methyl)carbamate (13 mg), sodium carbonate (8 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5 mg), and water (0.1 mL) were added to the reaction mixture, followed by stirring at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining tert-butyl ((4-(6-((5-isopropyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)-1-methyl-1H-pyrazol-3-yl)methyl) (methyl)carbamate (4.3 mg).

MSm/z(M+H):625.

0383-3

Water (0.2 mL) and trifluoroacetic acid (2 mL) were added to tert-butyl ((4-(6-((5-isopropyl-1,3,4-thiadiazol-2-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-1,5-naphthyridin-3-yl)-1-methyl-1H-pyrazol-3-yl)methyl) (methyl)carbamate (4.3 mg), followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 5-isopropyl-N-(7-(1-methyl-3-((methylamino)methyl)-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (1.6 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.83(1H,d,J=2.1 Hz),8.33(1H,d,J=2.1 Hz),8.24(1H,d,J=8.4 Hz),7.80(1H,s),7.35(1H,d,J=8.4 Hz),3.99(3H,s),3.94(2H,s),3.49-3.36(1H,m),2.54(3H,s),1.49(6H,d,J=7.2 Hz).

MSm/z(M+H):395.

›Example 0384

0384-1

Morpholine (0.051 mL) was added to a mixture of 3-(4-iodo-3-methyl-1H-pyrazol-1-yl)propylmethanesulfonate (135 mg), potassium carbonate (108 mg), and acetonitrile (2 mL), followed by stirring at 50° C. for 5 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-(3-(4-iodo-3-methyl-1H-pyrazol-1-yl)propyl)morpholine (44 mg).

MSm/z(M+H):336.

0384-2

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (32 mg), bis(pinacolato)diboron (50 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (11 mg), potassium acetate (26 mg), and 1,4-dioxane (1 mL) was stirred at 80° C. for 2 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and 4-(3-(4-iodo-3-methyl-1H-pyrazol-1-yl)propyl)morpholine (44 mg), sodium carbonate (28 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (9 mg), and water (0.1 mL) were added thereto, followed by stirring at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 4-(3-(4-(6-chloro-1,5-naphthyridin-3-yl)-3-methyl-1H-pyrazol-1-yl)propyl)morpholine (10 mg).

MSm/z(M+H):372.

0384-3

A mixture of 4-(3-(4-(6-chloro-1,5-naphthyridin-3-yl)-3-methyl-1H-pyrazol-1-yl)propyl)morpholine (10 mg), 5-isopropylpyridazine-3-amine (5.5 mg), tris(dibenzylideneacetone)dipalladium(0) (2.4 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.1 mg), cesium carbonate (22 mg), and 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining N-(5-isopropylpyridazin-3-yl)-7-(3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine (2.8 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.90(1H,brs),8.79(1H,d,J=1.8 Hz),8.71(1H,brs),8.22(1H,d,J=8.7 Hz),8.10(1H,d,J=1.8 Hz),7.78(1H,s),7.52(1H,d,J=8.7 Hz),4.22(2H,t,J=6.9 Hz),3.77-3.71(4H,m),3.10-2.99(1H,m),2.52-2.45(4H,m),2.51(3H,s),2.41(2H,t,J=7.2 Hz),2.17-2.05(2H,m),1.41(6H,d,J=7.5 Hz).

MSm/z(M+H):473.

›Example 0385

385-1

Ethyl 3-oxopentanoate (2.15 mL) was added to a solution of (3-(benzyloxy)propyl)hydrazine (2.27 g) in ethanol (12 mL), followed by stirring for 5 hours under heating to reflux. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 1-(3-(benzyloxy)propyl)-3-ethyl-1H-pyrazol-5(4H)-one (994 mg).

MSm/z(M+H):261.

0385-2

Trifluoromethanesulfonic acid anhydride (0.937 mL) was added to a solution of 1-(3-(benzyloxy)propyl)-3-ethyl-1H-pyrazol-5(4H)-one (994 mg) and pyridine (0.553 mL) in dichloromethane (19 mL) under ice-cooling, followed by stirring at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution and dichloromethane were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining (1-(3-(benzyloxy)propyl)-3-ethyl-1H-pyrazol-5-yl) trifluoromethanesulfonate (1.43 g).

1 H-NMR(CDCl 3 ) δ:7.372.50(5H,m),5.91(1H,s),4.49(2H,s),4.12(2H,t,J=7.2 Hz),3.46(2H,t,J=6.0 Hz),2.59(2H,q,J=7.2 Hz),2.19-2.08(2H,m),1.21(3H,t,J=7.2 Hz).

0385-3

(1-(3-(Benzyloxy)propyl)-3-ethyl-1H-pyrazol-5-yl) trifluoromethanesulfonate (1.43 g) was added to a mixture of 20% palladium hydroxide-carbon (150 mg) and methanol (30 mL), followed by stirring for 5 hours in a hydrogen atmosphere. The insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(3-ethyl-1H-pyrazol-1-yl)propan-1-ol (1.15 g).

1 H-NMR(CDCl 3 )δ:7.79(1H,d,J=2.7 Hz),6.42(1H,d,J=2.7 Hz),4.60(2H,t,J=6.6 Hz),3.73(2H,t,J=5.4 Hz),2.88(2H,q,J=8.1 Hz),2.27-2.14(2H,m),1.26(3H,t,J=8.1 Hz).

0385-4

Iodine (557 mg) and ammonium cerium nitrate (1.20 g) were added to a solution of 3-(3-ethyl-1H-pyrazol-1-yl)propan-1-ol (1.15 g) in acetonitrile (8 mL), followed by stirring at room temperature for 16 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed sequentially with a 10% sodium hydrogen sulfite aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(3-ethyl-4-iodo-1H-pyrazol-1-yl)propan-1-ol (821 mg).

MSm/z(M+H):281.

0385-5

Methanesulfonyl chloride (0.342 mL) was added to a solution of 3-(3-ethyl-4-iodo-1H-pyrazol-1-yl)propan-1-ol (821 mg) and triethylamine (0.823 mL) in dichloromethane (15 mL) under ice-cooling, followed by stirring at the same temperature for 1 hour. Dichloromethane and water were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(3-ethyl-4-iodo-1H-pyrazol-1-yl)propyl methanesulfonate (1.00 g).

1 H-NMR(CDCl 3 )δ:7.39(1H,s),4.20(2H,t,J=6.6 Hz),4.21(2H,t,J=6.6 Hz),3.03(3H,s),2.60(2H,q,J=7.8 Hz),2.33-2.22(2H,m),1.22(3H,t,J=7.8 Hz).

0385-6

Morpholine (0.182 mL) was added to a mixture of 3-(3-ethyl-4-iodo-1H-pyrazol-1-yl)propyl methanesulfonate (500 mg), potassium carbonate (384 mg), and acetonitrile (7 mL), followed by stirring at 50° C. for 5 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-(3-(3-ethyl-4-iodo-1H-pyrazol-1-yl)propyl)morpholine (204 mg).

MSm/z(M+H):350.

0385-7

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (142 mg), bis(pinacolato)diboron (223 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (47 mg), potassium acetate (115 mg), and 1,4-dioxane (3 mL) was stirred at 80° C. for 2 hours in a nitrogen atmosphere. 4-(3-(3-ethyl-4-iodo-1H-pyrazol-1-yl)propyl)morpholine (204 mg), sodium carbonate (124 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (41 mg), and water (0.3 mL) were added thereto, followed by stirring at 80° C. for 4 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 4-(3-(4-(6-chloro-1,5-naphthyridin-3-yl)-3-ethyl-1H-pyrazol-1-yl)propyl)morpholine (18 mg).

MSm/z(M+H):386.

0385-8

A mixture of 4-(3-(4-(6-chloro-1,5-naphthyridin-3-yl)-3-ethyl-1H-pyrazol-1-yl)propyl)morpholine (18 mg), 5-isopropylpyridazine-3-amine (9.6 mg), tris(dibenzylideneacetone)dipalladium(0) (4.2 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.4 mg), cesium carbonate (38 mg), and 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 7-(3-ethyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)-N-(5-isopropylpyridazin-3-yl)-1,5-naphthyridine-2-amine (6.9 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.94(1H,brs),8.76(1H,brs),8.71(1H,brs),8.22(1H,d,J=9.0 Hz),8.08(1H,brs),7.74(1H,s),7.51(1H,d,J=9.0 Hz),4.23(2H,t,J=7.2 Hz),3.78-3.71(4H,m),3.10-2.98(1H,m),2.89(2H,q,J=7.2 Hz),2.53-2.45(4H,m),2.42(2H,t,J=6.6 Hz),2.19-2.05(2H,m),1.40(6H,d,J=6.6 Hz),1.31(3H,t,J=7.2 Hz).

MSm/z(M+H):487.

›Example 0386

0386-1

Pyrrolidine (0.172 mL) was added to a mixture of 3-(3-ethyl-4-iodo-1H-pyrazol-1-yl)propyl methanesulfonate (500 mg), potassium carbonate (384 mg), and acetonitrile (7 mL), followed by stirring at 50° C. for 5 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-ethyl-4-iodo-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazole (250 mg).

MSm/z(M+H):334.

0386-2

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (182 mg), bis(pinacolato)diboron (286 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (61 mg), potassium acetate (147 mg), and 1,4-dioxane (4 mL) was stirred at 80° C. for 2 hours in a nitrogen atmosphere. 3-Ethyl-4-iodo-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazole (250 mg), sodium carbonate (158 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (53 mg), and water (0.4 mL) were added thereto, followed by stirring at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 2-chloro-7-(3-ethyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (161 mg).

MSm/z(M+H):370.

0386-3

A mixture of 2-chloro-7-(3-ethyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (161 mg), 5-isopropylpyridazine-3-amine (9.6 mg), tris(dibenzylideneacetone)dipalladium(0) (4.2 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.4 mg), cesium carbonate (38 mg), and 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 7-(3-ethyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-N-(5-isopropylpyridazin-3-yl)-1,5-naphthyridine-2-amine (9.3 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.95(1H,brs),8.78(1H,d,J=2.1 Hz),8.71(1H,m),8.22(1H,d,J=8.7 Hz),8.09(1H,d,J=2.1 Hz),7.77(1H,s),7.50(1H,d,J=8.7 Hz),4.22(2H,t,J=7.5 Hz),3.10-2.98(1H,m),2.89(2H,q,J=7.2 Hz),2.65-2.48(6H,m),2.21-2.07(2H,m),1.88-1.80(4H,m),1.41(6H,d,J=7.5 Hz),1.31(3H,t,J=7.2 Hz).

MSm/z(M+H):471.

›Example 0387

0387-1

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (100 mg), pyrimidine-5-amine (38 mg), tris(dibenzylideneacetone)dipalladium(0) (37 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (47 mg), cesium carbonate (267 mg), and 1,4-dioxane (2 mL) was stirred at 80° C. for 6 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 6-chloro-N-(pyrimidin-5-yl)-1,5-naphthyridine-3-amine (32 mg).

MSm/z(M+H):258.

0387-2

A mixture of 6-chloro-N-(pyrimidin-5-yl)-1,5-naphthyridine-3-amine (10 mg), 5-isopropylpyridazine-3-amine (8.0 mg), tris(dibenzylideneacetone)dipalladium(0) (3.5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.5 mg), cesium carbonate (25 mg), and 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and the solid matter was collected by filtration, thereby obtaining N 2 -(5-isopropylpyridazin-3-yl)-N 7 -(pyrimidin-5-yl)-1,5-naphthyridine-2,7-diamine (4.5 mg).

1 H-NMR(DMSO-d 6 )δ:10.63(1H,s),9.17(1H,s),8.83(1H,d,J=1.8 Hz),8.79(1H,s),8.77(2H,s),8.70(1H,d,J=1.8 Hz),8.62(1H,d,J=2.7 Hz),8.14(1H,d,J=9.0 Hz),7.67(1H,d,J=2.7 Hz),7.58(1H,d,J=9.0 Hz),3.07-2.93(1H,m),1.29(6H,d,J=7.2 Hz).

MSm/z(M+H):359.

›Example 0388

0388-1

A mixture of 6-chloro-N-(pyrimidin-5-yl)-1,5-naphthyridine-3-amine (10 mg), 5-methylpyridazine-3-amine (6.4 mg), tris(dibenzylideneacetone)dipalladium(0) (3.5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.5 mg), cesium carbonate (25 mg), and 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, and the solid matter was collected by filtration, thereby obtaining N 2 -(5-methylpyridazin-3-yl)-N 7 -(pyrimidin-5-yl)-1,5-naphthyridine-2,7-diamine (1.6 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.81(1H,s),8.75(2H,s),8.73(1H,brs),8.64(1H,brs),8.51(1H,d,J=2.4 Hz),8.12(1H,d,J=9.0 Hz),7.83(1H,d,J=2.4 Hz),7.36(1H,d,J=9.0 Hz),2.45(3H,s).

MSm/z(M+H):331.

›Example 0389

0389-1

A solution of 4-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole (521 mg) and potassium carbonate (850 mg) in 1,4-dioxane (3 mL) and water (6 mL) was stirred for 8 hours under heating to reflux. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining (4-bromo-1-methyl-1H-pyrazol-3-yl)methanol (334 mg).

MSm/z(M+H):191,193.

0389-2

A mixture of (4-bromo-1-methyl-1H-pyrazol-3-yl)methanol (334 mg), manganese dioxide (756 mg), and dichloromethane (8 mL) was stirred at 50° C. for 24 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure, thereby obtaining 4-bromo-1-methyl-1H-pyrazole-3-carbaldehyde (271 mg).

MSm/z(M+H):189,191.

0389-3

Potassium tert-butoxide (159 mg) was added to a solution of (methoxymethyl)triphenylphosphonium chloride (396 mg) in tetrahydrofuran (2 mL) under ice-cooling, followed by stirring at the same temperature for 30 minutes, and a solution of 4-bromo-1-methyl-1H-pyrazole-3-carbaldehyde (168 mg) in tetrahydrofuran (1 mL) was added to the reaction mixture, followed by stirring at room temperature for 4 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the obtained solution was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining (E)-4-bromo-3-(2-methoxyvinyl)-1-methyl-1H-pyrazole (49 mg).

MSm/z(M+H):217.

0389-4

(E)-4-bromo-3-(2-methoxyvinyl)-1-methyl-1H-pyrazole (49 mg) was added to a mixture of 10% palladium-carbon (20 mg) and methanol (5 mL), followed by stirring for 4 hours in a hydrogen atmosphere. The insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(2-methoxyethyl)-1-methyl-1H-pyrazole (46 mg).

1 H-NMR(CDCl 3 )δ:7.53(1H,brs),6.46(1H,brs),4.28(3H,s),3.76(2H,t,J=6.0 Hz),3.38(3H,s),3.15(2H,t,J=6.0 Hz).

0389-5

Iodine (34 mg) and ammonium cerium nitrate (74 mg) were added to a solution of 3-(2-methoxyethyl)-1-methyl-1H-pyrazole (46 mg) in acetonitrile (2 mL), followed by stirring at room temperature for 22 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed sequentially with a 10% sodium hydrogen sulfite aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-iodo-3-(2-methoxyethyl)-1-methyl-1H-pyrazole (35 mg).

MSm/z(M+H):267.

0389-6

A mixture of N-(7-bromo-1,5-naphthyridin-2-yl)-5-isopropyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (20 mg), bis(pinacolato)diboron (13 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (3 mg), potassium acetate (8 mg), and 1,4-dioxane (1 mL) was stirred at 80° C. for 2 hours in a nitrogen atmosphere. 4-Iodo-3-(2-methoxyethyl)-1-methyl-1H-pyrazole (11 mg), sodium carbonate (8 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5 mg), and water (0.1 mL) were added thereto, followed by stirring at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane), thereby obtaining 5-isopropyl-N-(7-(3-(2-methoxyethyl)-1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (5.6 mg).

MSm/z(M+H):540.

0389-7

Water (0.2 mL) and trifluoroacetic acid (2 mL) were added to 5-isopropyl-N-(7-(3-(2-methoxyethyl)-1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4-thiadiazole-2-amine (5.6 mg), followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 5-isopropyl-N-(7-(3-(2-methoxyethyl)-1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-2-yl)-1,3,4-thiadiazole-2-amine (5.2 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.80(1H,brs),8.31(1H,brs),8.24(1H,d,J=9.0 Hz),7.70(1H,s),7.35(1H,d,J=9.0 Hz),3.97(3H,s),3.75(2H,t,J=7.5 Hz),3.48-3.34(1H,m),3.40(3H,s),3.11(2H,t,J=7.5 Hz),1.48(6H,d,J=6.6 Hz).

MSm/z(M+H):410.

›Example 0390

0390-1

Ethyl 3-oxohexanoate (2.32 mL) was added to a solution of (3-(benzyloxy)propyl)hydrazine (2.19 g) in ethanol (12 mL), followed by stirring for 2 hours under heating to reflux. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 1-(3-(benzyloxy)propyl)-3-propyl-1H-pyrazol-5(4H)-one (930 mg).

MSm/z(M+H):275.

0390-2

Trifluoromethanesulfonic acid anhydride (0.834 mL) was added to a solution of 1-(3-(benzyloxy)propyl)-3-propyl-1H-pyrazol-5(4H)-one (930 mg) and pyridine (0.492 mL) in dichloromethane (17 mL) under ice-cooling, followed by stirring at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution and dichloromethane were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining (1-(3-(benzyloxy)propyl)-3-propyl-1H-pyrazol-5-yl) trifluoromethanesulfonate (1.41 g).

1 H-NMR(CDCl 3 )δ:7.367.24(5H,m),5.90(1H,s),4.48(2H,s),4.12(2H,t,J=6.6 Hz),3.45(2H,t,J=6.0 Hz),2.53(2H,t,J=8.1 Hz),2.19-2.08(2H,m),1.75-1.55(2H,m),0.94(3H,t,J=7.2 Hz).

390-3

(1-(3-(Benzyloxy)propyl)-3-propyl-1H-pyrazol-5-yl) trifluoromethanesulfonate (1.41 g) was added to a mixture of 20% palladium hydroxide-carbon (100 mg) and methanol (15 mL), followed by stirring for 2 hours in a hydrogen atmosphere. The insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(3-propyl-1H-pyrazol-1-yl)propan-1-ol (1.08 g).

1 H-NMR(CDCl 3 )δ:7.83(1H,d,J=2.7 Hz),6.41(1H,d,J=2.7 Hz),4.59(2H,t,J=6.6 Hz),3.73(2H,t,J=5.7 Hz),2.79(2H,t,J=8.1 Hz),2.25-2.14(2H,m),1.82-1.67(2H,m),1.00(3H,t,J=7.5 Hz).

0390-4

Iodine (516 mg) and ammonium cerium nitrate (1.12 g) were added to a solution of 3-(3-propyl-1H-pyrazol-1-yl)propan-1-ol (1.08 g) in acetonitrile (17 mL), followed by stirring at room temperature for 1 day. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed sequentially with a 10% sodium hydrogen sulfite aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(4-iodo-3-propyl-1H-pyrazol-1-yl)propan-1-ol (856 mg).

1 H-NMR(CDCl 3 )δ:7.36(1H,s),4.23(2H,t,J=6.0 Hz),3.62(2H,t,J=6.0 Hz),2.55(2H,t,J=7.8 Hz),2.06-1.95(2H,m),1.76-1.59(2H,m),0.95(3H,t,J=7.5 Hz).

0390-5

Methanesulfonyl chloride (0.192 mL) was added to a solution of 3-(4-iodo-3-propyl-1H-pyrazol-1-yl)propan-1-ol (856 mg) and triethylamine (0.460 mL) in dichloromethane (8 mL) under ice-cooling, followed by stirring at the same temperature for 1 hour. Dichloromethane and water were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(4-iodo-3-propyl-1H-pyrazol-1-yl)propyl methanesulfonate (539 mg).

1 H-NMR(CDCl 3 )δ:7.39(1H,s),4.24-4.17(4H,m),3.03(3H,s),2.55(2H,t,J=7.5 Hz),2.33-2.22(2H,m),1.76-1.57(2H,m),0.96(3H,t,J=7.5 Hz).

0390-6

Morpholine (0.094 mL) was added to a mixture of 3-(4-iodo-3-propyl-1H-pyrazol-1-yl)propyl methanesulfonate (269 mg), potassium carbonate (199 mg), and acetonitrile (4 mL), followed by stirring at 50° C. for 8 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-(3-(4-iodo-3-propyl-1H-pyrazol-1-yl)propyl)morpholine (43 mg).

MSm/z(M+H):364.

0390-7

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (29 mg), bis(pinacolato)diboron (36 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (10 mg), potassium acetate (23 mg), and 1,4-dioxane (1 mL) was stirred at 80° C. for 2 hours in a nitrogen atmosphere. 4-(3-(4-iodo-3-propyl-1H-pyrazol-1-yl)propyl)morpholine (43 mg), sodium carbonate (25 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (8 mg), and water (0.1 mL) were added thereto, followed by stirring at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 4-(3-(4-(6-chloro-1,5-naphthyridin-3-yl)-3-propyl-1H-pyrazol-1-yl)propyl)morpholine (11 mg).

MSm/z(M+H):400.

0390-8

A mixture of 4-(3-(4-(6-chloro-1,5-naphthyridin-3-yl)-3-propyl-1H-pyrazol-1-yl)propyl)morpholine (11 mg), 5-isopropylpyridazine-3-amine (5.6 mg), tris (dibenzylideneacetone)dipalladium(0) (5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), cesium carbonate (22 mg), and 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining N-(5-isopropylpyridazin-3-yl)-7-(1-(3-morpholinopropyl)-3-propyl-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine (6.5 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.95(1H,brs),8.76(1H,d,J=1.8 Hz),8.71(1H,brs),8.22(1H,d,J=9.0 Hz),8.08(1H,d,J=1.8 Hz),7.74(1H,s),7.50(1H,d,J=9.0 Hz),4.23(2H,t,J=6.6 Hz),3.78-3.70(4H,m),3.10-2.98(1H,m),2.83(2H,t,J=7.5 Hz),2.53-2.44(4H,m),2.41(2H,t,J=7.2 Hz),2.18-2.06(2H,m),1.79-1.66(2H,m),1.40(6H,d,J=6.6 Hz),0.99(3H,t,J=7.2 Hz).

MSm/z(M+H):501.

›Example 0391

0391-1

Pyrrolidine (0.089 mL) was added to a mixture of 3-(4-iodo-3-propyl-1H-pyrazol-1-yl)propyl methanesulfonate (269 mg), potassium carbonate (199 mg), and acetonitrile (4 mL), followed by stirring at 50° C. for 1 day. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 4-iodo-3-propyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazole (113 mg).

MSm/z(M+H):348.

0391-2

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (79 mg), bis(pinacolato)diboron (99 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (26 mg), potassium acetate (64 mg), and 1,4-dioxane (2 mL) was stirred at 80° C. for 2 hours in a nitrogen atmosphere. 4-Iodo-3-propyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazole (113 mg), sodium carbonate (69 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (23 mg), and water (0.2 mL) were added thereto, followed by stirring at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 2-chloro-7-(3-propyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (53 mg).

MSm/z(M+H):384.

0391-3

A mixture of 2-chloro-7-(3-propyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine (27 mg), 5-isopropylpyridazine-3-amine (14 mg), tris(dibenzylideneacetone)dipalladium(0) (5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), cesium carbonate (57 mg), and 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining N-(5-isopropylpyridazin-3-yl)-7-(3-propyl-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-2-amine (6.5 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.96(1H,brs),8.77(1H,brs),8.71(1H,brs),8.22(1H,d,J=9.3 Hz),8.08(1H,brs),7.77(1H,s),7.50(1H,d,J=9.3 Hz),4.22(2H,t,J=6.6 Hz),3.10-2.98(1H,m),2.83(2H,t,J=7.2 Hz),2.61-2.47(6H,m),2.20-2.08(2H,m),1.88-1.68(6H,m),1.41(6H,d,J=6.6 Hz),0.99(3H,t,J=7.2 Hz).

MSm/z(M+H):485.

›Example 0392

0392-1

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (50 mg), morpholine (18 mL), tris (dibenzylideneacetone)dipalladium(0) (18 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (24 mg), sodium tert-butoxide (39 mg), and 1,4-dioxane (2 mL) was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 4-(6-chloro-1,5-naphthyridin-3-yl)morpholine (5.5 mg).

MSm/z(M+H):250.

0392-2

A mixture of 4-(6-chloro-1,5-naphthyridin-3-yl)morpholine (5.5 mg), 5-isopropylpyridazine-3-amine (4.5 mg), tris (dibenzylideneacetone)dipalladium(0) (5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), cesium carbonate (20 mg), and 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining N-(5-isopropylpyridazin-3-yl)-7-morpholino-1,5-naphthyridine-2-amine (5.4 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.78(1H,brs),8.69(1H,brs),8.56(1H,brs),8.11(1H,d,J=8.4 Hz),7.35(1H,brs),7.34(1H,d,J=8.4 Hz),3.99-3.93(4H,m),3.42-3.36(4H,m),3.10-2.97(1H,m),1.40(6H,d,J=6.6 Hz).

MSm/z(M+H):351.

›Example 0393

0393-1

A solution of (4-bromo-1-methyl-1H-pyrazol-3-yl)methanol (325 mg), tert-butyldimethylsilyl chloride (307 mg), and imidazole (289 mg) in N,N-dimethylformamide (6 mL) was stirred at room temperature for 3 days. Ethyl acetate and water were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazole (446 mg).

1 H-NMR(CDCl 3 )δ:7.32(1H,s),4.65(2H,s),3.85(3H,s),0.91(9H,s),0.11(6H,s).

0393-2

A 1.6 mol/L n-butyllithium-hexane solution (1.36 mL) was added to a solution of 4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazole (446 mg) in tetrahydrofuran (7 mL) at −80° C., followed by stirring at the same temperature for 30 minutes, and 2-isopropyloxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.595 mL) was added thereto at the same temperature, followed by stirring while slowly heating to room temperature over a period of 2.5 hours. A saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (687 mg).

1 H-NMR(CDCl 3 )δ:7.57(1H,s),4.79(2H,s),3.85(3H,s),1.24(12H,s),0.92(9H,s),0.11(6H,s).

0393-3

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (80 mg), 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (231 mg), sodium carbonate (87 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (23 mg), water (0.3 mL), and 1,4-dioxane (3 mL) was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane), thereby obtaining 7-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-4-yl)-2-chloro-1,5-naphthyridine (76 mg).

MSm/z(M+H):389.

0393-4

A mixture of 7-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-4-yl)-2-chloro-1,5-naphthyridine (25 mg), 5-isopropylpyridazine-3-amine (13 mg), tris (dibenzylideneacetone)dipalladium(0) (5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), cesium carbonate (20 mg), and 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 7-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-4-yl)-N-(5-isopropylpyridazin-3-yl)-1,5-naphthyridine-2-amine (20 mg).

1 H-NMR(CDCl 3 )δ:8.95(1H,brs),8.86(1H,brs),8.71(1H,brs),8.27(1H,s),8.23(1H,d,J=9.0 Hz),7.79(1H,s),7.51(1H,d,J=9.0 Hz),4.85(2H,s),3.98(3H,s),3.10-2.98(1H,m),1.40(6H,d,J=6.6 Hz),0.83(9H,s),0.08(6H,s).

MSm/z(M+H):490.

›Example 0394

0394-1

Water (0.1 mL) and trifluoroacetic acid (2 mL) were added to 7-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-4-yl)-N-(5-isopropylpyridazin-3-yl)-1,5-naphthyridine-2-amine (20 mg), followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining (4-(6-((5-isopropylpyridazin-3-yl)amino)-1,5-naphthyridin-3-yl)-1-methyl-1H-pyrazol-3-yl)methanol (5.9 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.90(1H,d,J=2.1 Hz),8.87(1H,brs),8.71(1H,brs),8.36(1H,d,J=2.1 Hz),8.22(1H,d,J=9.3 Hz),7.81(1H,s),7.55(1H,d,J=9.3 Hz),4.76(2H,s),3.99(3H,s),3.10-2.97(1H,m),1.40(6H,d,J=6.6 Hz).

MSm/z(M+H):376.

›Example 0395

0395-1

60% sodium hydride (318 mg) was added to a solution of tetrahydro-2H-pyran-4-ol (542 mg), ethyl bromoacetate (0.590 mL), and tetrahydrofuran (25 mL), under ice-cooling, followed by stirring at room temperature for 2.5 hours. A saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed sequentially with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining ethyl 2-((tetrahydro-2H-pyran-4-yl)oxy)acetate (184 mg).

MSm/z(M+H):189.

395-2

A solution of ethyl 2-((tetrahydro-2H-pyran-4-yl)oxy)acetate (184 mg) in tetrahydrofuran (10 mL) was added to a mixture of lithium aluminium hydride (185 mg) and tetrahydrofuran (10 mL) under ice-cooling, followed by stirring at room temperature for 1 hour, and a 3 mol/L potassium sodium tartrate aqueous solution (10 mL) was added thereto under ice-cooling, followed by stirring at room temperature for 1 day. Ethyl acetate was added to the reaction mixture, and the insolubles were filtered off using celite. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 2-((tetrahydro-2H-pyran-4-yl)oxy)ethanol (95 mg).

MSm/z(M+H):147.

0395-3

Methanesulfonyl chloride (0.076 mL) was added to a solution of 2-((tetrahydro-2H-pyran-4-yl)oxy)ethanol (95 mg) and triethylamine (0.183 mL) in dichloromethane (6 mL) under ice-cooling, followed by stirring at the same temperature for 30 minutes. Dichloromethane and water were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl methanesulfonate (242 mg).

1 H-NMR(CDCl 3 )δ:3.75(2H,t,J=4.5 Hz),3.99-3.90(2H,m),3.74(2H,t,J=4.5 Hz),3.60-3.39(3H,m),3.06(3H,s),1.96-1.82(2H,m),1.66-1.52(2H,m).

0395-4

A mixture of 2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl methanesulfonate (242 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (80 mg), cesium carbonate (425 mg), acetonitrile (1 mL), and 1,4-dioxane (2 mL) was stirred at 80° C. for 5 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate-hexane), thereby obtaining 1-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (108 mg).

MSm/z(M+H):323.

0395-5 and 0395-6

The following compounds were obtained in the same manner as in Examples 0001-4 and 0001-5.

›Example 0396

0396-1

A mixture of 7-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-4-yl)-2-chloro-1,5-naphthyridine (25 mg), 5-methylpyridazine-3-amine (11 mg), tris (dibenzylideneacetone)dipalladium(0) (5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), cesium carbonate (20 mg), and 1,4-dioxane (1 mL) was stirred at 140° C. for 30 minutes using a microwave reaction apparatus. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining 7-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-4-yl)-N-(5-methylpyridazin-3-yl)-1,5-naphthyridine-2-amine (12 mg).

1 H-NMR(CDCl 3 )δ:8.97(1H,brs),8.78(1H,brs),8.73(1H,brs),8.37(1H,s),8.26(1H,d,J=8.4 Hz),7.71(1H,s),7.44(1H,d,J=8.4 Hz),4.84(2H,s),3.98(3H,s),2.45(3H,s),0.87(9H,s),0.11(6H,s).

MSm/z(M+H):462.

›Example 0397

0397-1

Water (0.1 mL) and trifluoroacetic acid (2 mL) were added to 7-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-pyrazol-4-yl)-N-(5-methylpyridazin-3-yl)-1,5-naphthyridine-2-amine (12 mg), followed by stirring at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate, NH silica), thereby obtaining (1-methyl-4-(6-((5-methylpyridazin-3-yl)amino)-1,5-naphthyridin-3-yl)-1H-pyrazol-3-yl)methanol (9.6 mg).

1 H-NMR(CDCl 3 /CD 3 OD=4/1)δ:8.90(1H,brs),8.79(1H,brs),8.64(1H,brs),8.35(1H,brs),8.20(1H,d,J=8.1 Hz),7.80(1H,s),7.53(1H,d,J=8.1 Hz),4.77(2H,s),3.36(3H,s),2.46(3H,s).

MSm/z(M+H):348.

›Example 0398

0398-1

Iodine (208 mg) and ammonium cerium nitrate (450 mg) were added to a solution of 3-(1H-pyrazol-1-yl)pyridine (200 mg) in acetonitrile (3 mL), followed by stirring at room temperature for 13 hours, and stirring for 8 hours under heating to reflux. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added thereto. The organic layer was collected by separation, washed sequentially with a 10% sodium hydrogen sulfite aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 3-(4-iodo-1H-pyrazol-1-yl)pyridine (333 mg).

MSm/z(M+H):272.

0398-2

A mixture of 7-bromo-2-chloro-1,5-naphthyridine (50 mg), bis(pinacolato)diboron (62 mg), (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (16 mg), potassium acetate (40 mg), and 1,4-dioxane (2 mL) was stirred at 80° C. for 2 hours in a nitrogen atmosphere. 3-(4-Iodo-1H-pyrazol-1-yl)pyridine (61 mg), sodium carbonate (43 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (17 mg), and water (0.2 mL) were added thereto, followed by stirring at 80° C. for 8 hours. The reaction mixture was cooled to room temperature, the insolubles were filtered off using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane), thereby obtaining 2-chloro-7-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)-1,5-naphthyridine (27 mg).

MSm/z(M+H):308.

0398-3

A mixture of 2-chloro-7-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)-1,5-naphthyridine (13 mg), 5-isopropylpyridazine-3-amine (7.4 mg), tris (dibenzylideneacetone)dipalladium(0) (5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), ces

›Tables in the description — 10

TABLE 1 — ERK2 enzyme

	PI3Kα enzyme	inhibitory activity
Example No.	inhibitory activity	(1)	(2)
0001	+++	+++
0002	+++	+++
0003	++	+++
0004	+++	+++
0005	+++
0006	+++	+++
0007	+++	+++
0008	+++	++
0009	++	++
0010	++	+++
0011	+++	++
0012	+++	++
0013	+++	++
0014	+++	+++	+++
0015	+++	+++	+++
0016	+++	+++	+++
0017	+++	+++	+++
0018	+++	+++	+++
0019	+++	+++
0020	+++	+++
0021	+++	+++	+++
0022	++	+
0023	++	++
0024	++	+
0025	++	+++	+++
0026	+++	+++	+++
0027	+++	+++	+++
0028		+++
0029	+++	+++
0030	+++	+++
0031		++
0032	+++	+++	+++
0033	++	++
0034	++
0035	+++	++
0036	++	++
0037	++	+++
0038	+	++
0039		+++
0040	+	+++
0041	+	+++
0042		+
0043	++	+++
0044		++
0045	+	+++
0046	++	+++
0047	+++
0048	++	+++
0049		++
0050	++	+++
0051	++	+++
0052	++	+++
0053	++	+++
0054	+++	+++
0055	++	+++
0056	+	+++
0057	+	++
0058	++	+++
0059	++	+++
0060	+	+++
0061	++	+++
0062	++	+++
0063	+++	+++
0064	++	+++
0065	++	+++
0066	+++	+++
0067	+++	+++
0068	++	+++
0069	+	++
0070	+++	+++
0071	+++	+++	+++
0072	+++	+++	+++
0073	+++	+++
0074	+++	+++
0075	+++	++
0076	+++	+++
0077	++	++
0078	+++	+++
0079	++	+++
0080		+++
0081	++	+++
0082	+++	+++
0083	+++	+++
0084	+++	+++	+++
0085	+++	+++	+++
0086	+++	+++	+++
0087	+++	+++	+++
0088	+++	+++	+++
0089	+++	+++	+++
0090	+++	+++	+++
0091	+++	+++	+++
0092	++	+++	+++
0093	++	+++	+
0094	+++	+	+
0095	+++	+++	++
0096	+++	+++	+++
0097	+++	+++
0098	+++	+++
0099	+++	+++
0100	++	+++

TABLE 1 — ERK2 enzyme

	PI3Kα enzyme	inhibitory activity
Example No.	inhibitory activity	(1)	(2)
0101	+++	+++
0102	+++	+++
0103	+++	+++
0104	++	+++
0105	+++	+++
0106	+++	+++
0107	+++	+++
0108	++	+++
0109	+++	++
0110	+++	+++
0111		+++	+++
0112	+++	+++	+++
0113		+++	+++
0114	+++	+++	+++
0115	+++	+++	+++
0116	+++	+++	+++
0117	+++	+++	+++
0118	+++	+++	+++
0119	+++	+++
0120	+++	+++	+++
0121	+++	+++	+++
0122	+++	+++	+++
0123	+++	+++
0124	+++	+++	++
0125	+++	+++
0126	+++	+++
0127	++	+++
0128	+++	+++
0129	+++	+++	++
0130	+++	+++	+++
0131	+++	+++	+++
0132	+++	+++	+++
0133	+++	+++	+++
0134	+++	+++	+++
0135	+++	+++	++
0136	+++	+++
0137	+++	+++	+++
0138	+++	+++	+++
0139	+++	+++	+++
0140	+++	+++	+++
0141	++	++
0142	+++	+++	+++
0143	++	+++
0144	+++	+++
0145	+++	+++	+++
0146	+++	+++
0147	+++	+++	+++
0148	+++	+++	+++
0149		++
0150	+++	+++	++
0151	+	+++	++
0152	++	+++
0153	++	+++
0154	++	+++
0155	++
0156	+++	+++
0157	+++	+++	+++
0158	+++	+++	++
0159	+++	+++	+++
0160	+++	+++	+++
0161	+++	+++	+++
0162	+++	+++	+++
0163	+++	+++	+++
0164		+++
0165	+	+++
0166	++	+++
0167	+++	+++	+++
0168		+++
0169		+++	+++
0170	++	+++	+++
0171	+	+++
0172	+++	+++	+++
0173	++	+++	+++
0174		+++
0175	+++	+++
0176	+++	+++
0177	+++	+++
0178	+++	+++
0179	+++	+++
0180	++	+++
0181	+++	+++
0182	++	+++
0183	++	+++
0184	++	+++
0185	+++	+++
0186	+++	+++
0187	+++	+++
0188	+++	+++
0189	+++	+++	+++
0190	++	+++
0191	+++	+++
0192	+++	+++
0193	+++	+++
0194	++	+++
0195	++	+++
0196	++	+++
0197	+++	+++
0198		+++
0199	++	++
0200	++	++

TABLE 1 — ERK2 enzyme

	PI3Kα enzyme	inhibitory activity
Example No.	inhibitory activity	(1)	(2)
0201	++	+++
0202	+	+++
0203		+++
0204		+++
0205	+++	+++
0206	+	+++
0207	+++	+++
0208	+++	+++
0209	+++	+++
0210	+++	+++
0211		+++
0212		+++
0213		+++
0214	++	+++	+++
0215	++	+++	+++
0216		+++
0217		+++	+++
0218		+++
0219	+	++
0220	+++	++
0221	+++	+++
0222	+++	+++
0223	++	+++
0224	+++	+++
0225	++	+++
0226	++	+++	+++
0227	+++	+++	+++
0228	+++	+++
0229	+++	+++
0230		+++
0231	+++	+++
0232	+++	+++
0233	+++	+++
0234	+++	+++
0235	+++	+++	+++
0236	+++	+++	+++
0237	+++	+++
0238	+++	+++
0239	+++	+++
0240	+++	+++	+++
0241	++	+++	+++
0242	+++	+++	+++
0243	+++	+++	+++
0244	+++	+++
0245	+++	+++
0246	++	+++	+++
0247	++	+++	+++
0248	++	+++	+++
0249	+++	+++
0250	+++	+++	+++
0251	++	+++	+++
0252	++	+++	+++
0253	++	+++	+++
0254	+++	+++
0255	++	+++
0256	+++	+++
0257	++	+++	+++
0258	+++	+++	+++
0259	+++	+++
0260	+++	+++
0261	+++	+++	+++
0262	+++	+++	+++
0263	+++	+++
0264	++	+++
0265	+++	+++	+++
0266	+++	+++	+++
0267	+++	+++	+++
0268	+++	+++
0269	+++	+++
0270	+++	+++
0271		+++
0272	++	+++
0273	+++	+++
0274	+++	++
0275	+++	+++
0276	+++	+++	++
0277	++	++
0278	+++	+++
0279	+++	+++
0280	+	++
0281	++	++
0282	++	++
0283	+++	+++
0284	+++	++
0285	+++	+++
0286	++	++
0287	+++	+++
0288	+++	+++
0289	+++	++
0290	+++	+++	+++
0291	+++	+++	+++
0292	+++	+++	+++
0293	+++	+++	+++
0294	+++	+++	+++
0295	+++	+++	+++
0296	+++	+++
0297	+++	+++
0298	+++	+++
0299	+	+++
0300	++	+++

TABLE 1 — ERK2 enzyme

	PI3Kα enzyme	inhibitory activity
Example No.	inhibitory activity	(1)	(2)
0301	+++	+++
0302	+++	+++
0303	+++	+++	+++
0304	+++	+++
0305	+++	+++
0306	+++	+++
0307	+++	+++
0308	++	+++
0309	++	+++
0310	++	+++
0311	++	+++	+++
0312	+++	+++
0313	++	+++
0314	++	+++
0315	++	+++
0316	+++	+++	+++
0317	+++	+++
0318	+++	+++	+++
0319	+++	+++
0320	+++	+++	+++
0321	+++	+++	+++
0322	+++	+++	+++
0323	+++	+++
0324	+++	+++
0325	+++	+++
0326	+++	+++
0327	++	+++	+++
0328		+++
0329	+++	+++
0330	++	+++
0331		++
0332	+	+++
0333	++	+++
0334	+++	+++
0335	+	+++
0336	+++	+++	+++
0337	+++	+++	+++
0338	+++	+++	+++
0339	+++	+++	+++
0340		+++
0341	+++	+++	+++
0342	+++	+++	+++
0343	+++	+++	+++
0344	+++	+++	+++
0345	+++	+++	+++
0346	+++	+++	+++
0347	+++	+++	+++
0348	++	+++	+++
0349		+++	++
0350	++	+++	+++
0351	+++	+++	+++
0352	+++	+++	+++
0353	+++	+++	+++
0354	+++	+++	+++
0355	+++	+++	+++
0356	+++	+++	+++
0357		++	++
0358	+++	+++	+++
0359	+++	+++	++
0360	+++	+++	+++
0361	++	+++
0362	+++	+++
0363	+++	+++
0364	+++	+++	+++
0365	+++	+++	+++
0366	+++	+++
0367	+++	+++
0368	+++	+++	+++
0369	++	+++
0370	+++	+++	+++
0371	+++	+++
0372	++	+++	+++
0373	+++	+++
0374	+++	+++
0375	+++	+++
0376	+++	+++
0377	+++	+++
0378	+++	+++
0379	+++	+++
0380	+++	+++
0381	+++	+++
0382	+++	+++	+++
0383	++	+++	+++
0384	+++	+++	+++
0385	+++	+++
0386	+++	+++
0387	+++	+++
0388	++	+++
0389	+++	+++
0390	+++	+++
0391	+++	+++
0392	+++	+++
0393	++	+++
0394	+++	+++
0395	+++	+++
0396	+	+++
0397	+++	+++
0398	+++	+++
0399	++	+++
0400	+++	+++

TABLE 1 — ERK2 enzyme

PI3Kα enzyme	inhibitory activity
Example No.	inhibitory activity	(1)	(2)
0401	+++	+++	+++
0402	+++	+++	+++
0403	+++	+++	+++
0404	+++	+++
0405	+++	+++
0406	+++	+++
0407	++	+++
0408		+++
0409	+++	++
0410	+++		+++
0411	+++		+++
0412	+++		+++
0413	+++		+++
0414	+++		+++
0415	+++		+++
0416	+++		+++
0417	+++		+++
0418	+++		+++
0419	+++		+++
0420	+++		+++
0421	+++		+++
0422	+++		+++
0423	+++		+++
0424	+++		+++
0425	+++		+++
0426	+++		+++
0427	+++		+++
0428	+++		+++
0429	+++		+++
0430	+++		+++
0431	+++		+++
0432	+++		+++
0433	+++		+++
0434	+++		+++
0435	+++		+++
0436	+++		+++
0437	+++		+++
0438	+++		+++
0439	+++		+++
0440	+++		+++
0441	+++		+++
0442	+++		+++
0443	+++		+++
0444	+++		+++
0445	+++		+++
0446	+++		+++
0447	+++		++
0448	+++		++
0449	+++		+++
0450	+++		+++
0451	+++		+++
0452	+++		+++
0453	+++		+++
0454	+++		+++
0455	+++		+++
0456	+++		+++
0457	+++		+
0458	+++		+
0459	+++		+++
0460	+++		+++
0461	+++		+++
0462	+++		+++
0463	+++		+++
0464	+++		+++
0465	+++		+++
0466	+++		+++
0467	+++		+++
0468	+++		+++
0469	+++		+++
0470	+++		+++
0471	+++	+++	+++
0472	+++	+++	+++
0473	+++	+++	+++
0474	+++	+++	+++
0475	+++	+++	+++
0476	+++	+++
0477	+++	+++
0478	+++		+++
0479	+++		+++
0480	+++		+++
0481	++		+++
0482	+++		+++
0483	+++		+++
0484	+++		+++
0485	+++		+++
0486	+++		+++
0487	+++		+++
0488	+++		+++
0489	+		++
0490	+++		+++
0491	+++		+++
0492	+++		+++
0493	+++		+++
0494	+++		+++
0495	+++		+++
0496	+++		+++
0497	++		+++
0498	+++		+++
0499	+++		+++
0500	+++		+++

TABLE 1 — ERK2 enzyme

PI3Kα enzyme	inhibitory activity
Example No.	inhibitory activity	(1)	(2)
0501	++		++
0502	+++		+++
0503	+++		+++
0504	+++		+++
0505	++		+++
0506	++		+++
0507	+++		+++
0508	+++		+++
0509	++		+++
0510	++		+++
0511	++		+++
0512	++		+++
0513			+++
0514	++		+++
0515	+++		+++
0516	+
0517	+++		+++
0518	+++		+++
0519	++		+++
0520	++		+++
0521	+++		+++
0522	+++		+++
0523	+++		+++
0524	+		+++
0525	+++		+++
0526	+++		+++
0527	+++		++
0528	+++		+++
0529	+++		+++
0530	+++		+++
0531	+++		+++
0532	+++		+++
0533	+++		+++
0534	+++		+++
0535	+++		+++
0536	+++		+++
0537	+++		+++
0538	+++		+++
0539	+++		+++
0540	+++		++
0541	+++		++
0542	+++		+++
0543	+++		+++
0544	+++		+++
0545	+++		+++
0546	+++
0547	+++		+++
0548	+++		+++
0549	+++		+++
0550	+++		+++
0551	+++		+
0552	+++		+++
0553	+++		+++
0554	+++		+++
0555	+++		+++
0556	+++		+++
0557	+++		+++
0558	+++		+++
0559	+		+++
0560	+++		+++
0561	+++		+++
0562	+++		+++
0563	+++		+++
0564	+++		+++
0565	+++		+++
0566	+++		+++
0567	+++		+++
0568	+++		+++
0569	+++		+++
0570			+++
0571	+++		+++
0572	+++		+++
0573	+++		+++
0574	++		+++
0575	+++		+++
0576	+++		+++
0577	+++		+++
0578	+++		+++
0579	+++		+++
0580	+++		+++
0581	+++		+++
0582	+++		+++
0583	+++		+++
0584	+++		+++
0585	+++		+++
0586	+++		+++
0587	+++		+++
0588	++	+++	+++
0589	+++	+++	+++
0590	++		+++
0591	++		+++
0592	+++		+++
0593	++		+++
0594	+++		+++
0595	++		+++
0596	+++		+++
0597	++		+++
0598	++		+++
0599	++		+++
0600	++		+++

TABLE 1 — ERK2 enzyme

PI3Kα enzyme	inhibitory activity
Example No.	inhibitory activity	(1)	(2)
0601	++		+++
0602	+++		+++
0603	+++		+++
0604	+		+++
0605	+++		+++
0606	++		+++
0607	+++		+++
0608	+++		+++
0609	+++		+++
0610	+++		+++
0611	+++		+++
0612	+++		+++
0613	+++		+++
0614	+++		+++
0615	+++		+++
0616	+++		+++
0617	+++		+++
0618	+++		+++
0619	+++		+++
0620	+++		+++
0621	++		+++
0622	+++		+++
0623	++		++
0624	++		+++
0625	+++		++
0626	+++		+++
0627	++		+++
0628	+		+++
0629	+++		+++
0630	+++		+++
0631	+++		+++
0632	+++		++
0633	+++		+++
0634	+++		+++
0635	+++		+++
0636	+++		+++
0637	+++		+++
0638	++		+++
0639	++		+
0640	++		+++
0641	+++		+++
0642	++		+++
0643			+
0644	+++		+++
0645	+++		+++
0646	+++		+++
0647			++
0648	+++		+++
0649	+++		+++
0650	+++		+++
0651	+++		+++
0652	+++		+++
0653	+++		+++
0654	+++		++
0655	++		++
0656	+++		++
0657	+++		+++
0658	+++		+++
0659	+++		+++
0660	+++		+++
0661	+++		+++
0662	+++		++
0663	++		++
0664	++		++
0665	+++		+++
0666	+++		+++
0667	+++		+++
0668			++
0669	++		++
0670	+++		+++
0671	+++		+++
0672	+++		+++
0673	+++		+++
0674	+++		+++
0675	+
0676	+++		+++
0677	++
0678	+++		+++
0679	+++		+++
0680	+++		+++
0681	+++		+++
0682	+++		+++
0683	+++		+++
0684	+++		+++
0685	+++		+++
0686	+++		+++
0687	+++		+++
0688	+++		+++
0689	+++		+++
0690	+++		+++
0691	+++		+++
0692	+++		+++
0693	+++		+++
0694	+++		+++
0695	+++		+++
0696	+++		+++
0697	+++		+++
0698	++		+++
0699	+++		+++
0700	+++		+++

TABLE 1 — ERK2 enzyme

PI3Kα enzyme	inhibitory activity
Example No.	inhibitory activity	(1)	(2)
0701	+++		+++
0702	+++		+++
0703	+++		+++
0704	+++		+++
0705	+++		+++
0706	+++		+++
0707	+++		+++
0708	+++		+++
0709	+++		+++
0710	+++		+++
0711	+++		+++
0712	+++		+++
0713	+++		+++
0714	+++		+++
0715	+++		+++
0716	+++		+++
0717	+++		+++
0718	+++		+++
0719	+++		+++
0720	+++		+++
0721	+++		+++
0722	+++		+++
0723	+++		+++
0724	+++		+++
0725	+++		+++
0726	+++		+++
0727	+++		+++
0728	+++		+++
0729	+++		+++
0730	+++		+++
0731	+++		+++
0732	+++		+++
0733	+++		+++
0734	+++		+++
0735	+++		+++
0736	+++		++
0737	+++		+++
0738	+++		+++
0739	++		+++
0740	+++		+++
0741	+++		+++
0742	+++		+++
0743	+++		+++
0744	+++		+++
0745	+++		+++
0746	+++		+++
0747	+++		+++
0748	+++		+++
0749	+++		+++
0750	+++		+++
0751	+++		+++
0752	+++		+++
0753	+++
0754	+++		+++
0755	+++		+++
0756	+++		+++
0757	+++		+++
0758	++		+++
0759	+++		+++
0760	+++		+++
0761	+++		+++
0762	+++		+++
0763			+++
0764	+++		+++
0765	+++		+++
0766	+++		+++
0767	+++		+++
0768	+++		++
0769	+++		+++
0770	+++		+++
0771	+++		+++
0772	+++		+++
0773	+++		+++
0774	+++		+++
0775	+++
0776	+
0777	+++		+++
0778	+++		+++
0779	+++		+++
0780	+++		+++
0781	+++		+++
0782	+++		+++
0783	+++		+++
0784	+++		+++
0785	+++		+++
0786	+++		+++
0787	+++		+++
0788	+++		+++
0789	+++		+++
0790	+++		+++
0791	+++		+++
0792	+++		+++
0793	+++		++
0794	+++		+++
0795	+++		+++
0796	+++		+++
0797	+++		+++
0798	+++		+++
0799	+++		+++
0800	+++		+++

TABLE 1 — ERK2 enzyme

PI3Kα enzyme	inhibitory activity
Example No.	inhibitory activity	(1)	(2)
0801	++		+++
0802	+++		+++
0803	+++		+++
0804	+++		+++
0805	+++		+++
0806	+++		+++
0807	+++		+++
0808	++		+++
0809	+++		+++
0810	+++		+++
0811	+++		+++
0812	+++		+++
0813	+++		+++
0814	+++		+++
0815	+++		+++
0816	+++		+++
0817	+++		+++
0818	+++		+++
0819	+++		+++
0820	+++		+++
0821	+++		+++
0822	+++		+++
0823	+++		+++
0824	+++		+++
0825	+++		+++
0826	+++		+++
0827	+++		+++
0828	+++		+++
0829	+++		+++
0830	+++		+++
0831	+++		+++
0832	+++		+++
0833	+++		+++
0834	+++		+++
0835	+++		+++
0836	+++		++
0837	++		+++
0838	+++		+++
0839	+		++
0840	++		++
0841	++		++
0842	++		++
0843	+++		+++
0844	+++		+++
0845	++		+++
0846	++		+++
0847	++		+++
0848	++		++
0849	++		+++
0850	+++		+++
0851	++		+++
0852	+++		+++
0853	+++		+++
0854	+++		+++
0855	+++		+++
0856	++		+++
0857	++		+++
0858	++		+++
0859	++		+++
0860	++		++
0861	+++		+++
0862	+++		+++
0863	++		+++
0864	+++		+++
0865	++		++
0866	++
0867	+++		+++
0868	++		+++
0869	++		+++
0870	++		++
0871	++		++
0872	+++		+++
0873	+++		+++
0874	+++		+++
0875	++		+++
0876	++		++
0877	+++		++
0878	+++		++
0879	+++		+++
0880	+++		+++
0881	++		+++
0882	+++		+++
0883	+++		+++
0884	++		+++
0885	+++		+++
0886	+++		+++
0887	+++		++
0888	++		++
0889	+		+
0890	+++		++
0891	++		+++
0892	++		++
0893	+++		+++
0894	+++		++
0895	++		+++
0896	++		++
0897	+++		+++
0898	+++		++
0899	++		++
0900	+++		++

TABLE 1 — ERK2 enzyme

PI3Kα enzyme	inhibitory activity
Example No.	inhibitory activity	(1)	(2)
0901	++		+++
0902	+++		+++
0903	+++		+++
0904	+++		++
0905	++		++
0906	++		+++
0907	+++		+++
0908	+++		+++
0909	+++		+++
0910	+++		+++
0911	+++		+++
0912	+++		+++
0913	+++		+++
0914	+++		+++
0915			+
0916	+++		+++
0917	+++		+++
0918	+++		+++
0919	+++		+++
0920	+++		+++
0921	+++		+++
0922	++		+++
0923	+++		+++
0924	+++		+++
0925	+++		+++
0926	+++		+++
0927	+++		+++
0928	+++		+++
0929	++		+++
0930	+++		+++
0931	+++		+++
0932	+++		+++
0933	+++		+++
0934	+++		+++
0935	+++		++
0936	+++		+++
0937	+++		+++
0938	+++		+++
0939	+++		+++
0940	+++		+++
0941	+++		+++
0942	+++		+++
0943	+++		+++
0944	+++		+++
0945	+++		+++
0946	+++		+++
0947	++		++
0948	+++		+++
0949	++		++
0950	+++		++
0951	+++		+++
0952	+++		+++
0953	+++		+++
0954	+++		+++
0955	+++		+++

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IPC · International Patent Classification

Section C — Chemistry; metallurgy

C07D519/00
C07D471/04

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