Abstract:
The present invention relates to a compound represented by general formula [1] satisfying the following (I) or (II), or a pharmaceutical acceptable salt of the compound. 
     
       
                 
         
             
             
         
       
       
         (I) X is CH or N; R 1  is a halogen atom,; and R 2  is H, a halogen atom, CN, [2], [3], [8], [9], an —O-alkyl, an —O-(saturated ring), etc. 
         [2]: —C(R C )(R D )(R E ) (R C  to R E  each are H, an alkyl, etc.) 
         [3]: —N(R F )(R G ) (R F  and R G  each are H, OH, amino, a (hetero)aryl, etc.) 
         [8]: —C(═O)R L  (R L  is an alkyl, OH, an alkoxy, amino, etc.) 
         [9]: a (substituted)phenyl; 
         (II) X is &gt;C—C(—O)R 3  (R 3  is a (substituted)amino, an alkoxy, OH, etc.); 
         R 1  is a halogen atom; R 2  is H; R 3  is H or OH; and R 3  and R 4  each are H or an alkyl.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This patent application is a U.S. national stage application under 35 U.S.C. §371 of International Patent Application No. PCT/JP2010/051722 filed on Feb. 5, 2010, which claims the benefit of foreign priority to Japanese Patent Application No. JP 2009-026470 filed on Feb. 6, 2009, and Japanese Patent Application No. JP 2009-276133 filed on Dec. 4, 2009, the disclosures of all of which are hereby incorporated by reference in their entireties. The International Application was published in Japanese on Aug. 12, 2010, as international Publication No. WO 2010/090290 A1 under PCT Article 21 (2). 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to a new aminopyrazine derivative and a pharmaceutical composition containing the aminopyrazine derivative as an active ingredient. 
       BACKGROUND OF THE INVENTION 
       [0003]    Myeloidproliferative neoplasms (chronic myeloid proliferative diseases) are a class of diseases mainly involving abnormal growth of hemocytes, which is caused by aberrant hematopoietic stem cells. Specifically, diseases such as polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are known (see, for example, Van Etten, et al., 2004, Cancer Cell, 6, 547-552). At present, there is no available therapy for myeloidproliferative neoplasms (chronic myeloid proliferative diseases) and thus there is an earnest desire of therapeutic agent for these diseases. 
         [0004]    In 2005, an activated mutation of JAK2, a kind of JAK family tyrosine kinases (JAK2 V617F mutation), was reported in a patient suffering from myeloidproliferative neoplasm (chronic myeloid proliferative disease) (see, for example, Robert Kralovics, et al., 2005, New England journal of Medicine, 352, 1779-1790). In a subsequent study, the activated mutation was confirmed in about 95% of polycythemia vera patients, about 50% of essential thrombocythemia patients, and about 50% of idiopathic myelofibrosis patients (see, for example, Peter J. Campbell, et al., 2006, New England Journal of Medicine, 355, 2452-2466). Further, another activated mutation of JAK2 (JAK2 0620E mutation) was found in a few cases of polycythemia vera patients (see, for example, L. Richeldi, et al., 2006, Leukemia, 20, 2210-2211). Moreover, activated mutations of c-Mpl in a thrombopoietin receptor (MPL W515L mutation and MPL W515K mutation) were found in about 10% of idiopathic myelofibrosis patients in whom JAK2 V617F was negative. 
         [0005]    Since JAK2 is located downstream of the intracellular signal transduction pathway of c-Mpl, a compound having a JAK2 tyrosine kinase inhibitory activity is expected to be an active ingredient for therapeutics in treatment of diseases caused not only by JAK2-activated mutation but also by c-Mpl mutation, e.g., myeloidproliferative neoplasms (chronic myeloid proliferative diseases) (see, for example, Yana Pikman, et al., 2006, PLoS Medicine, 3, 1140-1151, and Animesh D, et al., 2006, Blood, 108, 3472-3476). 
         [0006]    JAK2-activated mutations have also been found in other than myeloidproliferative neoplasms (chronic myeloid proliferative diseases). For example, it has been reported that a JAK2 V617F mutation is found at a high rate in patients belonging to a class of myelodysplastic syndrome (RARS-T) (see, for example, M M Ceesay, et al., 2006, Leukemia, 20, 2060-2061). JAK2-activated mutation (JAK2 R683S/G mutation etc.) has also been found in 16 (about 9%) of 187 cases in infantile acute lymphocytic leukemia patients (see, for example, C. Mullighan, et al., 2009, Proceedings of the National Academy of Science U.S.A, 106, 9414-9418), and in about 20% of infantile acute lymphocytic leukemia patients with Down&#39;s syndrome (see, for example, A. Gaikwad, et al., 2008, British journal of Haematology, 144, 930-932). 
         [0007]    It has also been reported that the activation of JAK2 tyrosine kinase generated by JAK2 fusion gene is involved in pathological formation. For example, a TEL-JAK2 fusion protein was found in patients of myeloidproliferative neoplasms (acute myeloid proliferative diseases) and of acute myeloid leukemia, and a BCR-JAK2 fusion protein and a PCM1-JAK2 fusion protein were found in patients of chronic myeloid leukemia-like hematic cancer (see, for example, Lyne Valentino, et al., 2006, Biochemical Pharmacology, 71, 713-721 (“Valentino”)). JAK2 signal transduction pathway is involved in the growth of Bcr-Ab1-positive chronic myeloid leukemia cells, suggesting that a compound having a JAK2 tyrosine kinase inhibitory activity will be effective for imatinib-resistant chronic myeloid leukemia (see, for example, Ajoy K. Samanta, et al., 2006, Cancer Research, 66, 6468-6472). In general, the JAK2 signal transduction pathway is one of important pathways in the growth of hematic cancer cell, and thus, a compound having a JAK2 tyrosine kinase inhibitory activity is expected to have a therapeutic effect for a variety of hematic cancers (see, for example, Valentino). 
         [0008]    JAK2 tyrosine kinase is also involved in intracellular signal transduction of cytokine receptors or hormone receptors. Interleukin-6 (IL-6) is an inflammatory cytokine which plays an important role in inflammation, immunoresponse and onset of cancers (see, for example, h. Yu, et al., 2009, Nature Reviews Cancer, 9, 798-809, H. Ogura, et al., 2008, Immunity, 29, 628-636, and R. Catlett-Falcone, et al., 1999, Immunity, 10, 105-115), and the IL-6 signal is transduced through JAK2 tyrosine kinase (see, for example, M. Narazaki, et al., 1994, Proceedings of the National Academy of Science U.S.A, 91, 2285-2289). Diseases in which IL-6 is involved include inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis), hematic cancers (e.g., multiple myeloma), solid cancer (e.g., prostatic cancer), and angiopathy (e.g., pulmonary hypertension, arteriosclerosis, aneurysm, varicose vein) (see, for example, P. Heinrich, et al., 2003, Biochemical Journal, 374, 1-20, M. Steiner, et al., 2009, Circulation Research, 104, 236-244, and h. Alexander, et al., 2009, Biochemical Pharmacology, 78, 539-552). Further, it is known that JAK2 tyrosine kinase contributes to intracellular signal transduction of prolactin receptors, and the expressed amount of prolactin receptor increases in breast cancer, resulting in acceleration of the proliferation of cancer cells by prolactin (for example, L. Neilson, et al., 2007, Molecular Endocrinology, 21, 2218-2232). 
         [0009]    Thus, it is expected that a compound having a JAK2 tyrosine kinase inhibitory activity exhibits a therapeutic effect for a variety of diseases such as inflammatory diseases, hematic cancers, solid cancers, and angiopathy since JAK2 tyrosine kinase is involved in transduction of extracellular stimulation. 
         [0010]    JAK3 is a tyrosine kinase which plays an important role in signal transduction of cytokine, and has attracted considerable attention as a target molecule of immunosuppressants since 10 or more years ago. In fact, compounds having a JAK3 tyrosine kinase inhibitory activity have been subjected to clinical trial as therapeutics for organ transplantation and rheumatoid arthritis (see, for example, Paul S. Changelian, et al., 2003, Science, 302, 875-878). 
       BRIEF SUMMARY OF TEL INVENTION 
       [0011]    The main purpose of the present invention is to provide a new aminopyrazine derivative. Another purpose of the present invention is to provide a pharmaceutical composition which contains such an aminopyrazine derivative as an active ingredient. 
         [0012]    In the present invention, the compound represented by the following general formula [1] (hereinafter referred to as “the compound of the invention”) or a pharmaceutically acceptable salt thereof is exemplified, wherein the compound is defined by the following (I) or (II). 
         [0000]    
       
                 
         
             
             
         
       
     
       (I): 
       [0013]    X represents CH or N;
 
R 1  represents a halogen;
 
R 2  represents:
 
         [0014]    (1) H, 
         [0015]    (2) a halogen, 
         [0016]    (3) cyano, 
         [0017]    (4) a group represented by the following general formula [2]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * indicates the binding position; and R C , R D  and R E  are the same or different and each represents (a) H, or (b) alkyl optionally substituted by hydroxy or alkoxy, or alternatively two of R C , R D  and R E  are taken together with the adjacent C to represent a N-containing saturated heterocyclic group and the other one is H, the saturated heterocyclic group optionally substituted by alkylsulfonyl), 
         [0018]    (5) a group represented by the following general formula [3]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * has the same meaning as described above; and R F  and R G  are the same or different and each represents (a) H, (b) alkyl optionally substituted by one or two groups selected from the group consisting of hydroxy, amino, dialkylamino, a saturated cyclic amino group, alkylcarbonylamino, alkylsulfonylamino, aryl, heteroaryl optionally substituted by alkyl, tetrahydrofuranyl, and carbamoyl, (c) alkylcarbonyl, (d) alkylsulfonyl, (e) carbamoyl, or (f) heteroaryl optionally substituted by alkyl, or alternatively R F  and R G  are taken together with the adjacent N to represent a saturated cyclic amino group, which may optionally be substituted by one or two groups selected from the group consisting of (a) halogen, (b) cyano, (c) hydroxy, (d) alkyl optionally substituted by one or two groups selected from the group consisting of hydroxy, alkoxy, amino, alkoxycarbonylamino, alkylsulfonylamino, and alkylcarbonylamino, (e) cycloalkyl, (f) haloalkyl, (g) alkoxy, (h) oxo, (i) a group represented by the following general formula [4]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * has the same meaning as described above; and R H  represents alkyl or aryl), (j) a group represented by the following general formula [5]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * has the same meaning as described above; and R I  and R J  are the same or different and each represents H, alkyl, carbamoyl, alkylcarbonyl, or alkylsulfonyl), (k) a group represented by the following general formula [6]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * has the same meaning as described above; and R K  represents alkyl, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, (cycloalkyl)alkylamino, (hydroxyalkyl)amino, (alkoxyalkyl)amino, alkoxy, alkylsulfonylamino, or a saturated cyclic amino group), and (l) a saturated cyclic amino group optionally substituted by hydroxy; and the saturated cyclic amino group, which is formed by combining R F , R G  and the adjacent N, may form a spiro-linkage with a group represented by the following general formula [7A] or [7B]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein has the same meaning as described above)), 
         [0019]    (6) a group represented by the following general formula [8]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * has the same meaning as described above; and R L  represents (a) alkyl, (b) hydroxy, (c) alkoxy, (d) saturated cyclic amino group optionally substituted by alkyl or alkylsulfonyl, or (e) an amino optionally substituted by one or two groups selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl; haloalkyl, dialkylaminoalkyl, alkoxyalkyl, and hydroxyalkyl), 
         [0020]    (7) a group represented by the following general formula [9]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * has the same meaning as described above; and R M , R N  and R O  are the same or different and each represents H, halogen, cyano, alkoxy, carbamoyl, sulfamoyl, monoalkylaminosulfonyl, or alkylsulfonyl, or alternatively two of R M , R N  and R O  are taken together to represent methylenedioxy), 
         [0021]    (8) —OR P  (R P  represents an alkyl optionally substituted by a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl, or an optionally O-containing saturated cyclic group optionally substituted by hydroxy), or 
         [0022]    (9) a heteroaryl optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl; 
         [0000]    R 3  represents H or hydroxy;
 
R 2  represents H or alkyl; and
 
R 5  represents H or alkyl;
 
       (II): 
       [0023]    X represents —CR A ;
 
R A  represents a group represented by the following general formula [10]:
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * has the same meaning as described above; and R B  represents (a) amino optionally substituted by one or two groups selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, and alkoxyalkyl, (b) alkoxy, (c) hydroxy, or (d) a saturated cyclic amino group);
 
R 1  represents a halogen;
 
R 2  represents H;
 
R 3  represents E or hydroxy;
 
R 4  represents H or alkyl; and
 
R 5  represents H or alkyl.
 
         [0024]    Among the compounds of the invention, the compound represented by the general formula [1], particularly the compound as defined by the following [i] or [ii], or pharmaceutically acceptable salts thereof, are preferred. 
         [0000]    [i]: 
       X is CH or N; and 
     R 2  is: 
       [0025]    (1) a group represented by the following general formula [11]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * has the same meaning as described above; and R F1  and R G1  are the same or different and each represents (a) H, (b) alkyl optionally substituted by one or two groups selected from the group consisting of hydroxy, amino, dialkylamino, a saturated cyclic amino group, alkylcarbonylamino, alkylsulfonylamino, aryl, heteroaryl optionally substituted by alkyl, tetrahydrofuranyl, and carbamoyl, (c) alkylcarbonyl, (d) alkylsulfonyl, (e) carbamoyl, or (f) heteroaryl optionally substituted by alkyl, or alternatively, R F1  and R G1  are taken together with the adjacent N to represent a saturated cyclic amino group, which may optionally be substituted by one or two groups selected from the group consisting of (a) halogen, (b) cyano, (c) hydroxy, (d) alkyl optionally substituted by one or two groups selected from the group consisting of hydroxy, alkoxy, amino, alkoxycarbonylamino, alkylsulfonylamino and alkylcarbonylamino, (e) cycloalkyl, (f) haloalkyl, (g) alkoxy, (h) oxo, (i) a group represented by the following general formula [4]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * and R H  have the same meanings as described above), (j) a group represented by the following general formula [5]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein *, R I  and R J  have the same meanings as described above), (k) a group represented by the following general formula [6]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * and R K  have the same meanings as described above), and (l) a saturated cyclic amino group optionally substituted by hydroxyl; 
         [0026]    (2) a group represented by the following general formula [8]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * and R L  have the same meanings as described above), 
         [0027]    (3) a group represented by the following general formula [9]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein *, R M , R N  and R O  have the same meanings as described above), 
         [0028]    (4) —OR P1  (wherein R P1  represents an alkyl optionally substituted by a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl.), or 
         [0029]    (5) a heteroaryl optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl; 
         [0000]    [ii]: 
       X is —CR A ; 
       [0030]    R A  is a group represented by the following general formula [10]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * and R B  have the same meanings as described above); and 
       R 2  is H. 
       [0031]    Among the compounds of the invention, those in which: 
       X is CH; 
     R 2  is: 
       [0032]    (1) a group represented by the following general formula [11]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein *, R F1  and R G1  have the same meanings as described above), 
         [0033]    (2) a group represented by the following general formula [8]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * and R L  have the same meanings as described above), 
         [0034]    (3) a group represented by the following general formula [9]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein *, R M , R N  and R O  have the same meanings as described above), 
         [0035]    (4) —OR P1  (wherein R P1  has the same meaning as described above), or 
         [0036]    (5) a heteroaryl optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl; or pharmaceutically acceptable salts thereof are particularly preferred. 
         [0037]    Among the compounds of the invention, the following specific compounds or pharmaceutically acceptable salts thereof are preferred.
   (1)   (S)-4-(2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazin-2-one,   (2)   N—{(S)-1-[2-{[(S)-1-(4-fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyrimidin-4-yl]pyrrolidin-3-yl}acetamide,   (3)   (S)-6-(3,3-difluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (4)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -[pyrazin-2-yl)pyridine-2,6-diamine,   (5)   (S)—N 2′ -[1-(4-fluorophenyl)ethyl]-N 6′ -(pyrazin-2-yl)-3,4′-bipyridine-2′,6′-diamine,   (6)   (S)—N 2′ -[1-(4-fluorophenyl)ethyl]-6-methoxy-N 6′ -(pyrazin-2-yl)-3,4′-bipyridine-2′,6′-diamine,   (7)   (S)-2′-[1-(4-fluorophenyl)ethylamino]-6′-(pyrazin-2-ylamino)-3,4′-bipyridin-6-ol,   (8)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(oxazol-5-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (9)   (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl) pyrimidine-2,4-diamine,   (10)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[4-(methylsulfonyl)phenyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (11)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrazol-4-yl)pyrimidine-2,4-diamine,   (12)   (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yloxy}ethanol,   (13)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-3-yl)pyrimidine-2,4-diamine,   (14)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-2-yl)pyrimidine-2,4-diamine,   (15)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-4-yl)pyrimidine-2,4-diamine,   (16)   (S)-1-(2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-one,   (17)   (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazine-2,6-dione,   (18)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}tetrahydropyrimidin-2(1H)-one,   (19)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyrrolidin-1-yl)pyrimidine-2,4-diamine,   (20)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-morpholino-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (21)   (S)-1-(2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl)imidazolidin-2-one,   (22)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(oxazol-5-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (23)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(6-methoxypyridin-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (24)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrazol3-yl)pyrimidine-2,4-diamine,   (25)   (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyridin-2-ol,   (26)   (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyridin-2-ol,   (27)   N—((R)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3-yl)acetamide,   (28)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrazol-4-yl)pyridine-2,6-diamine,   (29)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrazol-3-yl)pyridine-2,6-diamine,   (30)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[3-(methylsulfonyl)phenyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (31)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[4-(methylsulfonyl)phenyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (32)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-isopropyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (33)   N—{(S)-1-[2-{[(S)-1-(4-fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyridin-4-yl]pyrrolidin-3-yl}acetamide,   (34)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-morpholino-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (35)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-thiomorpholinopyridine-2,6-diamine,   (36)   (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}propan-1-ol,   (37)   (S)—N-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-yl}azetidin-3-yl)acetamide,   (38)   (S)-6-(azetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (39)   (S)-6-(3-fluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)-ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (40)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-2-one,   (41)   (S)-4-(1-ethyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluoro-phenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (42)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (43)   (S)-4-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (44)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(thiazol-5-yl)pyrimidine-2,4-diamine,   (45)   1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3-ol,   (46)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(5-methylthiazol-2-yl)-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine,   (47)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4,5′-bipyrimidine-2,6-diamine,   (48)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(2-methoxythiazol-5-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (49)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(thiazol-2-yl)pyrimidine-2,4-diamine,   (50)   (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}picolinonitrile,   (51)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxamide,   (52)   (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}picolinamide,   (53)   4-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazine-2-carboxamide,   (54)   6-(3-aminopyrrolidin-1-yl)-N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (55)   N-(1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-yl}pyrrolidin-3-yl)methanesulfonamide,   (56)   (S)-2-({2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}(2-hydroxyethyl)amino)ethan-1-ol,   (57)   (S)—N 2 -[2-(dimethylamino)ethyl]-N 2 -[1-(4-fluorophenyl)ethyl]N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine,   (58)   1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-3-carboxamide,   (59)   (S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidine-2-carboxamide,   (60)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (61)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrrol-3-yl)pyrimidine-2,4-diamine,   (62)   (R)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-4-hydroxypyrrolidin-2-one,   (63)   N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -((tetrahydrofuran-2-yl)methyl]pyrimidine-2,4,6-triamine,   (64)   ((S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-yl)methanol,   (65)   ((R)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-yl)methanol,   (66)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-4-ol,   (67)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-ol,   (68)   1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-3-ol,   (69)   (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}nicotinonitrile,   (70)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(2H-tetrazol-5-yl)pyrimidine-2,4-diamine,   (71)   (S)—N 4 -(2-aminoethyl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine,   (72)   (S)—N-(2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-ylamino}ethyl)methanesulfonamide,   (73)   (S)—N-(2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-ylamino}ethyl)acetamide,   (74)   (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}acetamide,   (75)   (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzamide,   (76)   (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzonitrile,   (77)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(furan-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (78)   ethyl   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxylate,   (79)   (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}nicotinamide,   (80)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxylic acid,   (81)   (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino}pyrimidin-4-ylamino)-2-phenylethanol,   (82)   (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-phenylpropan-1-ol,   (83)   (R)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-4-methylpentan-1-ol,   (84)   (S)—6-[2-(dimethylamino)ethoxy]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (85)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1H-pyrazole-4-carboxylic acid,   (86)   (S)-3-(2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzamide,   (87)   (S)-6-(benzo[d]1,3-dioxol-5-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (88)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(2-fluoropyridin-4-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (89)   N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[(tetrahydrofuran-2-yl)methoxy]pyrimidine-2,4-diamine,   (90)   (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yloxy}ethanol,   (91)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -[2-(pyrrolidin-1-yl)ethyl]pyrimidine-2,4,6-triamine,   (92)   (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}isonicotinamide,   (93)   (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}isonicotinonitrile,   (94)   (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-methylbutan-1-ol,   (95)   (S)—N 2 -[1-(4-chlorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (96)   (1S,2S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yloxy}cyclohexanol,   (97)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -[(5-methylpyrazin-2-yl)methyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine,   (98)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(furan-2-yl-methyl)-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine,   (99)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -[1-(pyridin-3-yl)ethyl]pyrimidine-2,4,6-triamine,   (100)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-4-(hydroxymethyl)piperidin-4-ol,   (101)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-2-ylmethyl)pyrimidine-2,4,6-triamine,   (102)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-3-ylmethyl)pyrimidine-2,4,6-triamine,   (103)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-4-ylmethyl)pyrimidine-2,4,6-triamine,   (104)   (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-hydroxypropanamide,   (105)   (3S,4S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidine-3,4-diol,   (106)   N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyrimidine-2,4-diamine,   (107)   (S)-8-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1,3-dioxo-8-azaspiro[4.5]decan-2-one,   (108)   (S)-4-(1-benzyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluoro-phenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (109)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[4-(phenylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (110)   (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}benzamide,   (111)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrrol-3-yl)pyridine-2,6-diamine,   (112)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-pyridine-2,6-diamine,   (113)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(4-methyl-1H-imidazol-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (114)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(4-methoxyphenyl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (115)   (S)-4-(4-fluorophenyl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (116)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-methyl-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (117)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(methylsulfonyl)piperidine-4-carboxamide,   (118)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(furan-3-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (119)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[4-(methylsulfonyl)piperazin-1-yl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (120)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-4-(hydroxymethyl)piperidin-4-ol,   (121)   (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}benzenesulfonamide,   (122)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-methoxy-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (123)   4-{2-[(1S)-1-(4-fluorophenyl)ethylamino]-6(pyrazin-2-ylamino)pyridin-4-yl}-1λ 6 ,4-thiomorpholin-1,1-dione,   (124)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}piperidin-4-ol,   (125)   (S)-1-(4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyridin-4-yl}-1,4-diazepan-1-yl)ethanone,   (126)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-N 4 -(pyrimidin-2-yl)pyridine-2,4,6-triamine,   (127)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-N 4 -(pyridin-2-yl)pyridine-2,4,6-triamine,   (128)   N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridine-2,6-diamine,   (129)   methyl   (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) isonicotinate,   (130)   (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-methylbenzenesulfonamide,   (131)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(4-methyl-1H-imidazol-1-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (132)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 ,N 6 -di(pyrazin-2-yl)pyridine-2,4,6-triamine,   (133)   (S)-4-(cyclopropylmethoxy)-N 2 -[1-(4-fluorophenyl)-ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (134)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 2 -methyl-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (135)   (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanol,   (136)   (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinic acid,   (137)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(2-methoxyethoxy)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (138)   (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-carbonitrile,   (139)   (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinonitrile,   (140)   (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) isonicotinamide,   (141)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(1,2,4-oxadiazol-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (142)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1,2,4-oxadiazol-3-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (143)   methyl   (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) nicotinate,   (144)   (S)-2-[1-(4-fluorophenyl)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)isonicotinamide,   (145)   (S)—N-[2-(dimethylamino)ethyl]-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,   (146)   (S)—N-t-butyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,   (147)   (S)—N-ethyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,   (148)   (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}[4-(methanesulfonyl)piperazin-1-yl]methanone,   (149)   (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}(pyrrolidin-1-yl)methanone,   (150)   (S)-2-[1-(4-fluorophenyl)ethylamino]-N-isopropyl-6-(pyrazin-2-ylamino)isonicotinamide,   (151)   (S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-2-carboxamide,   (152)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(tetrahydro-2H-pyran-4-yloxy)pyridine-2,6-diamine,   (153)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide,   (154)   (S)-2-[1-(4-fluorophenyl)ethylamino]-N-(2-hydroxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide,   (155)   (S)-2-[1-(4-fluorophenyl)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)isonicotinamide,   (156)   (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}(morpholino)methanone,   (157)   (S)—N-benzyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,   (158)   (S)—N-cyclopropyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,   (159)   (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}(4-methylpiperazin-1-yl)methanone,   (160)   (S)-2-[1-(4-fluorophenyl)ethylamino]-N-(2-methoxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide,   (161)   (S)-2-[1-(4-fluorophenyl)ethylamino]-N-propyl-6-(pyrazin-2-ylamino)isonicotinamide,   (162)   (S)—N-cyclopropylmethyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,   (163)   (S)—N-cyclobutyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,   (164)   (S)—N-butyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,   (165)   (S)-2-[1-(4-fluorophenyl)ethylamino]-N-isobutyl-6-(pyrazin-2-ylamino)isonicotinamide,   (166)   (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)-N-(2,2,2,-trifluoroethyl)isonicotinamide,   (167)   (S)-2-[1-(4-fluorophenyl)ethylamino]-N-(3-hydroxypropyl)-6-(pyrazin-2-ylamino)isonicotinamide,   (168)   (S)—N-(2-ethoxyethyl)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,   (169)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-methylazetidine-3-carboxamide,   (170)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(methoxymethyl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (171)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N,N-dimethylazetidine-3-carboxamide,   (172)   (S)—N-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methanesulfonamide,   (173)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carbonitrile,   (174)   2-(4-fluorophenyl)-2-[4-(1-methyl-1H-pyrazol-4-yl)-6-(pyrazin-2-ylamino)pyridin-2-ylamino]ethanol,   (175)   (S)—N-ethyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide,   (176)   (S)—N,N-diethyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide,   (177)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}ethanone,   (178)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(3-methoxy-azetidin-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (179)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-methylazetidin-3-ol,   (180)   (S)-2-[1-(4-fluorophenyl)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)nicotinamide,   (181)   (S)-2-[1-(4-fluorophenyl)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)nicotinamide,   (182)   (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) nicotinamide,   (183)   (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-3-yl}(morpholino)methanone,   (184)   (S)—N-(cyclopropylmethyl)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)nicotinamide,   (185)   (S)—N-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-yl}azetidin-3-yl)ethanesulfonamide,   (186)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-isopropylazetidine-3-carboxamide,   (187)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-(trifluoromethyl)azetidin-3-ol,   (188)   (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)(pyrrolidin-1-yl)methanone,   (189)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(2-methoxyethyl)azetidine-3-carboxamide,   (190)   (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)(piperidin-1-yl)methanone,   (191)   (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)(morpholino)methanone,   (192)   (S)—N-(cyclopropyl)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide,   (193)   (S)—N-(cyclopropylmethyl)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide,   (194)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(2-hydroxyethyl)azetidine-3-carboxamide,   (195)   (S)-3-cyclopropyl-1-{2-[1-(4-fluorophenyl)ethyl-amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-ol,   (196)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-isopropylazetidin-3-ol,   (197)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-ol,   (198)   (S)-3-cyclopropyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-ol,   (199)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-isopropylazetidin-3-ol,   (200)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-methylazetidin-3-ol,   (201)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-(trifluoromethyl)azetidin-3-ol,   (202)   (S)-4-(3,3-difluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (203)   (S)—N-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}acetamide,   (204)   (S)—N-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanesulfonamide,   (205)   (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}urea,   (206)   (S)-4-(3-cyclopropyl-3-methoxyazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (207)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(3-isopropyl-3-methoxyazetidin-1-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (208)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(3-methoxy-3-methylazetidin-1-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (209)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(5-methylpyrazin-2-yl)pyridine-2,6-diamine,   (210)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[1-(methanesulfonyl)piperidin-4-yl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (211)   (S)—N-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}propionamide,   (212)   (S)—W-[1-(4-fluorophenyl)ethyl]-4-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (213)   (S)-4-(1-cyclopropyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (214)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[1-(methoxymethyl)-1H-pyrazol-4-yl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,   (215)   (S)-6-[3-(dimethylamino)azetidin-1-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (216)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[3-(methylamino)azetidin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (217)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[3-(pyrrolidin-1-yl)azetidin-1-yl]pyrimidine-2,4-diamine,   (218)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(3-morpholinoazetidin-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (219)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[3-(4-methylpiperazin-1-yl)azetidin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (220)   (S)-(1-{1-[2-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)piperidin-4-ol,   (221)   4-{2-[(1S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1λ 6 ,4-thiomorpholin-1,1-dione,   (222)   (S)-1-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-yl}azetidin-3-yl)urea,   (223)   (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methanol,   (224)   t-butyl   (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methylcarbamate,   (225)   (S)-6-[3-(aminomethyl)azetidin-1-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,   (226).   (S)—N-[(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methyl]ethanesulfonamide,   (227)   (S)—N-[(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methyl]acetamide,   (228)   (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[3-morpholinoazetidin-1-yl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine, and   (229)   (S)-1-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyridin-4-yl}azetidin-3-yl)piperidin-4-ol.   
 
         [0500]    The compounds of the invention or their pharmaceutically acceptable salts are useful as medicaments. 
         [0501]    The following will describe in detail each term concerned in the invention. 
         [0502]    “Halogen” includes, for example, fluorine, chlorine, bromine and iodine. 
         [0503]    “Alkyl” means, for example, a straight or branched chain alkyl having 1 to 8 carbons, specifically including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl. In particular, those of 1 to 6 carbons are preferred, and those of 1 to 3 carbons more preferred. 
         [0504]    The alkyl moiety of “alkylsulfonyl”, “alkylcarbonylamino”, “hydroxyalkyl”, “(cycloalkyl)alkyl”, “alkoxyalkyl”, “alkylamino”, “(hydroxyalkyl)amino”, “(alkoxyalkyl)amino”, “dialkylamino”, dialkylaminoalkyl”, “(cycloalkyl)alkylamino”, “alkylcarbonyl”, “alkylcarbonylamino”, “alkylsulfonyl”, “alkylsulfonylamino”, and “monoalkylaminosulfonyl” can be exemplified by the same ones as the above-described “alkyl”. 
         [0505]    “Haloalkyl” means, for example, a straight or branched chain alkyl of 1 to 8 carbons on which one or more of halogen atoms are substituted at any replaceable optional position (s). The alkyl and halogen moieties of “haloalkyl” can be exemplified by the same ones as the above “alkyl” and “halogen”, respectively. 
         [0506]    “Cycloalkyl” means, for example, those having 3 to 8 carbons, specifically including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. 
         [0507]    The cycloalkyl moiety of “(cycloalkyl)alkyl”, “cycloalkylamino” and “(cycloalkyl)alkylamino” can be exemplified by the same ones as the above “cycloalkyl”. 
         [0508]    “Alkoxy” means, for example, a straight or branched chain alkoxy having 1 to 8 carbons, specifically including methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-Pentyloxy, n-hexyloxy, n-heptyloxy, and n-octyloxy. 
         [0509]    The alkoxy moiety of “alkoxyalkyl” and “(alkoxyalkyl)amino” is exemplified by the same ones as the above “alkoxy”. 
         [0510]    “Aryl” means those having 6 to 10 carbons, including for example phenyl, 1-naphthyl, and 2-naphthyl. In particular, phenyl is preferred. 
         [0511]    “Aralkyl” means, for example, a straight or branched chain alkyl of 1 to 8 carbons on which an aryl of 6 to 10 carbons is substituted at any replaceable optional position, including for example benzyl, phenylethyl (e.g. 1-phenylethyl, 2-phenylethyl), phenylpropyl (1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, etc.), and naphthylmethyl (e.g. 1-naphthylmethyl, 2-naphthylmethyl, etc.). 
         [0512]    “Saturated cyclic amino group” means, for example, a 4- to 7-membered saturated cyclic amino group which may contain one of O or S with one or two of N as ring-constituting atoms, specifically including 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, piperidino, 1-piperazinyl, 1-tetrahydropyrimidinyl, morpholino, thiomorpholino, and 1-homopiperazinyl. 
         [0513]    “N-containing saturated heterocyclic group” means, for example, a 5- or 6-membered saturated heterocyclic group containing one of N as a ring-constituting atom, specifically including for example 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl. 
         [0514]    “Optionally O-containing saturated cyclic group” means, for example, a 5- or 6-membered saturated cyclic group which may contain one of O as a ring-constituting atom, specifically including for example cyclopentyl, cyclohexyl, tetrahydrofuranyl, and tetrahydropyranyl. 
         [0515]    “Heteroaryl” means, for example, 5- or 6-membered heteroaryl containing 1 to 4 of N, O and S as (a) ring-constituting atom (s), specifically including for example furyl (e.g. 2-furyl, 3-furyl), thienyl (e.g. 2-thienyl, 3-thienyl), pyrrolyl (e.g. 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g. 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g. 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazolyl-4-yl), tetrazolyl (e.g. 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g. 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g. 1,3,4-oxadiazol-2-yl), triazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (e.g. 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (e.g. 2-pyridiyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), and pyrazinyl (e.g. 2-pyrazinyl). 
         [0516]    “Tetrahydrofuranyl” includes, for example, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl. 
         [0517]    “Tetrahydropyranyl” includes, for example, 2-tetrahydropyranyl, 3-tetrahydropyranyl, and 4-tetrahydropyranyl. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0518]    The compounds of the invention can be produced from known compounds or from readily synthesizable intermediates, for example, according to the following processes. In producing the compounds of the invention, when the starting material has a substituent influencing the reaction, the reaction is usually carried out after preliminary protection of the starting material with a suitable protecting group according to a known method. The protecting group may be removed after the reaction completion according to a known method. 
       Process 1: In the Case of R 2  Being Halogen 
       [0519]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein R 1  and R 5  have the same meanings as described above; X 1  represents CH or N; and Hal 1  and Hal 2  are the same or different, and each represents halogen.) 
         [0520]    The reaction is a condensation reaction of Compound [12] with Compound [13] using a palladium catalyst and thus may be carried out per se according to a known method. The usable solvent includes, for example, hydrocarbons such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The reaction is carried out at a temperature of 20° C. to 200° C. in the presence of a base. The usable palladium catalyst includes, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II)acetate. The amount of the palladium catalyst to be used is preferably within the range of 0.001-0.1 mole for 1 mole of the aryl halide. The usable ligand for the palladium catalyst includes, for example, 1,1′-bis-(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenylphosphino)phenyl]ether, and tri-t-butylphosphine. The usable base includes, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time depends on the kind of the starting material used and the reaction temperature, and is usually in the range of 10 minutes to 24 hours. 
         [0521]    Compound [12] as a starting material may be produced according to a known method (Bioorg. Med. Chem. Lett., 14, 2004, 4249-4252; Org. Lett., 6, 2004, 3671-3674). 
       Process 2: In the Case of R 2  being —OR P  (Wherein R P  has the Same Meaning as Described Above.) 
     Process 2-1 
       [0522]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 5 , and Hal 2  have the same meanings as described above; and R 6  represents an alkyl optionally substituted by a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl and cycloalkyl, or an optionally O-containing saturated cyclic group.) 
         [0523]    The reaction is carried out by condensing Compound [1a] with an alcohol compound [14] using a palladium catalyst. The usable solvent includes, for example, hydrocarbons such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The reaction is carried out at a temperature of 20° C. to 200° C. in the presence of a base. The usable palladium catalyst includes, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II)acetate. The amount of the palladium catalyst to be used is preferably within the range of 0.001-0.1 mole for 1 mole of the aryl halide. The usable ligand for the palladium catalyst includes, for example, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-(di-t-butylphosphino)biphenyl, and bis[2-(diphenylphosphino)phenyl]ether. The usable base includes, for example, sodium t-butoxide and tripotassium phosphate. The reaction time depends on the kind of the starting material used and the reaction temperature, and is usually in the range of 10 minutes to 24 hours. 
       Process 2-2 
       [0524]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 5 , R 6  and Hal 1  have the same meanings as described above.) 
         [0525]    The reaction is a condensation reaction of Compound [15] with Compound [13] using a palladium catalyst and thus may be carried out in the same manner as in Process 1 as mentioned above. 
         [0526]    Compound [15] as a starting compound may be produced, for example, according to the following method. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 6 , Hal 1  and Hal 2  have the same meanings as described above.) 
       Step 1 
       [0527]    Compound [18] may be produced by reacting Compound [16] with an alcohol compound [17] in a suitable solvent in the presence of a base at a temperature of −20° C. to 100° C. The usable base includes, for example, sodium hydride, sodium hydroxide, and the like. The usable solvent includes, for example, hydrocarbons such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; water; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The reaction time depends on the kind of the starting material used and the reaction temperature, and is usually in the range of 30 minutes to 24 hours. 
       Step 2 
       [0528]    The reaction is a condensation reaction of Compound [18] with Compound [19] using a palladium catalyst and thus may be carried out per se according to a known method. The usable solvent includes, for example, hydrocarbons such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The reaction is carried out at a temperature of 20° C. to 200° C. in the presence of a base. The usable palladium catalyst includes, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II)acetate. The amount of the palladium catalyst to be used is preferably within the range of 0.001-0.1 mole for 1 mole of the aryl halide. The usable ligand for the palladium catalyst includes, for example, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenylphosphino)phenyl]ether, and tri-t-butylphosphine. The usable base includes, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time depends on the kind of the starting material used and the reaction temperature, and is usually in the range of 10 minutes to 24 hours. 
       Process 3: In the Case of R 2  being Represented by the Following General Formula [9] 
       [0529]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein R M , R N , R O  and * have the same meanings as described above), or in the case of R 2  being a heteroaryl optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl (but the bonding site is limited to C.) 
       Process 3-1 
       [0530]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 5  and Hal 2  have the same meanings as described above; and R 7  and R 8  each represent hydroxy, or R 7  and R 8  are taken together to represent —O—C(CH 3 ) 2 —C(CH 3 ) 2 —O—, —O—(CH 2 ) 3 —O—, or —O—CH 2 —C(CH 3 ) 2 —CH 2 —O—; and
 
R 9  represents a group represented by the following general formula [9]:
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein R M , R N , R O  and * have the same meanings as described above),
 
or a heteroaryl optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl (but the bonding site is limited to C).)
 
         [0531]    The reaction is a cross-coupling reaction using Compound [1a] and an organoborane compound [20], and thus may be carried out per se according to a known method. The reaction may be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at 20-200° C. The usable palladium catalyst includes, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex. The amount of the palladium catalyst to be used is preferably within the range of 0.001-0.1 mole for 1 mole of the aryl halide. The usable solvent includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; alcohols such as methanol, ethanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; hydrocarbons such as benzene, toluene; water; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The usable base includes, for example, sodium hydroxide, potassium carbonate, and sodium carbonate. The reaction time depends on the kind of the starting material used and the reaction temperature, and is usually in the range of 30 minutes to 24 hours. 
       Process 3-2 
       [0532]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 5 , R 9  and Hal 1  have the same meanings as described above.) 
         [0533]    The reaction is a condensation reaction of Compound [21] with Compound [13] using a palladium catalyst and thus may be carried out per se according to a known method. The usable solvent includes, for example, hydrocarbons such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The reaction is carried out at a temperature of 20° C. to 200° C. in the presence of a base. The usable palladium catalyst includes, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II)acetate. The amount of the palladium catalyst to be used is preferably within the range of 0.001-0.1 mole for 1 mole of the aryl halide. The usable ligand for the palladium catalyst includes, for example, 1,1′-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis(2-(diphenylphosphino)phenyl)ether, and tri-t-butylphosphine. The usable base includes, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time depends on the kind of the starting material used and the reaction temperature, and is usually in the range of 10 minutes to 24 hours. 
         [0534]    Compound [21] as a starting compound may be produced, for example, according to the following 3 processes. 
       Process A 
       [0535]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 7 , R 8 , R 9 , Hal 1  and Hal 2  have the same meanings as described above; and Hal 3  represents a halogen.) 
       Step 1 
       [0536]    The reaction is a cross-coupling reaction using Compound [22] and an organoborane compound [20], and thus may be carried out per se according to a known method. The reaction may be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at a temperature of 20-200° C. The usable palladium catalyst includes, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex. The amount of the palladium catalyst to be used is preferably within the range of 0.001-0.1 mole for 1 mole of the aryl halide. The usable solvent includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; alcohols such as methanol, ethanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; hydrocarbons such as benzene, toluene; water; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The usable base includes, for example, sodium hydroxide, potassium carbonate, and sodium carbonate. The reaction time depends on the kind of the starting material used and the reaction temperature, and is usually in the range of 30 minutes to 24 hours. 
       Step 2 
       [0537]    The reaction is a condensation reaction of Compound [23] with Compound [19] using a palladium catalyst and thus may be carried out per se according to a known method. The usable solvent includes, for example, hydrocarbons such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The reaction is carried out at a temperature of 20° C. to 200° C. in the presence of a base. The usable palladium catalyst includes, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II)acetate. The amount of the palladium catalyst to be used is preferably within the range of 0.001-0.1 mole for 1 mole of the aryl halide. The usable ligand for the palladium catalyst includes, for example, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenylphosphino)phenyl]ether, and tri-t-butylphosphine. The usable base includes, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time depends on the kind of the starting material used and the reaction temperature, and is usually in the range of 10 minutes to 24 hours. 
       Process B 
       [0538]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 9 , Hal 1  and Hal 2  have the same meanings as described above; and R 10 , R 11  and R 12  are the same or different and each represents alkyl.) 
         [0539]    The reaction is a cross-coupling reaction using Compound [12] and an organotin compound [24], and thus may be carried out per se according to a known method. The reaction may be carried out, for example, in the presence of a palladium catalyst in a suitable solvent at 20-200° C. The usable palladium catalyst includes, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex, and palladium acetate. The amount of the palladium catalyst to be used is preferably within the range of 0.001-0.1 mole for 1 mole of the aryl halide. The usable solvent includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; hydrocarbons such as benzene, toluene; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. It is also possible to add an additive such as copper oxide or silver oxide. The reaction time depends on the kind of the starting material used and the reaction temperature, and is usually in the range of 1 to 24 hours. 
       Process C 
       [0540]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 7 , R 8 , R 9 , Hal 1  and Hal 2  have the same meanings as described above.) 
         [0541]    The reaction is a cross-coupling reaction using Compound [12] and an organoborane compound [20], and thus may be carried out per se according to a known method. The reaction may be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at a temperature of 20-200° C. The usable palladium catalyst includes, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex. The amount of the palladium catalyst to be used is preferably within the range of 0.001-0.1 mole for 1 mole of the aryl halide. The usable reaction solvent includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; alcohols such as methanol, ethanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; hydrocarbons such as benzene, toluene; water; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The usable base includes, for example, sodium hydroxide, potassium carbonate, and sodium carbonate. The reaction time depends on the kind of the starting material used and the reaction temperature, and is usually in the range of 30 minutes to 24 hours. 
       Process 4: In the Case of R 2  being Represented by the Following General Formula [3] 
       [0542]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein R F  and R G  each have the same meanings as described above.) 
       Process 4-1 
       [0543]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 5  and Hal 2  each have the same meanings as described above; and R 13  is a group represented by the following general formula [3]: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein R F  and R G  each have the same meanings as described above).) 
         [0544]    The reaction is a cross-coupling reaction using Compound [1a] and Compound [25], and thus may be carried out per se according to a known method. The usable solvent includes, for example, hydrocarbons such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The reaction may be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at a temperature of 20-200° C. The usable palladium catalyst includes, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II)acetate. The amount of the palladium catalyst to be used is preferably within the range of 0.001-0.1 mole for 1 mole of the aryl halide. The usable ligand for the palladium catalyst includes, for example, 1,1′-bis-(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenylphosphino)phenyl]ether, and tri-t-butylphosphine. The usable base includes, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time depends on the kind of the starting material used and the reaction temperature, and is usually in the range of 30 minutes to 24 hours. 
       Process 4-2 
       [0545]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 5 , R 13  and Hal 1  each have the same meanings as described above.) 
         [0546]    The reaction is a condensation reaction of Compound [26] with Compound [13] using a palladium catalyst and thus may be carried out per se according to a known method. The usable solvent includes, for example, hydrocarbons such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The reaction is carried out at a temperature of 20° C. to 200° C. in the presence of a base. The usable palladium catalyst includes, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II)acetate. The amount of the palladium catalyst to be used is preferably within the range of 0.001-0.1 mole for 1 mole of the aryl halide. The usable ligand for the palladium catalyst includes, for example, 1,1′-bis-(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis(2-(diphenylphosphino)phenyl)ether, and tri-t-butylphosphine. The usable base includes, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time depends on the kind of the starting material used and the reaction temperature, and is usually in the range of 10 minutes to 24 hours. 
         [0547]    Compound [26] as a starting compound may be produced, for example, according to the following 2 processes. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 13 , Hal 1  and Hal 2  each have the same meanings as described above.) 
       Process a 
       [0548]    Compound [26] may be produced by reacting Compound [12] with Compound [25] in a suitable solvent in the presence of a base at a temperature of 20° C. to 200° C. The usable base includes, for example, pyridine, triethylamine, N,N-diisopropylethylamine, potassium carbonate, and sodium bicarbonate. The usable solvent includes alcohols such as 1-butanol, 2-methoxyethanol; ethers such as tetrahydrofuran, 1,4-dioxane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; hydrocarbons such as benzene, toluene; acetonitrile; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The reaction time depends on the kind of the starting material used and the reaction temperature, and in general it is preferably in the range of 1 to 24 hours. 
       Process b 
       [0549]    Compound [26] can be produced by condensation reaction of Compound [12] with Compound [25] using a palladium catalyst per se according to a known method. The usable solvent includes, for example, hydrocarbons such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The reaction may be carried out in the presence of a base at a temperature of 20° C. to 200° C. The usable palladium catalyst includes, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II)acetate. The amount of the palladium catalyst to be used is preferably within the range of 0.001-0.1 mole for 1 mole of the aryl halide. The usable ligand for the palladium catalyst includes, for example, 1,1′-bis-(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenylphosphino)phenyl]ether, and tri-t-butylphosphine. The usable base includes, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time depends on the kind of the starting material used and the reaction temperature, and is usually in the range of 10 minutes to 24 hours. 
       Process 5: In the case of R 2  being a heteroaryl optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl (but the bonding site is limited to N.) 
       [0550]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 5  and Hal 1  each have the same meanings as described above; and R 14  is a heteroaryl optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl (but the bonding site is limited to N).) 
         [0551]    The reaction is a condensation reaction of Compound [27] with Compound [13] using a palladium catalyst, and may be carried out in the same manner as in Process 4-2 as mentioned above. 
         [0552]    Compound [27] as a starting compound may be produced according to the following method. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 14 , Hal 1  and Hal 2  each have the same meanings as described above.) 
         [0553]    The reaction is a cross-coupling reaction using Compound [12] and Compound [28], and may be carried out per se according to a known method. The reaction may be carried out, for example, in the presence or absence of a copper catalyst in a proper solvent at a temperature of 20 to 200° C. The usable copper catalyst includes, for example, copper iodide and copper acetate. The amount of the copper catalyst to be used is preferably in the range of 0.01 to 0.2 mole for 1 mole of the aryl halide. The ligand for copper such as trans-N,N′-dimethylcyclohexane-1,2-diamine, trans-1,2-cyclohexanediamine, 1,10-phenanthroline, etc. may be used. The usable reaction solvent includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; alcohols such as methanol, ethanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; hydrocarbons such as benzene, toluene; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The usable base includes, for example, tripotassium phosphate, potassium carbonate, sodium carbonate, and cesium carbonate. The reaction time depends on the kind of the starting material used and the reaction temperature, and in general it is preferably in the range of 30 minutes to 24 hours. 
       Process 6: In the Case of R 2  being Alkoxycarbonyl 
       [0554]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 5  and Hal 1  each have the same meanings as described above; and R 15  represents an alkyl.) 
         [0555]    The reaction is a condensation reaction of Compound [29] with Compound [13] using a palladium catalyst, and may be carried out in the same manner as in Process 4-2 as mentioned above. 
         [0556]    Compound [29] as a starting compound may be produced according to the following method. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 15 , Hal 1  and Hal 3  each have the same meanings as described above.) 
         [0557]    The reaction is a condensation reaction of Compound [30] with Compound [19] using a palladium catalyst, and may be carried out in the same manner as in Step 2 in the process for producing Compound [15] as a starting compound as mentioned above. 
       Process 7: In the Case of R 2  being Hydroxycarbonyl 
       [0558]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 5  and R 15  each have the same meanings as described above.) 
         [0559]    The reaction is a hydrolysis reaction of Compound [1f] and may be carried out per se according to a known method. In general, the reaction can be carried out by hydrolyzing Compound [1f] in the presence of an acid or base to yield Compound [1g]. The acid used in the reaction includes, for example, inorganic acids such as hydrochloric acid and sulfuric acid; the base includes, for example, inorganic bases such as sodium hydroxide and potassium hydroxide. The solvent usable in the reaction includes, for example, alcohols such as methanol, ethanol; ethers such as tetrahydrofuran, 1,4-dioxane; water; or a mixture of them. The reaction is conducted at a temperature of 0° C. to 100° C., usually for a period of 30 minutes to 24 hours. 
       Process 8: In the case of R 2  being (a) a saturated cyclic amino group optionally substituted by alkyl or alkylsulfonyl; or (b) an aminocarbonyl optionally substituted by one or two groups selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, alkoxyalkyl, and hydroxyalkyl 
       [0560]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1  and R 5  each have the same meanings as described above; R 16  and R 17  are the same or different and each represents H, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, alkoxyalkyl, or hydroxyalkyl, or they are taken together with the adjacent N to represent a saturated cyclic amino group; said saturated cyclic amino group may optionally be substituted by alkyl or alkylsulfonyl.) 
         [0561]    The reaction is a condensation reaction of Compound [1g] with Compound [31], and can be carried out per se according to a known method. Compound [1h] can be synthesized by reacting Compound [1g] as a carboxylic acid or a reactive derivative thereof with Compound [31]. The reactive derivative of Compound [1g] includes those conventionally used in the amide condensation reaction, for example, acid halides (e.g. acid chloride, acid bromide), mixed acid anhydrides, imidazolides, active amide, and the like. In case of using Compound [1g], the reaction is carried out in the presence or absence of a base using a condensing agent at a temperature of −20 to 100° C. The condensing agent usable in the reaction includes, for example, 1,1′-oxalyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophospate, and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate. The base usable in the reaction includes organic base, for example, triethylamine, N,N-diisopropylethylamine, N,N-dimethylanline, pyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene. The usable solvent includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; nitriles such as acetonitrile, propionitrile; hydrocarbons such as benzene, toluene; halogenated hydrocarbons such as chloroform, methylene chloride; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. If required, an additive may be used. The usable additive includes, for example, 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole. The reaction time depends on the kind of the starting material used and the reaction temperature, and in general it is preferably in the range of 10 minutes to 24 hours. The amount of Compound [31] and the condensing agent is preferably, for example, in the range of 1 equimolar to 3 equimolar amount for 1 mole of Compound [1g]. 
       Process 9: In the case of R 2  being H, alkylcarboyl, an N-containing saturated heterocyclic group optionally substituted by alkylsulfonyl or an alkyl optionally substituted by hydroxy or alkoxy 
       [0562]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 5  and Hal 1  each have the same meanings as described above; and R 18  represents H or alkyl optionally substituted by alkoxy.) 
         [0563]    The reaction is a condensation reaction of Compound [32] with Compound [13] using a palladium catalyst, and can be carried out in the same manner as in Process 1 as mentioned above. 
       Process 10: In the case of R 2  being cyano 
       [0564]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 5  and Hal 2  each have the same meanings as described above.) 
         [0565]    The reaction is a cyanation reaction of Compound [1a], and can be carried out per se according to a known method. The reaction may be carried out using a cyano compound, for example, in the presence or absence of a palladium catalyst at a temperature of 20 to 200° C., if required under microwave. The usable palladium catalyst includes, for example, tetrakis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex, and tris(dibenzylideneacetone)dipalladium(0). The amount of the palladium catalyst to be used is preferably within the range of 0.001-0.1 mole for 1 mole of the aryl halide. If required, a palladium ligand such as 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, and the like may be used. The usable cyano compound includes copper (I) cyanide, zinc(II) cyanide, potassium cyanide, and sodium cyanide. The usable solvent includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane; alcohols such as methanol, ethanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; hydrocarbons such as benzene, toluene; dimethylsulfoxide; water; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The reaction time depends on the kind of the starting material used and the reaction temperature, and in general it is preferably in the range of 30 minutes to 24 hours. 
       Process 11: In the case of X being —CR A , and R A  being alkoxycarbonyl 
       [0566]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein R 1 , R 5  and Hal 1  each have the same meanings as described above; and R 19  represents an alkyl.) 
         [0567]    The reaction is a condensation reaction of Compound [33] with Compound [13] using a palladium catalyst, and can be carried out in the same manner as in Process 4-2 as mentioned above. 
         [0568]    Compound [33] as a starting compound may be produced according to the following method. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein R 1 , R 19 , Hal 1  and Hal 3  each have the same meanings as described above.) 
         [0569]    The reaction is a condensation reaction of Compound [34] with Compound [19] using a palladium catalyst, and can be carried out in the same manner as in Step 2 of Process A, Process 3-2 as mentioned above. 
       Process 12: In the case of X being —CR A , and R A  being hydroxycarbonyl 
       [0570]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein R 1 , R 5  and R 19  each have the same meanings as described above.) 
         [0571]    The reaction is a hydrolytic reaction of Compound [1k] and can be carried out in the same manner as in Process 7 as mentioned above. 
       Process 13: In the case of X being —CR A ; and R A  being a group as represented by the general formula [35] 
       [0572]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein * has the same meaning as described above; R 20  and R 21  are the same or different, and each represents H, alkyl, cycloalkyl, (cycloalkyl)alkyl, or alkoxyalkyl, or they are taken together with the adjacent N to represent a saturated cyclic amino group.) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein R 1 , R 5 , R 20  and R 21  each have the same meanings as described above.) 
         [0573]    The reaction is a condensation reaction of Compound [1j] with Compound [36], and can be carried out in the same manner as in Process 8 as mentioned above. 
       Process 14: In the case of R 4  being alkyl 
       [0574]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X, R 1 , R 2 , R 3 , R 5  and Hal 1  each have the same meanings as described above; and R 22  represents an alkyl.) 
         [0575]    The reaction is a condensation reaction of Compound [37] with Compound [13] using a palladium catalyst, and can be carried out in the same manner as in Process 4-2 as mentioned above. 
         [0576]    Compound [37] as a starting compound may be produced according to the following method. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X, R 1 , R 2 , R 22  and Hal 1  each have the same meanings as described above; and Hal 4  represents a halogen.) 
         [0577]    In this step, Compound [38] is allowed to react with Compound [39] in a suitable solvent in the presence of a base at 20° C. to 200° C., if required under a microwave. The usable base includes, for example, sodium hydride, lithium diisopropylamide, and n-butyllithium. The usable solvent includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; hydrocarbons such as benzene, toluene; acetonitrile; or a mixture of them, but there is no particular limitation as long as they have no influence on the reaction. The reaction time depends on the kind of the starting material used and the reaction temperature, and in general it is preferably in the range of 10 minutes to 24 hours. 
       Process 15: In the case of R 3  being hydroxy 
       [0578]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 1 , R 2 , R 5  and Hal 1  each have the same meanings as described above.) 
         [0579]    The reaction is a condensation reaction of Compound [40] with Compound [13] using a palladium catalyst, and can be carried out in the same manner as in Process 1 as mentioned above. As for the base usable in this reaction, sodium t-butoxide is appropriate. 
         [0580]    Compound [40] as a starting compound may be produced according to the following method. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (wherein X 1 , R 2 , Hal 1  and Hal 3  each have the same meanings as described above.) 
       Step 1 
       [0581]    Compound [42] can be produced according to a known method (J. Org. Chem., 65, 2000, 9059-9068). 
       Step 2 
       [0582]    In this step, Compound [42] is subjected to the condensation reaction with Compound [43] using a palladium catalyst, and the reaction can be carried out in the same manner as in Process 1 as mentioned above. 
         [0583]    Though the compounds of the invention can be utilized as such as medicaments, they may also be used in a form of pharmaceutically acceptable salts according to a known method. Such salts include those with mineral acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or with organic acids, e.g. acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, etc. 
         [0584]    For example, the hydrochlorides of the compounds of the invention can be produced by dissolving the compounds of the invention in a solution of hydrogen chloride in an alcohol or ethyl acetate or diethyl ether. 
         [0585]    Since some of the compounds of the invention have an asymmetric carbon, all of the optical isomers and their mixtures are encompassed in the invention. The optical isomers can be obtained by optical resolution of the racemates prepared as mentioned above with an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) utilizing their basicity according to a known method, or alternatively the optical isomers may be obtained from optically active starting compounds prepared in advance. Otherwise, they may be produced by optical resolution with a chiral column or by asymmetric synthesis. 
         [0586]    When the compounds of the invention exist in a form of geometrical isomers or tautomers, not only one of the isomers but also their mixtures are encompassed in the invention. 
         [0587]    The compounds of the invention or pharmaceutically acceptable salts thereof are useful as medicaments. The pharmaceutical compositions containing the compounds of the invention or pharmaceutically acceptable salts thereof as active ingredients can be used as preventives or therapeutics for cancers (e.g. hematic cancers (e.g. polycythemia vera, essential thrombocythemia, myeloidproliferative neoplasms such as idiopathic myelofibrosis (chronic myeloid proliferative diseases), osteomyelodysplasia syndrome, acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma), solid cancers (e.g. prostatic cancer, breast cancer)), inflammatory diseases (e.g. rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis), and angiopathy (e.g., pulmonary hypertension, arteriosclerosis, aneurysm, varicose vein). 
         [0588]    When the compounds of the invention or pharmaceutically acceptable salts thereof are administered as medicaments, they may be administered as such or as a pharmaceutical compositions containing, for example, 0.001% to 99.5%, preferably 0.1% to 90% of the active ingredient in (a) pharmaceutically acceptable nontoxic and inactive carrier(s) to mammals including humans. 
         [0589]    As for the carrier, one or more members of solid, semi-solid, or liquid excipients, fillers, and other auxiliaries for pharmaceutical formulation may be used. The pharmaceutical compositions of the invention may desirably be administered in a unit dosage form. The pharmaceutical composition may be administered through tissue, orally, intravenously, locally (percutaneously, eye drops, etc.) or rectally. The composition may naturally be administered in a dosage form suitable for these administration methods. 
         [0590]    The dose as medicament is desirably determined depending on the state of a patient, such as age, weight, the kind and condition of a disease, and administration route, and in general it is appropriate to administer in the range of 0.1 mg-5 g/day, preferably 1 mg-500 mg/day for an adult as the compound of the invention or a pharmaceutically acceptable salt thereof as an active ingredient in oral administration. In some cases, the dose may be lower than the above range or if required, may be higher. In general, it may be administered in a single or divided doses or intravenously continuously over 1 to 24 hours. 
       EXAMPLE 
       [0591]    The present invention will now be described in more detail by way of Reference Examples, Examples, Test Examples and Formulation Examples of the compound of the present invention, to which, however, the present invention is not limited. 
       Reference Example 1 
     (S)-4,6-Dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidin-2-amine 
       [0592]    2.4 g of 2,4,6-trichloropyrimidine was dissolved in 24 ml of tetrahydrofuran, and 2.0 ml of triethylamine was added at room temperature, and a solution of 2.0 g of (S)-(−)-1-(4-fluorophenyl)ethylamine in 12 mL of tetrahydrofuran was added dropwise, and then the mixture was stirred at room temperature for 9.5 hours. The reaction mixture was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography to obtain 1.77 g of the objective compound. 
         [0593]    MS (ESI) m/z 286 (M+H) −   
       Reference Example 2 
     (S)-4-Chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
     Step 1 
     (S)-4,6-Dichloro-N-[1-(4-fluorophenyl)ethyl]pyridin-2-amine 
       [0594]    7.2 g of 2,4,6-trichloropyridine and 2.74 g of (S)-(−)-1-(4-fluorophenyl)ethylamine were dissolved in 25 ml of 1-butanol, and 13.7 ml of N,N-diisopropylethylamine was added thereto, and the mixture was stirred at 120° C. for 42 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 2.57 g of the objective compound as yellow oil. 
         [0595]    MS (ESI) m/z 285 (M+H) +   
       Step 2 
     (S)-4-Chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [0596]    To 734 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyridine-2-amine, 343 mg of 2-aminopyrazine, 1.39 g of tripotassium phosphate, 190 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene and 170 mg of tris(dibenzylideneacetone)(chloroform)dipalladium was added 17 ml of 1,4-dioxane, the mixture was subjected to degassing and was substituted with argon, and was stirred at 100° C. for 19 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 654 mg of the objective compound as brown powder. 
         [0597]    MS (ESI) m/z 344 (M+H) 
       Example 1 
     (S)-4-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazin-2-one 
     Step 1 
     (S)-4-{6-Chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}piperazin-2-one 
       [0598]    To a solution of 150 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine and 58 mg of piperazin-2-one in 1.5 ml of 1-butanol was added 183 μl of N,N-diisopropylethylamine, and the mixture was stirred at 60° C. for 20 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 196 mg of the objective compound as white powder. 
         [0599]    MS (ESI) m/z 355 (M+H) 
       Step 2 
     (S)-4-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazin-2-one 
       [0600]    196 mg of (S)-4-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}piperidin-2-one, 55 mg of 2-aminopyrazine, 50 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 101 mg of sodium t-butoxide and 27 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 196 mg of the objective compound as pale brown powder. 
         [0601]    MS (ESI) m/z 409 (M+H) +   
       Example 2 
     N—{(S)-1-[2-{[(S)-1-(4-Fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyrimidin-4-yl]pyrrolidin-3-yl}acetamide hydrochloride 
       [0602]    N-{(S)-1-[2-{[(S)-1-(4-Fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyrimidin-4-yl]pyrrolidin-3-yl}acetamide was obtained by the same process as in Example 1 using (S)—N-(pyrrolidin-3-yl)acetamide instead of piperazin-2-one. The obtained compound was dissolved in methanol, and an equivalent of 1N hydrochloric acid was added thereto, and then the solvent was removed to obtain the objective compound as white powder. 
         [0603]    MS (ESI) m/z 437 (M+H) +   
       Example 3 
     (S)-6-(3,3-Difluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
       [0604]    (S)-6-(3,3-Difluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine was obtained by the same process as in Example 1 using 3,3-difluoroazetidine hydrochloride instead of piperazin-2-one. The obtained compound was dissolved in methanol, and an equivalent of 1N hydrochloric acid was added thereto, and then the solvent was removed to obtain the objective compound as white powder. 
         [0605]    MS (ESI) m/z 402 (M+H) −   
       Example 4 
     (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
     Step 1 
     2,6-Dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine 
       [0606]    500 mg of 2,6-dichloro-4-iodopyridine, 379 mg of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole, 753 mg of potassium carbonate and 74 mg of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex were added in turn to a degassed mixed solvent of 7.5 ml of 1,4-dioxane and 2.5 ml of water, and the mixture was stirred at 90° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 257 mg of the objective compound. 
         [0607]    MS (ESI) m/z 228 (M+H) +   
       Step 2 
     (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine 
       [0608]    257 mg of 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine obtained by Step 1, 164 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 66 mg of 2-(di-t-butylphosphino)biphenyl, 271 mg of sodium t-butoxide and 25 mg of palladium acetate were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 85° C. for 2 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 240 mg of the objective compound as pale yellow powder. 
         [0609]    MS (ESI) m/z 331 (M+H) 
       Step 3 
     (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
       [0610]    235 mg of (S)-6-chloro-N-(1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine, 74 mg of 2-aminopyrazine, 68 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 95 mg of sodium t-butoxide and 37 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 204 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow powder. The obtained compound was dissolved in ethanol, and an equivalent of 1N hydrochloric acid was added thereto, and then the solvent was removed to obtain the objective, compound as pale yellow powder. 
         [0611]    MS (ESI) m/z 390 (M+H) 
       Example 5 
     (S)—N 2′ -[1-(4-Fluorophenyl)ethyl]-N 6′ -(pyrazin-2-yl)-3,4′-bipyridine-2′,6′-diamine hydrochloride 
       [0612]    (S)—N 2′ -[1-(4-Fluorophenyl)ethyl]-N 6′ -(pyrazin-2-yl)-3,4′-bipyridine-2′,6′-diamine was obtained by the same process as in Example 4 using 3-(1,3,2-dioxaborinan-2-yl)pyridine instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole. The obtained compound was dissolved in ethanol, and an equivalent of 1N hydrochloric acid was added thereto, and then the solvent was removed to obtain the objective compound as yellow powder. 
         [0613]    MS (ESI) m/z 387 (M+H) 
       Example 6 
     (S)—N 2′ -[1-(4-Fluorophenyl)ethyl]-6-methoxy-N 6′ -(pyrazin-2-yl)-3,4′-bipyridine-2′,6′-diamine 
       [0614]    The objective compound was obtained as pale yellow powder by the same process as in Example 4 using 2-methoxy-5-pyridine boronic acid instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 
         [0615]    MS (ESI) m/z 417 (M+H) 
       Example 7 
     (S)-2′-[1-(4-Fluorophenyl)ethylamino]-6′-(pyrazin-2-ylamino)-3,4′-bipyridin-6-ol hydrochloride 
       [0616]    108 mg of (S)—N 2′ -[1-(4-fluorophenyl)ethyl]-6-methoxy-N 6′ -(pyrazin-2-yl)-3,4′-bipyridine-2′,6′-diamine was dissolved in 3 ml of acetonitrile, 116 mg of sodium iodide and 99 μl of trimethylsilyl chloride were added, and the mixture was stirred at 70° C. for 3.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate and water, and the pH of the mixture was adjusted to 9 by using saturated sodium bicarbonate aqueous solution. The organic layer was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 78 mg of (S)-2′-[1-(4-fluorophenyl)ethylamino]-6′-(pyrazin-2-ylamino)-3,4′-bipyridin-6-ol as pale yellow powder. The obtained compound was dissolved in methanol, and an equivalent of 1N hydrochloric acid was added thereto, and then the solvent was removed to obtain the objective compound as pale yellow powder. 
         [0617]    MS (ESI) m/z 403 (M+H) −   
       Example 8 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(oxazol-5-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
     Step 1 
     5-(2,6-Dichloropyridin-4-yl)oxazole 
       [0618]    528 mg of 2,6-dichloroisonicotinaldehyde (this compound was prepared by the method described in J. Chem. Soc., Chem. Commun., 1998, 1567-1568) was dissolved in 10 ml of methanol, and 586 mg of p-toluenesulfonyl methyl isocyanide and 415 mg of potassium carbonate ware added, and the mixture was stirred at 50° C. for 30 minutes. The reaction solution was concentrated, and then diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 630 mg of the objective compound as white powder. 
         [0619]    MS (ESI) m/z 215 (M+H) 
       Step 2 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(oxazol-5-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [0620]    630 mg of 5-(2,6-dichloropyridin-4-yl)oxazole obtained by Step 1, 408 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 182 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1.9 g of cesium carbonate and 66 mg of palladium acetate were added in turn to 30 ml of degassed toluene, and the mixture was stirred at 100° C. for 1.5 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 600 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(oxazol-5-yl)pyridine-2-amine as pale yellow powder. 10 ml of degassed toluene was added to the obtained powder, and 180 mg of 2-aminopyrazine, 180 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl biphenyl, 254 mg of sodium t-butoxide and 98 mg of tris(dibenzylideneacetone)dipalladium were added in turn, and the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 390 mg of the objective compound as pale yellow powder. 
         [0621]    MS (ESI) m/z 377 (M+H) −   
       Example 9 
     (S)-6-Chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
       [0622]    To 1.37 g of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 460 mg of 2-aminopyrazine, 277 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2.04 g of tripotassium phosphate and 248 mg of tris(dibenzylideneacetone)(chloroform)dipalladium, was added 30 ml of 1,4-dioxane, and the mixture was subjected to degassing and was substituted with argon gas, and then was stirred at 100° C. for 2 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled of f under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 960 mg of the objective compound as pale yellow powder. 
         [0623]    MS (ESI) m/z 345 (M+H) −   
       Example 10 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-[4-(methylsulfonyl)phenyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
       [0624]    100 mg of (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine, 145 mg of 4-(methylsulfonyl)phenylboronic acid, 123 mg of sodium carbonate and 17 mg of tetrakis(triphenylphosphine)palladium were added in turn to a degassed mixed solvent of 3 ml of 1,4-dioxane and 1.2 ml of water, and the mixture was stirred at 100° C. for 3 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 124 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[4-(methylsulfonyl)phenyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine as white powder. The obtained compound was dissolved in methanol, and an equivalent of 1N hydrochloric acid was added thereto, and then the solvent was removed to obtain the objective compound as white powder. 
         [0625]    MS (ESI) m/z 465 (M+H) 
       Example 11 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrazol-4-yl)pyrimidine-2,4-diamine hydrochloride 
       [0626]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrazol-4-yl)pyrimidine-2,4-diamine was obtained by the same process as in Example 10 using t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazol-1-carbamate instead of 4-(methylsulfonyl)phenylboronic acid. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [0627]    MS (ESI) m/z 377 (M+H) 
       Example 12 
     (S)-2-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yloxy}ethanol hydrochloride 
       [0628]    To 150 mg of (S)-4-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine, 187 mg of tripotassium phosphate, 84 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and 46 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added 3 ml of ethylene glycol and 1.5 ml of 1,4-dioxane, and the mixture was degassed, and substituted by argon gas, and the mixture was stirred at 100° C. for 13 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 62 mg of (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yloxy}ethanol as pale brown powder. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 52 mg of the objective compound as yellow powder. 
         [0629]    MS (ESI) m/z 370 (M+H) −   
       Example 13 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-3-yl)pyrimidine-2,4-diamine 
     Step 1 
     (S)-4-Chloro-N-[1-(4-fluorophenyl)ethyl]-6-(pyridin-3-yl)pyrimidine-2-amine 
       [0630]    500 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 314 mg of 3-(1,3,2-dioxaborinan-2-yl)pyridine, 927 mg of sodium carbonate and 202 mg of tetrakis(triphenylphosphine)palladium were added in turn to a degassed mixed solvent of 15 ml of toluene, 7 ml of ethanol and 10 ml of water, and the mixture was stirred at 110° C. for 3 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 218 mg of the objective compound as white powder. 
       Step 2 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-3-yl)pyrimidine-2,4-diamine 
       [0631]    To 100 mg of (S)-4-chloro-N-[1-(4-fluorophenyl)ethyl]-6-(pyridin-3-yl)pyrimidine-2-amine, 35 mg of 2-aminopyrazine, 18 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 129 mg of tripotassium phosphate and 16 mg of tris(dibenzylideneacetone)(chloroform)dipalladium, was added 2 ml of 1,4-dioxane, and the mixture was degassed, and substituted by argon gas, and then was stirred at 100° C. for 1 hour. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 54 mg of the objective compound as white powder. 
         [0632]    MS (ESI) m/z 388 (M+H) −   
         [0633]    Specific rotation [α] D   2C =−29.60° (c=0.5, methanol) 
       Example 14 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-2-yl)pyrimidine-2,4-diamine 
     Step 1 
     (S)-4-Chloro-N-[1-(4-fluorophenyl)ethyl]-6-(pyridin-2-yl)pyrimidine-2-amine 
       [0634]    200 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 0.22 ml 2-(tributylstannyl)pyridine, 55 mg of copper oxide and 81 mg of tetrakis(triphenylphosphine)palladium were added in turn to degassed toluene, and the mixture was stirred at 110° C. for 4 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 63 mg of the objective compound as colorless oil. 
       Step 2 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-2-yl)pyrimidine-2,4-diamine 
       [0635]    To 62 mg of (S)-4-chloro-N-[1-(4-fluorophenyl)ethyl]-6-(pyridin-2-yl)pyrimidine-2-amine, 22 mg of 2-aminopyrazine, 22 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 80 mg of tripotassium phosphate and 20 mg of tris (dibenzylideneacetone)(chloroform)dipalladium, was added 2 ml of 1,4-dioxane, and the mixture was degassed, and substituted by argon gas, and then was stirred at 100° C. for 2 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 25 mg of the objective compound as white powder. 
         [0636]    MS (ESI) m/z 388 (M+H) 
         [0637]    Specific rotation [α] D   20 =−61.20° (c=0.5, methanol) 
       Example 15 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-4-yl)pyrimidine-2,4-diamine 
       [0638]    The objective compound was obtained as pale yellow powder by the same process as in Example 14 using 4-(tributylstannyl)pyridine instead of 2-(tributylstannyl)pyridine. 
         [0639]    MS (ESI) m/z 388 (M+H) 
       Example 16 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-one 
     Step 1 
     (S)-1-{6-Chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}pyrrolidin-2-one 
       [0640]    100 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 33 mg of 2-pyrrolidone, 20 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 149 mg of tripotassium phosphate and 19 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 3 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 3 hours under argon atmosphere. The reaction solution was filtrated to remove precipitates, and the solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 106 mg of the objective compound as yellow oil. 
       Step 2 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-one 
       [0641]    104 mg of (S)-1-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}pyrrolidin-2-one, 33 mg of 2-aminopyrazine, 18 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 132 mg of tripotassium phosphate and 17 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 3 ml of degassed 1,4-dioxane, and then the mixture was stirred at 100° C. for 11 hours under argon atmosphere. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 74 mg of the objective compound as pale brown powder. 
         [0642]    MS (ESI) m/z 394 (M+H) +   
         [0643]    Specific rotation [α] D   20 =−19.60° (c=0.5, methanol) 
       Example 17 
     (S)-4-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazine-2,6-dione 
     Step 1 
     (S)-4-{6-Chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}piperazine-2,6-dione 
       [0644]    182 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1) and 80 mg of piperazine-2,6-dione were dissolved in 2 ml of tetrahydrofuran and 2 ml of N,N-dimethylformamide, and 122 μl of N,N-diisopropylethylamine was added thereto, and the mixture was stirred at 80° C. for 32 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 136 mg of the objective compound as white powder. 
       Step 2 
     (S)-4-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazine-2,6-dione 
       [0645]    119 mg of (8)-4-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}piperazine-2,6-dione, 34 mg of 2-aminopyrazine, 19 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 139 mg of tripotassium phosphate and 17 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added to 2.5 ml of degassed 1,4-dioxane, and then the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed with water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 26 mg of the objective compound as pale yellow powder. 
         [0646]    MS (ESI) m/z 423 (M+H) 
       Example 18 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}tetrahydropyrimidin-2(1H)-one 
       [0647]    The objective compound was obtained as pale yellow powder by the same process as in Example 16 using tetrahydro-2-pyrimidinone instead of 2-pyrrolidone. 
         [0648]    MS (ESI) m/z 409 (M+H) −   
       Example 19 
     (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyrrolidin-1-yl)pyrimidine-2,4-diamine 
       [0649]    The objective compound was obtained as a pale yellow amorphous solid by the same process as in Example 1 using pyrrolidine instead of piperazin-2-one. 
         [0650]    MS (ESI) m/z 380 (M+H) 
       Example 20 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-morpholine-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
       [0651]    The objective compound was obtained as a pale yellow amorphous solid by the same process as in Example 1 using morpholine instead of piperazin-2-one. 
         [0652]    MS (ESI) m/z 396 (M+H) 
         [0653]    Specific rotation [α] D   20 =−25.19° (c=0.5, methanol) 
       Example 21 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}imidazolidin-2-one hydrochloride 
       [0654]    150 mg of (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 9), 224 mg of 2-imidazolidinone, 26 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 185 mg of tripotassium phosphate and 23 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 5 ml of degassed 1,4-dioxane, and then the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed with water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 80 mg of (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}imidazolidin-2-one as white powder. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 56 mg of the objective compound as pale yellow powder. 
         [0655]    MS (ESI) m/z 395 (M+H) 
         [0656]    Elemental analysis value (as C 19 H 19 FN 2 O HCl+0.5H 2 O+0.1C 2 H 5 OH) 
         [0657]    Calculated value (%) C, 51.88; H, 4.90; N, 25.21. 
         [0658]    Found value (%) C, 51.71; H, 4.77; N, 24.87. 
       Example 22 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(oxazol-5-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
     Step 1 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[2-(triisopropylsilyl)oxazol-5-yl]pyrimidine-2,4-diamine 
       [0659]    150 mg of (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 9), 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl)oxazole (synthesized according to the method described in WO2007/17096), and 25 mg of tetrakis(triphenylphosphine)palladium were added in turn to 5 ml of degassed dimethylformamide, and then the mixture was stirred at 100° C. for 2.5 hours under argon atmosphere. 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl)oxazole was added thereto, and the mixture was further stirred for four hours. The reaction solution was diluted with water, and then subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 153 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[2-(triisopropylsilyl)oxazol-5-yl]pyrimidine-2,4-diamine as pale orange oil. 
       Step 2 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(oxazol-5-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
       [0660]    122 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[2-(triisopropylsilyl)oxazol-5-yl]pyrimidine-2,4-diamine was dissolved in 1.2 ml of tetrahydrofuran, and 0.5 ml of 1 M tetrabutylammonium fluoride tetrahydrofuran solution was added. The reaction solution was stirred at room temperature for 20 min, and then diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 60 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(oxazol-5-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine as white powder. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 45 mg of the objective compound as pale orange powder. 
         [0661]    MS (ESI) m/z 378 (M+H) 
         [0662]    Elemental analysis value (as C 19 H 16 N 7 O HCl) 
         [0663]    Calculated value (%) C, 55.14; H, 4.14; N, 23.69. 
         [0664]    Found value (%) C, 54.94; H, 3.92; N, 23.81. 
       Example 23 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(6-methoxypyridin-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
       [0665]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(6-methoxypyridin-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine was obtained by the same process as in Example 10 using 2-methoxy-5-pyridine boronic acid instead of 4-(methylsulfonyl)phenylboronic acid. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [0666]    MS (ESI) m/z 418 (M+H) +   
         [0667]    Elemental analysis value (as C 22 H 20 FN 7 O HCl) 
         [0668]    Calculated value (%) C, 58.21; H, 4.66; N, 21.60. 
         [0669]    Found value (%) C, 57.80; H, 4.48; N, 21.54. 
         [0670]    Specific rotation [α] D   20 =−24.80° (c=0.5, methanol) 
       Example 24 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrazol-3-yl)pyrimidine-2,4-diamine hydrochloride 
       [0671]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrazol-3-yl)pyrimidine-2,4-diamine was obtained by the same process as in Example 10 using 1H-pyrazol-3-boronic acid instead of 4-(methylsulfonyl)phenylboronic acid. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [0672]    MS (ESI) m/z 377 (M+H) 
         [0673]    Elemental analysis value (as C 19 H 17 FN 8  HCl+0.8H 2 O) 
         [0674]    Calculated value (%) C, 53.41; H, 4.62; N, 26.23. 
         [0675]    Found value (%) C, 53.21; H, 4.31; N, 26.25. 
         [0676]    Specific rotation [α] D   20 =−86.40° (c=0.5, methanol) 
       Example 25 
     (S)-4-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyridin-2-ol 
     Step 1 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(2-fluoropyridin-4-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
       [0677]    The objective compound was obtained by the same process as in Example 10 using 2-fluoropyridine-4-boronic acid instead of 4-(methylsulfonyl)phenylboronic acid. 
       Step 2 
     (S)-4-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyridin-2-ol 
       [0678]    1 ml of 1,2-dimethoxyethane and 10% hydrochloric acid were added to 80 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(2-fluoropyridin-4-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine, and the mixture was stirred at 85° C. for 2 hours. 0.5 ml of 10% hydrochloric acid was added thereto, and the mixture was further stirred for 2 hours. The reaction solution was diluted with ethyl acetate and alkalified with a saturated aqueous solution of sodium bicarbonate. The mixture was subjected to extraction, and the obtained organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained solid was washed with diethyl ether and filtrated, and then dried under reduced pressure to obtain 54 mg of the objective compound as white powder. 
         [0679]    MS (ESI) m/z 404 (M+H) 
       Example 26 
     (S)-5-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyridin-2-ol 
       [0680]    The objective compound was obtained as pale brown powder by the same process as in Example 7 using (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(6-methoxypyridin-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 23) instead of (S)—N 2′ -[1-(4-fluorophenyl)ethyl]-6-methoxy-N 6′ -(pyrazin-2-yl)-3,4′-bipyridine-2′,6′-diamine. 
         [0681]    MS (ESI) m/z 404 (M+H) −   
         [0682]    Specific rotation [α] D   20 —−39.60° (c—0.5, methanol) 
       Example 27 
     N—((R)-1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3-yl)acetamide hydrochloride 
       [0683]    N—((R)-1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3-yl)acetamide was obtained by the same process as in Example 1 using (R)—N-(pyrrolidin-3-yl)acetamide instead of piperazin-2-one. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [0684]    MS (ESI) m/z 437 (M+H) −   
         [0685]    Elemental analysis value (as C 22 H 25 FN 8 O HCl) 
         [0686]    Calculated value (%) C, 55.87; H, 5.54; N, 23.69. 
         [0687]    Found value (%) C, 55.49; H, 5.21; N, 23.59. 
         [0688]    Specific rotation [α] D   20 =113.59° (c=0.5, methanol) 
       Example 28 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrazol-4-yl)pyridine-2,6-diamine 
     Step 1 
     2,6-Dichloro-4-(1H-pyrazol-4-yl)pyridine 
       [0689]    188 mg of 2,6-dichloro-4-iodopyridine, 201 mg of t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazol-1-carbamate, 284 mg of potassium carbonate and 56 mg of 1,1′-bis(diphenylphosphino)ferrocene-palladiuM(II)dichloride-dichloromethane complex were added in turn to a degassed mixed solution of 3 ml of 1,4-dioxane and 1 ml of water, and then the mixture was stirred at 90° C. for 5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 90 mg of the objective compound. 
       Step 2 
     2,6-Dichloro-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)pyridine 
       [0690]    Under argon atmosphere, 90 mg of 2,6-dichloro-4-(1H-pyrazol-4-yl)pyridine was dissolved in 2 ml of tetrahydrofuran, and 20 mg of 60% sodium hydride was added at 0° C., and the mixture was stirred at 0° C. for 15 minutes. Subsequently, 82 μl of (2-chloromethoxy)ethyl trimethylsilane was added to the mixture, and the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction solution was added with water and was subjected to extraction with ethyl acetate. The organic layer was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 106 mg of the objective compound. 
       Step 3 
     (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)pyridine-2-amine 
       [0691]    100 mg of 2,6-dichloro-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)pyridine obtained by Step 2, 44 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 17 mg of 2-(di-t-butylphosphino)biphenyl, 70 mg of sodium t-butoxide and 6 mg of palladium acetate were added in turn to 3 ml of degassed toluene, and then the mixture was stirred at 85° C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 70 mg of the objective compound as colorless oil. 
       Step 4 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)pyridine-2,6-diamine 
       [0692]    68 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)pyridine-2-amine obtained by Step 3, 17 mg of 2-aminopyrazine, 15 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 21 mg of sodium t-butoxide and 8 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 70 mg of the objective compound as colorless oil. 
       Step 5 
     (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrazol-4-yl)pyridine-2,6-diamine 
       [0693]    To 53 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)pyridine-2,6-diamine obtained by Step 4, was added a mixed solvent of 1 ml of trifluoroacetic acid and 0.1 ml of water, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and then the obtained residue was diluted with water and alkalified with a saturated aqueous solution of sodium bicarbonate. The reaction solution was subjected to extraction with ethyl acetate, and the organic layer was washed with water and then dried over magnesium sulfate. The solvent was distilled off, and then the obtained residue was purified by silica gel column chromatography to obtain 15 mg of the objective compound as a pale yellow amorphous solid. 
         [0694]    MS (ESI) m/z 376 (M+H) +   
         [0695]    Specific rotation [α] D   20 —−103.59° (c—0.5, methanol) 
       Example 29 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrazol-3-yl)pyridine-2,6-diamine 
     Step 1 
     2,6-Dichloro-N-methoxy-N-methylisonicotinamide 
       [0696]    586 mg of 2,6-dichloroisonicotinic acid was dissolved in 10 ml of dimethylformamide, and 690 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 490 mg of 1-hydroxybenzotriazole, 440 mg of N,O-dimethylhydroxyamine hydrochloride and 1.67 ml of triethylamine were added, and the mixture was stirred at room temperature for 17 hours. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, and the mixture was diluted with ethyl acetate. The mixture was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 500 mg of the objective compound. 
       Step 2 
     1-(2,6-Dichloropyridin-4-yl)ethanone 
       [0697]    490 mg of 2,6-dichloro-N-methoxy-N-methyl isonicotinamide was dissolved in tetrahydrofuran, 2.1 ml of 3M methyl magnesium bromide tetrahydrofuran solution was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 hour. To the reaction solution was added ammonium chloride aqueous solution, and the mixture was diluted with ethyl acetate. The mixture was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 325 mg of the objective compound. 
       Step 3 
     2,6-Dichloro-4-(1H-pyrazol-3-yl)pyridine 
       [0698]    5 ml of N,N-dimethylformamide diethyl acetal was added to 325 mg of 1-(2,6-dichloropyridin-4-yl)ethanone, and the mixture was heated at reflux for 30 minutes. N,N-Dimethylformamide diethyl acetal was distilled off under reduced pressure, and to the obtained residue, 5 ml of ethanol and 91 μl of hydrazine monohydrate were added, and the mixture was heated at reflux for 1 hour. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 320 mg of the objective compound. 
       Step 4 
     2,6-Dichloro-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)pyridine 
       [0699]    Under argon atmosphere, 250 mg of 2,6-dichloro-4-(1H-pyrazol-3-yl)pyridine was dissolved in 6 ml of tetrahydrofuran, and 56 mg of 60% sodium, hydride was added by small portions at 0° C., and the mixture was stirred at 0° C. for 30 minutes. Subsequently, 0.25 ml of (2-chloromethoxy)ethyl trimethylsilane was added to the mixture, and the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction solution was added with water. The solution was subjected to extraction with ethyl acetate. The organic layer was washed with brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 440 mg of the objective compound. 
       Step 5 
     (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]-6-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)pyridine-2-amine 
       [0700]    100 mg of 2,6-dichloro-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)pyridine obtained by Step 4, 45 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 17 mg of 2-(di-t-butylphosphino)biphenyl, 70 mg of sodium t-butoxide and 7 mg of palladium acetate were added in turn to 3 ml of degassed toluene, and then the mixture was stirred at 85° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 130 mg of the objective compound as brown oil. 
       Step 6 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)pyridine-2,6-diamine 
       [0701]    130 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-6-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)pyridine-2-amine obtained by Step 5, 35 mg of 2-aminopyrazine, 30 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 42 mg of sodium t-butoxide and 18 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 95 mg of the objective compound as brown oil. 
       Step 7 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrazol-3-yl)pyridine-2,6-diamine 
       [0702]    A mixed solvent of 3 ml of trifluoroacetic acid and 0.3 ml of water was added to 95 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)pyridine-2,6-diamine obtained by Step 6, and the mixture was stirred at 60° C. for 1 hour. The solvent was distilled off under reduced pressure, and then the obtained residue was diluted with water and alkalified with a saturated aqueous solution of sodium bicarbonate. The reaction solution was subjected to extraction with ethyl acetate, and the organic layer was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 20 mg of the objective compound as pale yellow powder. 
         [0703]    MS (ESI) m/z 376 (M+H) +   
       Example 30 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine maleate 
       [0704]    1.34 g of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine synthesized by the same method as in Steps 1 and 2 of Example 4, 423 mg of 2-aminopyrazine, 154 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 544 mg of sodium t-butoxide and 74 mg of tris(dibenzylideneacetone)dipalladium were added in turn to 13 ml of degassed toluene, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 1.26 g of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow powder. Subsequently, 1.0 g of the obtained (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine was dissolved in 1 ml of methanol, and 300 mg of maleic acid was added. The reaction solution was added with 6 ml of ethyl acetate, and stirred at room temperature for 2 hours. The precipitated solid was filtered to obtain 1.1 g of the objective compound as white powder. 
         [0705]    MS (ESI) m/z 390 (M+H) +   
         [0706]    Elemental analysis value (as C 25 H 24 FN 7 O 4 ) 
         [0707]    Calculated value (%) C, 59.40; H, 4.79; N, 19.40. 
         [0708]    Found value (%) C, 59.19; H, 4.58; N, 19.36. 
         [0709]    Specific rotation [α] D   20 =68.40° (c=0.5, methanol) 
       Example 31 
     (S)—N 2 -(1-(4-Fluorophenyl)ethyl]-6-morpholino-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine maleate 
       [0710]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-morpholino-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine synthesized in Example 20 was converted to maleate by the same method as in Example 30. 
         [0711]    MS (ESI) m/z 396 (M+H) 
         [0712]    Elemental analysis value (as C 24 H 26 FN 7 O 5 ) 
         [0713]    Calculated value (%) C, 56.35; H, 5.12; N, 19.17. 
         [0714]    Found value (%) C, 56.42; H, 5.07; N, 19.41. 
         [0715]    Specific rotation [α] D   20 =81.20° (c=0.5, methanol) 
       Example 32 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-3-yl)pyrimidine-2,4-diamine1/2maleate 
       [0716]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-3-yl)pyrimidine-2,4-diamine synthesized in Example 13 was converted to maleate by the same method as in Example 30. 
         [0717]    MS (ESI) m/z 388 (M+H) 
         [0718]    Elemental analysis value (as C 23 H 20 FN 7 O 2 ) 
         [0719]    Calculated value (%) C, 62.02; H, 4.53; N, 22.01. 
         [0720]    Found value (%) C, 61.79; H, 4.50; N, 22.14. 
         [0721]    Specific rotation [α] D   n =−42.00° (c=0.5, methanol) 
       Example 33 
     N-{(S)-1-[2-{[(S)-1-(4-Fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyrimidin-4-yl]pyrrolidin-3-yl}acetamide maleate 
       [0722]    N-{(S)-1-[2-{[(S)-1-(4-Fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyrimidin-4-yl]pyrrolidin-3-yl}acetamide synthesized in Example 2 was converted to maleate by the same method as in Example 30. 
         [0723]    MS (ESI) m/z 437 (M+H) 
         [0724]    Elemental analysis value (as C 26 H 29 FN 2 O 5 ) 
         [0725]    Calculated value (%) C, 56.52; H, 5.29; N, 20.28. 
         [0726]    Found value (%) C, 56.49; H, 5.24; N, 20.45. 
         [0727]    Specific rotation [α] D   20 =26.39° (c=0.5, methanol) 
       Example 34 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrazol-4-yl)pyrimidine-2,4-diamine maleate 
       [0728]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrazol-4-yl)pyrimidine-2,4-diamine synthesized in Example 11 was converted to maleate by the same method as in Example 30. 
         [0729]    MS (ESI) m/z 377 (M+H) 
         [0730]    Elemental analysis value (as C 23 H 21 FN 2 O 4 +0.2H 2 O) 
         [0731]    Calculated value (%) C, 55.69; H, 4.35; N, 22.59. 
         [0732]    Found value (%) C, 55.32; H, 4.33; N, 22.61. 
         [0733]    Specific rotation [α] D   20 =−51.60° (c=0.5, methanol) 
       Example 35 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-[3-(methylsulfonyl)phenyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
       [0734]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-[3-(methylsulfonyl)phenyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine was obtained by the same process as in Example 10 using 3-(methylsulfonyl)phenylboronic acid instead of 4-(methylsulfonyl)phenylboronic acid. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [0735]    MS (ESI) m/z 465 (M+H) 
         [0736]    Elemental analysis value (as C 23 H 21 FN 6 O 2 S HCl+0.5H 2 O) 
         [0737]    Calculated value (%) C, 54.17; H, 4.55; N, 16.48. 
         [0738]    Found value (%) C, 54.04; H, 4.35; N, 16.10. 
         [0739]    Specific rotation [α] D   20 =−12.40° (c=0.5, methanol) 
       Example 36 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-[4-(methylsulfonyl)phenyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
       [0740]    (S)—N 2 -(1-(4-Fluorophenyl)ethyl]-4-(4-(methylsulfonyl)phenyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine was obtained by the same process as in Example 4 using 4-(methylsulfonyl)phenylboronic acid instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as yellow powder. 
         [0741]    MS (ESI) m/z 464 (M+H) 
         [0742]    Elemental analysis value (as C 24 H 22 FN 5 O 2 S HCl+0.2H 2 O) 
         [0743]    Calculated value (%) C, 57.24; H, 4.68; N, 13.91. 
         [0744]    Found value (%) C, 56.97; H, 4.35; N, 13.71. 
         [0745]    Specific rotation [α] D   20 =74.00° (c=0.5, methanol) 
       Example 37 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(1-isopropyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
     Step 1 
     4-Iodo-1-isopropyl-1H-pyrazole 
       [0746]    Under argon atmosphere, 96 mg of 60% sodium hydride was suspended in 6 ml of N,N-dimethylformamide, and 388 mg of 4-iodo-1H-pyrazol was added at 0° C., and the mixture was stirred at 0° C. for 30 minutes. Subsequently, 0.21 ml of 2-bromopropane was added and the reaction mixture was stirred at 100° C. for 2 hours. The reaction solution was added with water. The solution was subjected to extraction with ethyl acetate. The organic layer was washed with brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 328 mg of the objective compound. 
       Step 2 
     2,6-Dichloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyridine 
       [0747]    251 mg of 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridine (synthesized by a method described in J. Am. Chem. Soc., 2003, 125, 7792-7793), 325 mg of 4-iodo-1-isopropyl-1H-pyrazole, 381 mg of potassium carbonate and 22 mg of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex were added in turn to a degassed mixed solvent of 6 ml of 1,4-dioxane and 2 ml of water, and the mixture was stirred at 90° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 145 mg of the objective compound. 
       Step 3 
     (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-isopropyl-1H-pyrazol-4-yl)pyridine-2-amine 
       [0748]    145 mg of 2,6-dichloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyridine obtained by Step 2, 87 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 34 mg of 2-(di-t-butylphosphino)biphenyl, 109 mg of sodium t-butoxide and 13 mg of palladium acetate were added in turn to 6 ml of degassed toluene, and then the mixture was stirred at 85° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 59 mg of the objective compound as pale yellow powder. 
       Step 4 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(1-isopropyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
       [0749]    59 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-isopropyl-1H-pyrazol-4-yl)pyridine-2-amine, 19 mg of 2-aminopyrazine, 16 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, mg of sodium t-butoxide and 9 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 5 ml of degassed toluene, and the mixture was stirred at 85° C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 40 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-isopropyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow powder. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 30 mg of the objective compound as brown powder. 
         [0750]    MS (ESI) m/z 418 (M+H) 
         [0751]    Specific rotation [α] D   20 =76.40° (c=0.5, methanol) 
       Example 38 
     N-{(S)-1-[2-{](S)-1-(4-Fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyridin-4-yl]pyrrolidin-3-yl}acetamide hydrochloride 
       [0752]    100 mg of (S)-4-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine (Reference Example 2), 112 mg of (S)—N-(pyrrolidin-3-yl)acetamide, 69 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 92 mg of sodium t-butoxide and 30 mg of tris (dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 115 mg of N-{(S)-1-[2-{[(S)-1-(4-fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyridin-4-yl]pyrrolidin-3-yl}acetamide as pale brown powder. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 67 mg of the objective compound as brown powder. 
         [0753]    MS (ESI) m/z 436 (M+H) 
         [0754]    Specific rotation [α] D   20 =63.20° (c=0.5, methanol) 
       Example 39 
     (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-morpholino-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [0755]    The objective compound was obtained as brown powder by the same process as in Example 38 using morpholine instead of (S)—N-(pyrrolidin-3-yl)acetamide. 
         [0756]    MS (ESI) m/z 395 (M+H) 
         [0757]    Specific rotation [α] D   20 =38.80° (c=0.5, methanol) 
       Example 40 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-thiomorpholinopyridine-2,6-diamine 
       [0758]    The objective compound was obtained as brown powder by the same process as in Example 38 using thiomorpholine instead of (S)—N-(pyrrolidin-3-yl)acetamide. 
         [0759]    MS (ESI) m/z 411 (M+H) 
       Example 41 
     (S)-3-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}propan-1-ol hydrochloride 
       [0760]    The objective compound was obtained as yellow powder by the same process as in Example 12 using 1,3-propanediol instead of ethylene glycol. 
         [0761]    MS (ESI) m/z 364 (M+H) 
       Example 42 
     (S)—N-(1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)acetamide 
       [0762]    100 mg of t-butyl azetidin-3-ylcarbamate was dissolved in 5 ml of methylene chloride, and 225 mg of N,N-diisopropylethylamine was added. Under ice-cooling, the reaction mixture was added with 68 mg of acetyl chloride, and stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with 5% citric acid aqueous solution and brine in turn, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 146 mg of a brown oily matter. The obtained residue was dissolved in 2.5 ml of methylene chloride, and 1 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then 66 mg of N-(azetidin-3-yl)acetamide trifluoroacetate was obtained. Subsequently, 33 mg of N-(azetidin-3-yl)acetamide trifluoroacetate, 148 mg of triethylamine, 100 mg of (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine, 28 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 56 mg of sodium t-butoxide and 30 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 3 ml of degassed 1,4-dioxane, and the mixture was stirred at 90° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 17 mg of the objective compound as bright golden yellow powder. 
         [0763]    MS (ESI) m/z 423 (M+H) +   
       Example 43 
     (S)-6-(Azetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
       [0764]    The objective compound was obtained as a white amorphous solid by the same process as in Example 1 using azetidine hydrochloride instead of piperazin-2-one. 
         [0765]    MS (ESI) m/z 366 (M+H) 
       Example 44 
     (S)-6-(3-Fluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
       [0766]    The objective compound was obtained as a pale yellow amorphous solid by the same process as in Example 1 using 3-fluoroazetidine hydrochloride instead of piperazin-2-one. 
         [0767]    MS (ESI) m/z 384 (M+H) 
         [0768]    Specific rotation [α] D   20 =84.00° (c=0.5, methanol) 
       Example 45 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-2-one 
       [0769]    100 mg of (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl) pyrimidine-2,4-diamine (Example 9), 41 mg of 2-azetidinone, 34 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 123 mg of tripotassium phosphate and 30 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 3 ml of degassed 1,4-dioxane, and the mixture was stirred at 90° C. for 5 hours under argon atmosphere. The reaction mixture was filtrated to remove precipitates, and the solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 58 mg of the objective compound as white powder. 
         [0770]    MS (ESI) m/z 380 (M+H) 
         [0771]    Specific rotation [α] D   20 =−62.40° (c=0.5, methanol) 
       Example 46 
     (S)-4-(1-Ethyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [0772]    The objective compound was obtained as pale yellow powder by the same process as in Example 37 using iodoethane instead of 2-bromopropane. 
         [0773]    MS (ESI) m/z 404 (M+H) 
         [0774]    Specific rotation [α] D   20 =−83.60° (c=0.5, methanol) 
       Example 47 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [0775]    The objective compound was obtained as white powder by the same process as in Example 4 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 
         [0776]    MS (ESI) m/z 390 (M+H) 
       Example 48 
     (S)-4-[1-(Cyclopropylmethyl)-1H-pyrazol-4-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [0777]    The objective compound was obtained as yellow ocher powder by the same process as in Example 37 using (bromomethyl)cyclopropane instead of 2-bromopropane. 
         [0778]    MS (ESI) m/z 430 (M+H) 
       Example 49 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(thiazol-5-yl)pyrimidine-2,4-diamine 
     Step 1 
     (S)-4-Chloro-N-[1-(4-fluorophenyl)ethyl]-6-(thiazol-5-yl)pyrimidine-2-amine 
       [0779]    286 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 411 mg of 5-(tributylstannyl)thiazole and 115 mg of tetrakis(triphenylphosphine)palladium were added in turn to degassed dimethylformamide, and then the mixture was stirred at 100° C. for 5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 175 mg of (S)-4-chloro-N-[1-(4-fluorophenyl)ethyl]-6-(thiazol-5-yl)pyrimidine-2-amine as a white solid. 
       Step 2 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(thiazol-5-yl)pyrimidine-2,4-diamine 
       [0780]    To 155 mg of (S)-4-chloro-N-[1-(4-fluorophenyl)ethyl]-6-(thiazol-5-yl)pyrimidine-2-amine, 53 mg of 2-aminopyrazine, 72 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 196 mg of tripotassium phosphate and 81 mg of tris(dibenzylideneacetone)(chloroform)dipalladium, was added 4 ml of 1,4-dioxane, and the mixture was subjected to degassing, and substituted by argon gas, and then was stirred at 100° C. for 5 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 105 mg of the objective compound as pale yellow powder. 
         [0781]    MS (ESI) m/z 394 (M+H) −   
       Example 50 
     1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3-ol hydrochloride 
     Step 1 
     1-{6-Chloro-2-[(S)-1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}pyrrolidin-3-ol 
       [0782]    The objective compound was obtained as white powder by the same process as in Example 1, Step 1 using DL-3-pyrrolidinol instead of piperazin-2-one. 
       Step 2 
     1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3-ol hydrochloride 
       [0783]    119 mg of 1-{6-chloro-2-[(S)-1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}pyrrolidin-3-ol, 40 mg of 2-aminopyrazine, 20 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 150 mg of tripotassium phosphate and 19 mg of tris(dibenzylideneacetone)dipalladium were added in turn to 3 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 2.5 hours under argon atmosphere. The reaction mixture was filtrated to remove precipitates, and the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 47 mg of 1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidine-3-ol. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 32 mg of the objective compound as pale yellow powder. 
         [0784]    MS (ESI) m/z 396 (M+H) 
         [0785]    Elemental analysis value (as C 20 H 22 FN 7 O HCl+0.25H 2 O) 
         [0786]    Calculated value (%) C, 55.04; H, 5.43; N, 22.47. 
         [0787]    Found value (%) C, 55.06; H, 5.12; N, 22.50. 
       Example 51 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(5-methylthiazol-2-yl)-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine 
       [0788]    The objective compound was obtained as pale yellow powder by the same process as in Example 16 using 2-amino-5-methylthiazole instead of 2-pyrrolidone. 
         [0789]    MS (ESI) m/z 423 (M+H) 
       Example 52 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4,5′-bipyrimidine-2,6-diamine 
     Step 1 
     (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]-4,5′-bipyrimidine-2-amine 
       [0790]    210 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 91 mg of pyrimidine-5-boronic acid, 304 mg of potassium carbonate and 60 mg of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex were added in turn to a degassed mixed solution of 3 ml of 1,4-dioxane and 1 ml of water, and the mixture was stirred at 90° C. for 6 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 73 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4,5′-bipyrimidine-2-amine as a white amorphous solid. 
       Step 2 
     (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4,5′-bipyrimidine-2,6-diamine 
       [0791]    To 90 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4,5′-bipyrimidine-2-amine, 31 mg of 2-aminopyrazine, 31 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 116 mg of tripotassium phosphate and 28 mg of tris(dibenzylideneacetone)(chloroform)dipalladium, was added 2 ml of 1,4-dioxane, and the mixture was subjected to degassing, and substituted by argon gas, and then was stirred at 100° C. for 3 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 30 mg of the objective compound as pale yellow powder. 
         [0792]    MS (ESI) m/z 389 (M+H) 
       Example 53 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(2-methoxythiazol-5-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
       [0793]    The objective compound was obtained as pale orange powder by the same process as in Example 49 using 2-methoxy-5-(tributylstannyl)thiazole instead of 5-(tributylstannyl)thiazole. 
         [0794]    MS (ESI) m/z 424 (M+H) +   
       Example 54 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(thiazol-2-yl)pyrimidine-2,4-diamine 
     Step 1 
       [0795]    t-Butyl 
       ((S)-4,6-dichloropyrimidin-2-yl)[1-(4-fluorophenyl)ethyl]carbamate 
       [0796]    300 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine was dissolved in 7 ml of tetrahydrofuran, and 0.70 ml of di-t-butyldicarbonate and 58 mg of 4-dimethylaminopyridine were added, and then the reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 285 mg of the objective compound as colorless oil. 
       Step 2 
       [0797]    t-Butyl 
       (S)-4-chloro-6-(thiazol-2-yl)pyrimidin-2-yl-[1-(4-fluorophenyl)ethyl]carbamate 
       [0798]    270 mg of t-butyl ((S)-4,6-dichloropyrimidin-2-yl)[1-(4-fluorophenyl)ethyl]carbamate, 314 mg of 2-(tributylstannyl)thiazole and 81 mg of tetrakis(triphenylphosphine)palladium were added in turn to 5 ml of degassed toluene, and the mixture was stirred at 100° C. for 3 hours under argon atmosphere. The solvent of the reaction solution was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 150 mg of the objective compound as pale yellow oil. 
       Step 3 
     (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(thiazol-2-yl)pyrimidine-2,4-diamine 
       [0799]    130 mg of t-butyl (S)-4-chloro-6-(thiazol-2-yl)pyrimidin-2-yl[1-(4-fluorophenyl)ethyl]carbamate, 34 mg of 2-aminopyrazine, 35 mg of 4,5-bis (diphenylphosphino)-9,9′-dimethylxanthene, 127 mg of tripotassium phosphate and 31 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 4 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 3 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 90 mg of pale yellow oil. To the obtained oil, 2 ml of trifluoroacetic acid was added, and stirred at room temperature for 2 hours. Trifluoroacetic acid was distilled off under reduced pressure, and then the obtained residue was diluted with water and alkalified with a saturated aqueous solution of sodium bicarbonate. The reaction solution was subjected to extraction with ethyl acetate, and the organic layer was washed with water and brine in turn, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 25 mg of the objective compound as white powder. 
         [0800]    MS (ESI) m/z 394 (M+H) 
       Example 55 
     (S)-5-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}picolinonitrile 
       [0801]    The objective compound was obtained as pale yellow powder by the same process as in Example 52 using 2-cyanopyridine-5-boronic acid pinacol ester instead of pyrimidine-5-boronic acid. 
         [0802]    MS (ESI) m/z 413 (M+H) −   
       Example 56 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxamide hydrochloride 
       [0803]    The objective compound was obtained by the same process as in Example 1 using isonipecotamide instead of piperazin-2-one. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [0804]    MS (ESI) m/z 437 (M+H) 
       Example 57 
     (S)-5-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}picolinamide 
       [0805]    To 38 mg of (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}picolinonitrile, was added t-butanol, and 60 mg of potassium fluoride supported on activated alumina was added thereto, and the mixture was stirred at 90° C. for 4 hours. The reaction solution was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 25 mg of the objective compound as an amorphous solid. 
         [0806]    MS (ESI) m/z 431 (M+H) 
       Example 58 
     4-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazin-2-carboxamide 
       [0807]    The objective compound was obtained as a pale yellow amorphous solid by the same process as in Example 1 using piperazine-2-carboxamide instead of piperazin-2-one. 
         [0808]    MS (ESI) m/z 438 (M+H) −   
       Example 59 
     6-(3-Aminopyrrolidin-1-yl)-N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
       [0809]    t-Butyl 
         [0810]    1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3-yl carbamate was obtained by the same process as in Example 1 using 3-(t-butoxycarbonylamino)pyrrolidine instead of piperazin-2-one. 2 ml of trifluoroacetic acid was added to the obtained compound, and the mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid was distilled off, and then the obtained residue was diluted with water and alkalified with a saturated aqueous solution of sodium bicarbonate. The reaction solution was subjected to extraction with ethyl acetate, and the organic layer was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the objective compound as pale yellow powder. 
         [0811]    MS (ESI) m/z 395 (M+H) 
       Example 60 
     N-(1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-yl}pyrrolidin-3-yl)methanesulfonamide hydrochloride 
       [0812]    110 mg of 6-(3-aminopyrrolidin-1-yl)-N 2 —[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 59) was dissolved in 3 ml of tetrahydrofuran, and 91 μl of N,N-diisopropylethylamine and 21 μl of methanesulfonyl chloride were added at 0° C., and the mixture was stirred at 0° C. for 1 hour. Water was added to the reaction solution, and then the reaction solution was subjected to extraction with ethyl acetate, and the organic layer was washed with water and brine in turn, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 92 mg of N-(1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-yl}pyrrolidin-3-yl)methanesulfonamide as a pale yellow amorphous solid. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 70 mg of the objective compound as pale yellow powder. 
         [0813]    MS (ESI) m/z 473 (M+H) 
         [0814]    Elemental analysis value (as C 21 H 25 FN 8 O 2 S HCl+0.5H 2 O+0.2CH 3 CO 2 C 2 H 5 ) 
         [0815]    Calculated value (%) C, 48.88; H, 5.38; N, 20.92. 
         [0816]    Found value (%) C, 48.64; H, 5.17; N, 20.73. 
       Example 61 
     (S)-2-({2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}(2-hydroxyethyl)amino)ethan-1-ol hydrochloride 
       [0817]    (S)-2-({2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}(2-hydroxyethyl)amino) ethan-1-ol was obtained by the same process as in Example 1 using diethanolamine instead of piperazin-2-one. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [0818]    MS (ESI) m/z 414 (M+H) +   
         [0819]    Elemental analysis value (as C 20 H 24 FN 7 O 2  HCl+H 2 O) 
         [0820]    Calculated value (%) C, 52.97; H, 5.65; N, 21.62. 
         [0821]    Found value (%) C, 52.91; H, 5.45; N, 21.37. 
       Example 62 
     (S)—N 4 -[2-(Dimethylamino)ethyl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine dihydrochloride 
       [0822]    (S)—N 4 -[2-(Dimethylamino)ethyl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine was obtained by the same process as in Example 1 using N,N-dimethylethylenediamine instead of piperazin-2-one. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale brown powder. 
         [0823]    MS (ESI) m/z 397 (M+H) 
         [0824]    Elemental analysis value (as C 20 H 25 FN 8  2HCl+1.5H 2 O) 
         [0825]    Calculated value (%) C, 48.39; H, 6.09; N, 22.57. 
         [0826]    Found value (%) C, 48.30; H, 5.81; N, 22.45. 
       Example 63 
     1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-3-carboxamide hydrochloride 
       [0827]    1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-3-carboxamide was obtained by the same process as in Example 1 using nipecotamide instead of piperazin-2-one. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [0828]    MS (ESI) m/z 437 (M+H) 
       Example 64 
     (S)-1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-carboxamide hydrochloride 
       [0829]    (S)-1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-carboxamide was obtained by the same process as in Example 1 using L-prolinamide instead of piperazin-2-one. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as yellow powder. 
         [0830]    MS (ESI) m/z 423 (M+H) −   
         [0831]    Elemental analysis value (as C 21 H 23 FN 8 O HCl+1.5H 2 O) 
         [0832]    Calculated value (%) C, 51.90; H, 5.60; N, 23.06. 
         [0833]    Found value (%) C, 51.89; H, 5.26; N, 22.97. 
       Example 65 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
       [0834]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine was obtained by the same process as in Example 1 using 1-methanesulfonylpiperazine instead of piperazin-2-one. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [0835]    MS (ESI) m/z 473 (M+H) +   
         [0836]    Elemental analysis value (as C 21 H 25 FN 8 O 2 S HCl+1.6H 2 O) 
         [0837]    Calculated value (%) C, 46.90; H, 5.47; N, 20.83. 
         [0838]    Found value (%) C, 46.52; H, 5.09; N, 20.69. 
       Example 66 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrrol-3-yl)pyrimidine-2,4-diamine 
     Step 1 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]pyrimidine-2,4-diamine 
       [0839]    The objective compound was obtained by the same process as in Example 52 using 1-(triisopropylsilyl)-1H-pyrrole-3-boronic acid instead of pyrimidine-5-boronic acid. 
       Step 2 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrrol-3-yl)pyrimidine-2,4-diamine 
       [0840]    305 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]pyrimidine-2,4-diamine was dissolved in 3 ml of tetrahydrofuran, and 0.86 ml of 1M tetrabutylammonium fluoride/tetrahydrofuran solution was added under ice water cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was added with water. The solution was subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 199 mg of the objective compound as pale brown powder. 
         [0841]    MS (ESI) m/z 376 (M+H) 
       Example 67 
     (R)-1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-4-hydroxypyrrolidin-2-one 
       [0842]    The objective compound was obtained as a pale yellow amorphous solid by the same process as in Example 16 using (R)-(+)-4-hydroxy-2-pyrrolidinone instead of 2-pyrrolidone. 
         [0843]    Ms (ESI) m/z 410 (M+H) 
       Example 68 
     N 2 -[(S)-1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 [(tetrahydrofuran-2-yl)methyl]pyrimidine-2,4,6-triamine 
       [0844]    The objective compound was obtained as an amorphous solid by the same process as in Example 1 using tetrahydrofurfurylamine instead of piperazin-2-one. 
         [0845]    MS (ESI) m/z 410 (M+H) 
       Example 69 
     ((S)-1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-yl)methanol hydrochloride 
       [0846]    ((S)-1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-yl)methanol was obtained by the same process as in Example 1 using L-prolinol instead of piperazin-2-one. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [0847]    MS (ESI) m/z 410 (M+H) 
         [0848]    Elemental analysis value (as C 21 H 24 FN 7 O HCl+0.4H 2 O+0.5CH 3 OH) 
         [0849]    Calculated value (%) C, 55.04; H, 5.97; N, 20.90. 
         [0850]    Found value (%) C, 55.05; H, 5.75; N, 20.57. 
       Example 70 
     ((R)-1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-yl)methanol hydrochloride 
       [0851]    ((R)-1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-yl)methanol was obtained by the same process as in Example 1 using D-prolinol instead of piperazin-2-one. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [0852]    MS (ESI) m/z 410 (M+H) 
         [0853]    Elemental analysis value (as C 21 H 24 FN 7 O HCl+0.4H 2 O+0.5CH 3 OH) 
         [0854]    Calculated value (%) C, 55.04; H, 5.97; N, 20.90. 
         [0855]    Found value (%) C, 54.74; H, 5.70; N, 20.70. 
       Example 71 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-4-ol hydrochloride 
       [0856]    (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-4-ol was obtained by the same process as in Example 1 using 4-hydroxypiperidine instead of piperazin-2-one. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [0857]    MS (ESI) m/z 410 (M+H) 
         [0858]    Elemental analysis value (as C 21 H 24 FN 7 O HCl) 
         [0859]    Calculated value (%) C, 56.56; H, 5.65; N, 21.99. 
         [0860]    Found value (%) C, 56.23; H, 5.53; N, 21.99. 
       Example 72 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-ol hydrochloride 
       [0861]    (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-ol was obtained by the same process as in Example 1 using 3-hydroxyazetidine hydrochloride instead of piperazin-2-one. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [0862]    MS (ESI) m/z 382 (M+H) +   
         [0863]    Elemental analysis value (as C 19 H 20 FN 7 O HCl+1.2H 2 O+0.2CH 3 OH) 
         [0864]    Calculated value (%) C, 51.72; H, 5.47; N, 21.99. 
         [0865]    Found value (%) C, 51.45; H, 5.14; N, 22.29. 
       Example 13 
     1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-3-ol hydrochloride 
       [0866]    1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-3-ol was obtained by the same process as in Example 1 using 3-hydroxypiperidine instead of piperazin-2-one. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [0867]    MS (ESI) m/z 410 (M+H) 
         [0868]    Elemental analysis value (as C 21 H 24 FN 7 O HCl+0.9H 2 O+0.4CH 3 OH) 
         [0869]    Calculated value (%) C, 54.12; H, 6.03; N, 20.64. 
         [0870]    Found value (%) C, 53.90; H, 5.78; N, 20.93. 
       Example 74 
     (S)-5-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}nicotinonitrile 
     Step 1 
     5-(Trimethylstannyl)nicotinonitrile 
       [0871]    300 mg of 5-bromo-3-cyanopyridine, 750 mg of hexamethylditin and 185 mg of tetrakis(triphenylphosphine)palladium were added in turn to 5 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 3 hours under argon atmosphere. The solvent of the reaction solution was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 178 mg of the objective compound as colorless oil. 
       Step 2 
     (S)-5-{6-Chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}nicotinonitrile 
       [0872]    187 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 175 mg of 5-(trimethylstannyl)nicotinonitrile, 25 mg of copper iodide and 75 mg of tetrakis(triphenylphosphine)palladium were added in turn to 3 ml of degassed toluene, and the mixture was stirred at 110° C. for 17 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 58 mg of (S)-5-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin 4-yl}nicotinonitrile as colorless oil. 
       Step 3 
     (S)-5-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}nicotinonitrile 
       [0873]    55 mg of (S)-5-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}nicotinonitrile, 16 mg of 2-aminopyrazine, 15 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 21 mg of sodium t-butoxide and 8 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2 ml of degassed toluene, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 21 mg of the objective compound as white powder. 
         [0874]    MS (ESI) m/z 413 (M+H) 
       Example 75 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(2H-tetrazol-5-yl)pyrimidine-2,4-diamine 
     Step 1 
     (S)-6-[2-(Benzyloxymethyl)-2H-tetrazol-5-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
       [0875]    (S)-6-[2-(Benzyloxymethyl)-2H-tetrazol-5-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine was obtained by the same process as in Example 74 using 2-(benzyloxymethyl)-5-(tributylstannyl)-2H-tetrazole (synthesized according to the method described in Tetrahedron Lett., 2000, 41, 2805-2809) instead of 5-(trimethylstannyl)nicotinonitrile. 
       Step 2 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(2H-tetrazol-5-yl)pyrimidine-2,4-diamine 
       [0876]    50 mg of (S)-6-[2-(Benzyloxymethyl)-2H-tetrazol-5-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine was dissolved in 1.5 ml of methanol, and 1.5 ml of 10% hydrochloric acid was added thereto, and the mixture was stirred at 80° C. for 20 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate, and the pH of the mixture was adjusted to 4 by using saturated sodium bicarbonate aqueous solution. The organic layer was subjected to extraction, and washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was washed with methanol and filtered and dried under reduced pressure to obtain 15 mg of the objective compound as white powder. 
         [0877]    MS (ESI) m/z 379 (M+H) 
       Example 76 
     (S)—N 4 -(2-Aminoethyl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine dihydrochloride 
       [0878]    (S)—N 4 -(2-Aminoethyl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine was obtained by the same process as in Example 59 using t-butyl N-(2-aminoethyl)carbamate instead of 3-(t-butoxycarbonylamino)pyrrolidine. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [0879]    MS (ESI) m/z 369 (M+H) −   
         [0880]    Elemental analysis value (as C 18 H 21 FN e  2HCl+0.5H 2 O) 
         [0881]    Calculated value (%) C, 48.01; H, 5.37; N, 24.88. 
         [0882]    Found value (%) C, 47.72; H, 5.51; N, 24.70. 
       Example 77 
     (S)—N-(2-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-ylamino}ethyl)methanesulfonamide hydrochloride 
       [0883]    (S)—N-(2-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}ethyl)methanesulfonamide was obtained by the same process as in Example 60 using (S)—N 4 -(2-aminoethyl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine instead of 6-(3-aminopyrrolidin-1-yl)-N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [0884]    MS (ESI) m/z 447 (M+H) 
         [0885]    Elemental analysis value (as C 15 H 23 FN 8 O 2 S HCl+H 2 O) 
         [0886]    Calculated value (%) C, 45.55; H, 5.23; N, 22.37. 
         [0887]    Found value (%) C, 45.61; H, 5.07; N, 22.24. 
       Example 78 
     (S)—N-(2-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-ylamino}ethyl)acetamide hydrochloride 
       [0888]    Saturated sodium bicarbonate aqueous solution and chloroform added to 141 mg of were (S)—N 4 -(2-aminoethyl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine dihydrochloride (Example 76), and the mixture was subjected to extraction. The organic layer washed with brine, and dried over magnesium sulfate. The solvent was distilled of f under reduced pressure, and then the obtained residue was dissolved in 3 ml of tetrahydrofuran, and 223 μl of diisopropylethylamine and 23 μl of acetyl chloride were added at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The reaction solution was added with water and subjected to extraction with ethyl acetate. The organic layer washed with brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 95 mg of (S)—N-(2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-ylamino}ethyl)acetamide as white powder. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 74 mg of the objective compound as pale yellow powder. 
         [0889]    MS (ESI) m/z 411 (M+H) 
         [0890]    Elemental analysis value (as C 20 H 23 FN 8 O HCl) 
         [0891]    Calculated value (%) C, 53.75; H, 5.41; N, 25.07. 
         [0892]    Found value (%) C, 53.47; H, 5.55; N, 24.87. 
       Example 79 
     (S)-2-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}acetamide hydrochloride 
       [0893]    (S)-2-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}acetamide was obtained by the same process as in Example 1 using 2-aminoacetamide instead of piperazin-2-one. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale brown powder. 
         [0894]    MS (ESI) m/z 383 (M+H) 
         [0895]    Elemental analysis value (as C 18 H 19 FN 8 O HCl+1.2H 2 O) 
         [0896]    Calculated value (%) C, 49.08; H, 5.13; N, 25.44. 
         [0897]    Found value (%) C, 49.33; H, 5.45; N, 25.14. 
       Example 80 
     (S)-4-(2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzamide hydrochloride 
       [0898]    (S)-4-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzamide was obtained by the same process as in Example 10 using 4-carbamoylphenylboronic acid instead of 4-(methylsulfonyl)phenylboronic acid. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [0899]    MS (ESI) m/z 430 (M+H) 
         [0900]    Elemental analysis value (as C 23 H 20 FN 7 O HCl+H 2 O) 
         [0901]    Calculated value (%) C, 57.09; H, 4.79; N, 20.26. 
         [0902]    Found value (%) C, 57.16; H, 4.68; N, 20.45. 
       Example 81 
     (S)-3-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzonitrile 
       [0903]    The objective compound was obtained as a pale yellow amorphous solid by the same process as in Example 10 using 3-cyanophenylboronic acid instead of 4-(methylsulfonyl)phenylboronic acid. 
         [0904]    MS (ESI) m/z 412 (M+H) 
       Example 82 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(furan-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
       [0905]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(furan-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine was obtained by the same process as in Example 10 using 3-furylboronic acid instead of 4-(methylsulfonyl)phenylboronic acid. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [0906]    MS (ESI) m/z 377 (M+H) 
         [0907]    Elemental analysis value (as C 20 H 17 FN 6 O HCl) 
         [0908]    Calculated value (%) C, 58.18; H, 4.39; N, 20.36. 
         [0909]    Found value (%) C, 57.88; H, 4.58; N, 20.24. 
       Example 83 
     Ethyl 
     (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-4-carboxylate 
       [0910]    The objective compound was obtained as a pale yellow amorphous solid by the same process as in Example 1 using ethyl isonipecotate instead of piperazin-2-one. 
         [0911]    MS (ESI) m/z 466 (M+H) 
       Example 84 
     (S)-5-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}nicotinamide 
       [0912]    The objective compound was obtained as an amorphous solid by the same process as in Example 57 using (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}nicotinonitrile instead of (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}picolinonitrile. 
         [0913]    MS (ESI) m/z 431 (M+H) 
       Example 85 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxylic acid 
       [0914]    128 mg of ethyl (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxylate (Example 83) was dissolved in 3 ml of ethanol, 0.28 ml of 12% sodium hydroxide aqueous solution was added thereto, and the mixture was stirred at room temperature for 6 hours. Ethanol was distilled off and then the obtained residue was diluted with water and the aqueous layer was washed with diethyl ether. The aqueous layer was neutralized with a 10% hydrochloric acid to pH 7 and subjected to extraction with ethyl acetate, and the organic layer was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was washed with diethyl ether, and filtered and dried under reduced pressure to obtain 58 mg of the objective compound as white powder. 
         [0915]    MS (ESI) m/z 438 (M+H) 
       Example 86 
     (S)-2-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-2-phenylethanol 
       [0916]    The objective compound was obtained as brown powder by the same process as in Example 1 using (S)-(+)-2-phenylglycinol instead of piperazin-2-one, and using ethoxyethanol as a reaction solvent in Step 1, which was subjected to reaction at 135° C. 
         [0917]    MS (ESI) m/z 446 (M+H) +   
       Example 87 
     (S)-2-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-phenylpropan-1-ol 
       [0918]    The objective compound was obtained as brown powder by the same process as in Example 1 using L-phenylalaninol instead of piperazin-2-one, and using ethoxyethanol as a reaction solvent in Step 1, which was subjected to reaction at 135° C. 
         [0919]    MS (ESI) m/z 460 (M+H) 
       Example 88 
     (R)-2-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-4-methylpentan-1-ol 
       [0920]    The objective compound was obtained as brown powder by the same process as in Example 1 using D-leucinol instead of piperazin-2-one, and using ethoxyethanol as a reaction solvent in Step 1, which was subjected to reaction at 135° C. 
         [0921]    MS (ESI) m/z 426 (M+H) 
       Example 89 
     (S)-6-[2-(Dimethylamino)ethoxy]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine dihydrochloride 
       [0922]    To 172 mg of (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine, 212 mg of tripotassium phosphate, 95 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and 52 mg of tris(dibenzylideneacetone)(chloroform)dipalladium was added 4 ml of 2-dimethyl aminoethanol, and the mixture was subjected to degassing, and substituted by argon gas, and then was stirred at 100° C. for 1 hour. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 118 mg of (S)-6-[2-(dimethylamino)ethoxy]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 101 mg of the objective compound as pale yellow powder. 
         [0923]    MS (ESI) m/z 398 (M+H) 
         [0924]    Elemental analysis value (as C 20 H 24 FN 7 O 2HCl+1.2H 2 O) 
         [0925]    Calculated value (%) C, 48.83; H, 5.82; N, 19.93. 
         [0926]    Found value (%) C, 48.89; H, 5.63; N, 19.86 
       Example 90 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1H-pyrazole-4-carboxylic acid 
     Step 1 
     Ethyl 
     (S)-1-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}-1H-pyrazole-4-carboxylate 
       [0927]    500 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 270 mg of ethyl 4-pyrazole carboxylate, 0.20 ml of trans-N,N′-dimethylcyclohexane-1,2-diamine, 780 mg of tripotassium phosphate and 100 mg of copper iodide were added in turn to 10 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 6 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 51 mg of the objective compound as white powder. 
         [0928]    MS (ESI) m/z 390 (M+H) 
       Step 2 
     Ethyl 
     (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1H-pyrazole-4-carboxylate 
       [0929]    50 mg of ethyl (S)-1-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}-1H-pyrazole-4-carboxylate, 15 mg of 2-aminopyrazine, 12 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 17 mg of sodium t-butoxide and 7 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 10 ml of degassed toluene, and the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 45 mg of the objective compound as white powder. 
         [0930]    MS (ESI) m/z 449 (M+H) 
       Step 3 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1H-pyrazole-4-carboxylic acid 
       [0931]    2 ml of ethanol, 1 ml of tetrahydrofuran and 80 μl of 12% sodium hydroxide aqueous solution were added to 35 mg of ethyl (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1H-pyrazole-4-carboxylate, and the mixture was stirred at room temperature for 18 hours. 160 μl of 12% sodium hydroxide aqueous solution was added thereto, and the mixture was further stirred for 3 hours. Ethanol was distilled off. The obtained residue was diluted with ethanol, and diluted with water, and the ply of the mixture was adjusted to 7 by using 10% hydrochloric acid, the mixture was subjected to extraction with ethyl acetate, and the organic layer was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 14 mg of the objective compound as white powder. 
         [0932]    MS (ESI) m/z 421 (M+H) 
       Example 91 
     (S)-3-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzamide 
       [0933]    192 mg of (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzonitrile (Example 81) was added to 5 ml of t-butanol, and 384 mg of potassium fluoride supported on activated alumina was added thereto, and the mixture was stirred at 80° C. for 2 hours. 384 mg of potassium fluoride supported on activated alumina was added thereto, and the mixture was further stirred for 15 hours. The reaction solution was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 158 mg of the objective compound as white powder. 
         [0934]    MS (ESI) m/z 430 (M+H) 
       Example 92 
     (S)-6-(Benzo[d]1,3-dioxol-5-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
       [0935]    (S)-6-(Benzo[d]1,3-dioxol-5-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine was obtained by the same process as in Example 10 using 3,4-(methylenedioxy)phenylboronic acid instead of 4-(methylsulfonyl)phenylboronic acid. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [0936]    MS (ESI) m/z 431 (M+H) 
         [0937]    Elemental analysis value (as C 23 H 19 FN 6 O 2  HCl+H 2 O) 
         [0938]    Calculated value (%) C, 56.97; H, 4.57; N, 17.33. 
         [0939]    Found value (%) C, 56.58; H, 4.38; N, 17.45. 
       Example 93 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(2-fluoropyridin-4-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
       [0940]    The objective compound was obtained as white powder by the same process as in Example 10 using 2-fluoropyridine-4-boronic acid instead of 4-(methylsulfonyl)phenylboronic acid. 
         [0941]    MS (ESI) m/z 406 (M+H) 
       Example 94 
     N 2 -[(S)-1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[(tetrahydrofuran-2-yl)methoxy]pyrimidine-2,4-diamine 
       [0942]    To 200 mg of (S)-6-chloro-N 2 -(1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine, 246 mg of tripotassium phosphate, 111 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and 60 mg of tris(dibenzylideneacetone)(chloroform)dipalladium, 4 ml of tetrahydrofurfurylalcohol and 2 ml of 1,4-dioxane were added, and the mixture was subjected to degassing, and substituted by argon gas, and then was stirred at 100° C. for 1 hour. The reaction solution was diluted with ethyl acetate and was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 77 mg of the objective compound as pale yellow powder. 
         [0943]    MS (ESI) m/z 411 (M+H) 
       Example 95 
     (S)-2-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yloxy}ethanol hydrochloride 
       [0944]    (S)-2-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yloxy}ethanol was obtained by the same process as in Example 94 using ethylene glycol instead of tetrahydrofurfurylalcohol. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [0945]    MS (ESI) m/z 371 (M+H) −   
         [0946]    Elemental analysis value (as C 18 H 19 FN 6 O 2  HCl) 
         [0947]    Calculated value (%) C, 53.14; H, 4.95; N, 20.66. 
         [0948]    Found value (%) C, 52.94; H, 4.95; N, 20.52. 
       Example 96 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -[2-(pyrrolidin-1-yl)ethyl]pyrimidine-2,4,6-triamine 
       [0949]    The objective compound was obtained as brown powder by the same process as in Example 1 using 1-(2-aminoethyl)pyrrolidine instead of piperazin-2-one. 
         [0950]    MS (ESI) m/z 423 (M+H) 
       Example 97 
     (S)-3-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}isonicotinamide 
       [0951]    150 mg of (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine, 235 mg of 4-cyanopyridine-3-boronic acid neopentyl glycol ester, 184 mg of sodium carbonate and 25 mg of tetrakis(triphenylphosphine)palladium were added in turn to a degassed mixed solution of 3.5 ml of 1,4-dioxane and 1.5 ml of water, and the mixture was stirred at 100° C. for 5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained powder was washed with ethyl acetate, and filtered and dried under reduced pressure to obtain 31 mg of (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}isonicotinamide as white powder. 
         [0952]    MS (ESI) m/z 431 (M+H) +   
       Example 98 
     (S)-3-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}isonicotinonitrile 
       [0953]    The filtrate obtained in Example 97 was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 15 mg of (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}isonicotinonitrile as white powder. 
         [0954]    MS (ESI) m/z 413 (M+H) −   
       Example 99 
     (S)-2-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-methylbutan-1-ol hydrochloride 
       [0955]    The objective compound was obtained as pale yellow powder by the same process as in Example 1 using L-valinol instead of piperazin-2-one. 
         [0956]    MS (ESI) m/z 412 (M+H) +   
         [0957]    Elemental analysis value (as C 21 H 26 FN 7 O HCl+H 2 O) 
         [0958]    Calculated value (%) C, 54.13; H, 6.27; N, 21.04. 
         [0959]    Found value (%) C, 54.18; H, 5.91; N, 21.14. 
       Example 100 
     (S)—N 2 -[1-(4-Chlorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
     Step 1 
     (S)-6-Chloro-N-[1-(4-chlorophenyl)ethyl]-4-[4-(methylsulfonyl)piperazin-1-yl]pyrimidine-2-amine 
       [0960]    200 mg of (S)-4,6-dichloro-N-[1-(4-chlorophenyl)ethyl]pyrimidine-2-amine and 119 mg of 1-methanesulfonyl piperazine were dissolved in 3 ml of 1-butanol, and 0.23 ml of N,N-diisopropylethylamine was added thereto, and the mixture was stirred at 60° C. for 20 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 196 mg of the objective compound as white powder. 
         [0961]    MS (ESI) m/z 430 (M+H) 
       Step 2 
     (S)—N 2 -[1-(4-Chlorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
       [0962]    210 mg of (S)-6-chloro-N-[1-(4-chlorophenyl)ethyl]-4-[4-(methylsulfonyl)piperazin-1-yl]pyrimidine-2-amine, 56 mg of 2-aminopyrazine, 47 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 66 mg of sodium t-butoxide and 25 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 4 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 120 mg of (S)—N 2 -[1-(4-chlorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [0963]    MS (ESI) m/z 489 (M+H) +   
         [0964]    Elemental analysis value (as C 21 H 25 ClFN 3 O 2 S HCl+0.4H 2 O) 
         [0965]    Calculated value (%) C, 47.35; H, 5.07; N, 21.04. 
         [0966]    Found value (%) C, 47.24; H, 4.79; N, 20.97. 
       Example 101 
     (1S,2S)-2-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yloxy}cyclohexanol hydrochloride 
       [0967]    (1S,2S)-2-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yloxy}cyclohexanol was obtained by the same process as in Example 94 using (1S,2S)-trans-1,2-cyclohexanediol instead of tetrahydrofurfurylalcohol. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [0968]    MS (ESI) m/z 425 (M+H) 
         [0969]    Elemental analysis value (as C 22 H 25 FN 6 O 2  HCl+0.2H 2 O) 
         [0970]    Calculated value (%) C, 56.88; H, 5.73; N, 18.09. 
         [0971]    Found value (%) C, 56.94; H, 5.53; N, 18.14. 
       Example 102 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -[(5-methylpyrazin-2-yl) methyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine hydrochloride 
       [0972]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -[(5-methylpyrazin-2-yl)methyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine was obtained by the same process as in Example 1 using 2-(aminomethyl)-5-methylpyrazine instead of piperazin-2-one. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [0973]    MS (ESI) m/z 432 (M+H) 
         [0974]    Elemental analysis value (as C 22 H 22 FN 9  HCl+H 2 O+0.5CH 3 OH) 
         [0975]    Calculated value (%) C, 53.84; H, 5.42; N, 25.11. 
         [0976]    Found value (%) C, 53.44; H, 5.05; N, 25.40. 
       Example 103 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(furan-2-ylmethyl)-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine hydrochloride 
       [0977]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(furan-2-ylmethyl)-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine was obtained by the same process as in Example 1 using furfurylamine instead of piperazin-2-one. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [0978]    MS (ESI) m/z 406 (M+H) 
         [0979]    Elemental analysis value (as C 21 H 20 FN 7 O HCl+1.5H 2 O) 
         [0980]    Calculated value (%) C, 53.79; H, 5.16; N, 20.91. 
         [0981]    Found value (%) C, 53.85; H, 4.84; N, 20.85. 
       Example 104 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -[1-(pyridin-3-yl)ethyl]pyrimidine-2,4,6-triamine 
       [0982]    The objective compound was obtained as brown powder by the same process as in Example 1 using 1-(3-pyridyl)ethylamine instead of piperazin-2-one and using ethoxyethanol as a reaction solvent in Step 1, which was subjected to reaction at 135° C. 
         [0983]    MS (ESI) m/z 431 (M+H) 
       Example 105 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-4-(hydroxymethyl)piperidin-4-ol 
     Step 1 
     4-(Hydroxymethyl)piperidin-4-ol hydrochloride 
       [0984]    500 mg of 1-benzyl-4-(hydroxymethyl)piperidin-4-ol (synthesized according to the method described in J. Med. Chem., 1988, 486-491) was dissolved in 10 ml of ethanol, 300 mg of 10% palladium carbon and 0.38 ml of concentrated hydrochloric acid were added thereto, and the mixture was subjected to hydrogenation at room temperature overnight. The reaction mixture was filtrated to remove precipitates, the precipitates were wasted with ethanol and water, and the filtrate was concentrated under reduced pressure. The obtained residue was turned into powder by adding diethylether to obtain 374 mg of the objective compound as white powder. 
       Step 2 
     (S)-1-{6-Chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}-4-(hydroxymethyl)piperidin-4-ol 
       [0985]    150 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine and 97 mg of 4-(hydroxymethyl)piperidin-4-ol hydrochloride were dissolved in 3 ml of 2-ethoxyethanol, and 274 μl of N,N-diisopropylethylamine was added thereto, and the mixture was stirred at 135° C. for 20 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 194 mg of the objective compound as brown oil. 
       Step 3 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-4-(hydroxymethyl)piperidin-4-ol 
       [0986]    100 mg of (S)-1-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}-4-(hydroxymethyl)piperidin-4-ol, 32 mg of 2-aminopyrazine, 45 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 38 mg of sodium t-butoxide and 27 mg of tris(dibenzylideneacetone)(chloroform)palladium were added in turn to a degassed mixed solution of 3 ml of toluene and 2 ml of 1,4-dioxane, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 80 mg of the objective compound as brown powder. 
         [0987]    MS (ESI) m/z 440 (M+H) 
       Example 106 
     (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-2-ylmethyl)pyrimidine-2,4,6-triamine 
       [0988]    The objective compound was obtained as brown powder by the same process as in Example 1 using 2-(aminomethyl)pyridine instead of piperazin-2-one, and using ethoxyethanol as a reaction solvent in Step 1, which was subjected to reaction at 135° C. 
         [0989]    MS (ESI) m/z 417 (M+H) 
       Example 107 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-3-ylmethyl)pyrimidine-2,4,6-triamine 
       [0990]    The objective compound was obtained as brown powder by the same process as in Example 1 using 3-(aminomethyl)pyridine instead of piperazin-2-one, and using ethoxyethanol as a reaction solvent in Step 1, which was subjected to reaction at 135° C. 
         [0991]    MS (ESI) m/z 417 (M+H) 
       Example 108 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-4-ylmethyl)pyrimidine-2,4,6-triamine 
       [0992]    The objective compound was obtained as brown powder by the same process as in Example 1 using 4-(aminomethyl)pyridine instead of piperazin-2-one, and using ethoxyethanol as a reaction solvent in Step 1, which was subjected to reaction at 135° C. 
         [0993]    MS (ESI) m/z 417 (M+H) 
       Example 109 
     (S)-2-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-hydroxypropanamide 
       [0994]    The objective compound was obtained as white powder by the same process as in Example 1 using L-serinamide instead of piperazin-2-one, and using ethoxyethanol as a reaction solvent in Step 1, which was subjected to reaction at 135° C. 
         [0995]    MS (ESI) m/z 413 (M+H) 
       Example 110 
     (3S,4S)-1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3,4-diol 
       [0996]    The objective compound was obtained as yellow powder by the same process as in Example 1 using (3S,4S)-3,4-pyrrolidinol instead of piperazin-2-one. 
         [0997]    MS (ESI) m/z 412 (M+H) 
       Example 111 
     N 2 -[(S)-1-(4-Fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyrimidine-2,4-diamine 
       [0998]    The objective compound was obtained as brown powder by the same process as in Example 1 using 1,4-dioxa-8-azaspiro[4.5] decane instead of piperazin-2-one, and using ethoxyethanol as a reaction solvent in Step 1, which was subjected to reaction at 135° C. 
         [0999]    MS (ESI) m/z 452 (M+H) −   
       Example 112 
     (S)-8-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1,3-dioxo-8-azaspiro[4.5]decan-2-one 
       [1000]    50 mg of (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-4-(hydroxymethyl)piperidin-4-ol (Example 105) and 24 mg of N,N′-carbonyldiimidazole were dissolved in 2 ml of methylene chloride, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was purified by silica gel column chromatography to obtain 52 mg of the objective compound as pale brown powder. 
         [1001]    MS (ESI) m/z 466 (M+H) 
       Example 113 
     (S)-4-(1-Benzyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [1002]    The objective compound was obtained as pale yellow powder by the same process as in Example 4 using 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 
         [1003]    MS (ESI) m/z 466 (M+H) 
       Example 114 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(4-(phenylsulfonyl)piperazin-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
       [1004]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-[4-(phenylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine was obtained by the same process as in Example 50 using 1-phenylsulfonylpiperazine instead of DL-3-pyrrolidinol. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [1005]    MS (ESI) m/z 535 (M+H) 
         [1006]    Elemental analysis value (as C 26 H 27 FN 2 O 2 S HCl+1.3H 2 O) 
         [1007]    Calculated value (%) C, 52.53; H, 5.19; N, 18.85. 
         [1008]    Found value (%) C, 52.65; H, 5.02; N, 18.54. 
       Example 115 
     (S)-4-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}benzamide dihydrochloride 
       [1009]    150 mg of (S)-4-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine (Reference Example 2), 108 mg of 4-carbamoylphenylboronic acid, 567 mg of cesium carbonate, 21 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and 13 mg of tris(dibenzylideneacetone)dipalladium were added in turn to a degassed mixed solution of 3 ml of 1,4-dioxane and 0.6 ml of water, and the mixture was stirred at 100° C. for 17 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 39 mg of (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}benzamide. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 31 mg of the objective compound as orange powder. 
         [1010]    MS (ESI) m/z 429 (M+H) 
         [1011]    Elemental analysis value (as, C 24 H 21 FN 6 O 2HCl+H 2 O) 
         [1012]    Calculated value (%) C, 55.50; H, 4.85; N, 16.18. 
         [1013]    Found value (%) C, 55.57; H, 4.70; N, 16.25. 
       Example 116 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrrol-3-yl)pyridine-2,6-diamine dihydrochloride 
       [1014]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrrol-3-yl)pyridine-2,6-diamine was obtained by the same process as in Example 115 using 1-(triisopropylsilyl)-1H-pyrrole-3-boronic acid instead of 4-carbamoylphenylboronic acid. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as orange powder. 
         [1015]    MS (ESI) m/z 375 (M+H) +   
         [1016]    Elemental analysis value (as C 21 H 19 FN 6  2HCl+0.4H 2 O) 
         [1017]    Calculated value (%) C, 55.49; H, 4.83; N, 18.49. 
         [1018]    Found value (%) C, 55.70; H, 4.80; N, 18.11. 
       Example 117 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine dihydrochloride 
     Step 1 
     (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]pyridine-2-amine 
       [1019]    300 mg of 2,6-dichloropyridine, 296 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 119 mg of 2-(di-t-butylphosphino)biphenyl, 487 mg of sodium t-butoxide and 45 mg of palladium acetate were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 85° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 210 mg of the objective compound as pale yellow oil. 
       Step 2 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine dihydrochloride 
       [1020]    207 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]pyridine-2-amine, 86 mg of 2-aminopyrazine, 79 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 111 mg of sodium t-butoxide and 43 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 4 ml of degassed toluene, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 202 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow powder. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 128 mg of the objective compound as pale orange powder. 
         [1021]    MS (ESI) m/z 310 (M+H) 
       Example 118 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(4-methyl-1H-imidazol-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
     Step 1 
     (S)-4-Chloro-N-[1-(4-fluorophenyl)ethyl]-6-(4-methyl-1H-imidazol-1-yl)pyrimidine-2-amine 
       [1022]    200 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine and 63 mg of 4-methylimidazole were dissolved in 2 ml of dimethylformamide, and 193 mg of potassium carbonate was added thereto, and the mixture was stirred at 100° C. for 17 hours. The reaction solution was diluted with water, and then subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 62 mg of the objective compound as a white solid. 
       Step 2 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(4-methyl-1H-imidazol-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
       [1023]    60 mg of (S)-4-chloro-N-[1-(4-fluorophenyl)ethyl]-6-(4-methyl-1H-imidazol-1-yl)pyrimidine-2-amine, 19 mg of 2-aminopyrazine, 17 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 35 mg of sodium t-butoxide and 9 mg of tris(dibenzylideneacetone)dipalladium were added in turn to 2 ml of degassed toluene, and the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 69 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(4-methyl-1H-imidazol-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 48 mg of the objective compound as pale yellow powder. 
         [1024]    MS (ESI) m/z 391 (M+H) 
       Example 119 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(4-methoxyphenyl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
       [1025]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(4-methoxyphenyl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine was obtained by the same process as in Example 37 using 4-bromoanisole instead of 4-iodo-1-isopropyl-1H-pyrazole. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [1026]    MS (ESI) m/z 416 (M+H) 
         [1027]    Elemental analysis value (as C 24 H 22 FN 5 O HCl+1.5H 2 O) 
         [1028]    Calculated value (%) C, 60.19; H, 5.47; N, 14.62. 
         [1029]    Found value (%) C, 60.37; H, 5.08; N, 14.71. 
       Example 120 
     (S)-4-(4-Fluorophenyl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
       [1030]    (S)-4-(4-Fluorophenyl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine was obtained by the same process as in Example 37 using 4-bromofluorobenzene instead of 4-iodo-1-isopropyl-1H-pyrazole. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [1031]    MS (ESI) m/z 404 (M+H) 
       Example 121 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-methyl-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
     Step 1 
     (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]-4-methylpyridine-2-amine 
       [1032]    500 mg of 2,6-dichloro-4-iodopyridine, 0.51 ml of trimethylboroxine, 1.0 g of potassium carbonate and 208 mg of tetrakis(triphenylphosphine)palladium were added in turn to 6 ml of degassed dimethylformamide, and the mixture was stirred at 110° C. for 3 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 330 mg of a pale yellow solid. The obtained solid was dissolved in 6 ml of degassed toluene, 253 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 147 mg of bis[2-(diphenylphosphino)phenyl]ether, 244 mg of sodium t-butoxide and 40 mg of palladium acetate were added in turn thereto, and the mixture was stirred at 80° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 100 mg of the objective compound as colorless oil. 
       Step 2 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-methyl-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
       [1033]    95 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-methylpyridine-2-amine, 40 mg of 2-aminopyrazine, 34 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 48 mg of sodium t-butoxide and 19 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 85 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-methyl-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 38 mg of the objective compound as yellow powder. 
         [1034]    MS (ESI) m/z 324 (M+H) 
         [1035]    Elemental analysis value (as C 18 H 18 FN 5  HCl+0.5H 2 O) 
         [1036]    Calculated value (%) C, 58.62; H, 5.47; N, 18.99. 
         [1037]    Found value (%) C, 58.86; H, 5.68; N, 18.61. 
       Example 122 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(methylsulfonyl)piperidine-4-carboxamide 
       [1038]    Under argon atmosphere, 92 mg of (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxylic acid (Example 85) was dissolved in 2 ml of tetrahydrofuran, and 41 mg of N,N′-carbonyldiimidazole was added thereto, and the mixture was stirred at 70° C. for 1 hour. The reaction solution was air-cooled to room temperature, and 80 mg of methanesulfonamide and 63 μl of 1,8-diazabicyclo[5,4,0]-7-undecene were added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water, and the pH of the mixture was adjusted to 4 by using acetic acid. The reaction solution was subjected to extraction with ethyl acetate, and the organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 42 mg of the objective compound as white powder. 
         [1039]    MS (ESI) m/z 515 (M+H) 
       Example 123 
     (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(furan-3-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [1040]    The objective compound was obtained as pale yellow powder by the same process as in Example 37 using 3-bromofuran instead of 4-iodo-1-isopropyl-1H-pyrazole. 
         [1041]    MS (ESI) m/z 376 (M+H) 
       Example 124 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-[4-(methylsulfonyl)piperazin-1-yl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
       [1042]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-[4-(methylsulfonyl)piperazin-1-yl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine was obtained by the same process as in Example 38 using 1-methanesulfonylpiperazine instead of (S)—N-(pyrrolidin-3-yl)acetamide, and using 1,4-dioxane as a reaction solvent. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [1043]    MS (ESI) m/z 472 (M+H) 
       Example 125 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-4-(hydroxymethyl)piperidin-4-ol 
       [1044]    (S)-4-(2,2-Dimethyl-1,3-dioxa-8-azaspiro[4.5]decan-8-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine was obtained by the same process as in Example using 2,2-dimethyl-1,3-dioxa-8-azaspiro[4.5]decane instead of (S)—N-(pyrrolidin-3-yl)acetamide, and using 1,4-dioxane as a reaction solvent. 46 mg of the obtained compound was dissolved in 1 mL of chloroform, and 0.5 ml of 50% trifluoroacetic acid aqueous solution was added at 0° C. thereto, and the mixture was stirred. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 21 mg of the objective compound as brown powder. 
         [1045]    MS (ESI) m/z 439 (M+H) 
       Example 126 
     (S)-4-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}benzenesulfonamide 
       [1046]    The objective compound was obtained as brown powder by the same process as in Example 37 using 4-bromobenzene sulfonamide instead of 4-iodo-1-isopropyl-1H-pyrazole. 
         [1047]    MS (ESI) m/z 465 (M+H) 
       Example 127 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-methoxy-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [1048]    The objective compound was obtained as white powder by the same process as in Example 4 using 2,6-dichloro-4-methoxypyridine (synthesized according to the method described in WO2007/21710A1) instead of 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine. 
         [1049]    MS (ESI) m/z 340 (M+H) 
       Example 128 
     4-{2-[(1S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-1λ 6 ,4-thiomorpholin-1,1-dione 
       [1050]    The objective compound was obtained as brown powder by the same process as in Example 38 using thiomorpholin-1,1-dioxide instead of (S)—N-(pyrrolidin-3-yl)acetamide, and using 1,4-dioxane as a reaction solvent. 
         [1051]    MS (ESI) m/z 443 (M+H) 
       Example 129 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}piperidin-4-ol 
       [1052]    The objective compound was obtained as brown powder by the same process as in Example 38 using 4-hydroxypiperidine instead of (S)—N-(pyrrolidin-3-yl)acetamide, and using 1,4-dioxane as a reaction solvent. 
         [1053]    MS (ESI) m/z 409 (M+H) 
       Example 130 
     (S)-1-(4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyridin-4-yl}-1,4-diazepan-1-yl)ethanone 
       [1054]    The objective compound was obtained as brown powder by the same process as in Example 38 using N-acetylhomopiperazine instead of (S)—N-(pyrrolidin-3-yl)acetamide. 
         [1055]    MS (ESI) m/z 450 (M+H) 
       Example 131 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-N 4 -(pyrimidin-2-yl)pyridine-2,4,6-triamine 
       [1056]    The objective compound was obtained as brown powder by the same process as in Example 38 using 2-aminopyrimidine instead of (S)—N-(pyrrolidin-3-yl)acetamide, and using 1,4-dioxane as a reaction solvent. 
         [1057]    MS (ESI) m/z 403 (M+H) 
       Example 132 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-N 4 -(pyridin-2-yl)pyridine-2,4,6-triamine 
       [1058]    The objective compound was obtained as brown powder by the same process as in Example 38 using 2-aminopyridine instead of (S)—N-(pyrrolidin-3-yl)acetamide, and using 1,4-dioxane as a reaction solvent. 
         [1059]    MS (ESI) m/z 402 (M+H) 
       Example 133 
     N 2 -[(S)-1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1,4-dioxa-8-azaspiro(4.5]decan-8-yl)pyridine-2,6-diamine 
       [1060]    The objective compound was obtained as brown powder by the same process as in Example 38 using 1,4-dioxa-8-azaspiro[4.5]decane instead of (S)—N-(pyrrolidin-3-yl)acetamide, and using 1,4-dioxane as a reaction solvent. 
         [1061]    MS (ESI) m/z 451 (M+H) 
       Example 134 
     Methyl 
     (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) isonicotinate 
     Step 1 
     Methyl 
     (S)-2-chloro-6-[1-(4-fluorophenyl)ethylamino]isonicotinate 
       [1062]    8.3 g of methyl 2,6-dichloroisonicotinate, 6.1 ml of (S)-(−)-1-(4-fluorophenyl)ethylamine, 20.5 g of cesium carbonate, 2.1 g of (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 505 mg of palladium acetate were added in turn to 100 ml of degassed 1,4-dioxane, and the mixture was stirred at 70° C. for 7 hours under argon atmosphere. The reaction mixture was purified by silica gel column chromatography to obtain 4.4 g of the objective compound as pale yellow powder. 
       Step 2 
     Methyl 
     (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) isonicotinate 
       [1063]    4.4 g of methyl (S)-2-chloro-6-[1-(4-fluorophenyl)ethylamino]isonicotinate, 1.3 g of 2-aminopyrazine, 2.67 g of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 5.0 g of tripotassium phosphate and 1.28 g of tris(dibenzylideneacetone)dipalladium were added in turn to 100 ml of degassed toluene, and the mixture was stirred at 100° C. for 24 hours under argon atmosphere. The reaction mixture was filtrated by celite, and the filtrate was concentrated under reduced pressure, and the obtained residue Was purified by silica gel column chromatography to obtain 4.9 g of the objective compound as white powder. 
         [1064]    MS (ESI) m/z 368 (M+H) 
       Example 135 
     (S)-4-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-methylbenzenesulfonamide hydrochloride 
       [1065]    (S)-4-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-methylbenzenesulfonamide was obtained by the same process as in Example 10 using 4-(N-methylsulfamoyl)phenylboronic acid pinacol ester instead of 4-(methylsulfonyl)phenylboronic acid. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [1066]    MS (ESI) m/z 480 (M+H) −   
         [1067]    Elemental analysis value (as C 21 H 22 FN 7 O 2 S HCl+0.2H 2 O) 
         [1068]    Calculated value (%) C, 53.17; H, 4.54; N, 18.87. 
         [1069]    Found value (%) C, 52.98; H, 4.34; N, 18.84. 
       Example 136 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(4-methyl-1H-imidazol-1-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine dihydrochloride 
       [1070]    1.10 g of 2,6-dichloro-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2-yl)pyridine, 164 mg of 4-methylimidazole, 0.56 ml of triethylamine and 0.32 ml of pyridine were dissolved in 4 ml of methylene chloride, and 545 mg of copper acetate was added thereto, and the mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with water, and chloroform and concentrated ammonia aqueous solution were added thereto, and the mixture was subjected to extraction. The aqueous layer was further subjected to extraction with chloroform, and the obtained organic layers were combined, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 117 mg of 2,6-dichloro-4-(4-methyl-1H-imidazol-1-yl)pyridine. Subsequently, (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(4-methyl-1H-imidazol-1-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine was obtained by the same process as in Steps 2 and 3 of Example 4 using 2,6-dichloro-4-(4-methyl-1H-imidazol-1-yl)pyridine instead of 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as yellow powder. 
         [1071]    MS (ESI) m/z 390 (M+H) 
       Example 137 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 4 ,N 6 -di(pyrazin-2-yl)pyridine-2,4,6-triamine 
       [1072]    The objective compound was obtained as brown powder by the same process as in Example 38 using 2-aminopyrazine instead of (S)—N-(pyrrolidin-3-yl)acetamide. 
         [1073]    MS (ESI) m/z 403 (M+H) 
       Example 138 
     (S)-4-(Cyclopropylmethoxy)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
     Step 1 
     2,6-Dichloro-4-(cyclopropylmethoxy)pyridine 
       [1074]    109 mg of cyclopropylcarbinol was dissolved in 2 ml of dimethylformamide, and 60 mg of 60% sodium hydride was added thereto under ice water cooling, and the mixture was stirred at room temperature for 20 minutes. To the reaction solution was added 400 mg of 2,4,6-trichloropyridine, and stirred at room temperature for 30 minutes. The reaction solution was added with water and subjected to extraction with ethyl acetate. The organic layer was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 133 mg of the objective compound as colorless oil. 
       Step 2 
     (S)-6-Chloro-4-(cyclopropylmethoxy)-N-[1-(4-fluorophenyl)ethyl]pyridine-2-amine 
       [1075]    130 mg of 2,6-dichloro-4-(cyclopropylmethoxy)pyridine, 92 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 36 mg 2-(di-t-butylphosphino)biphenyl, 144 mg of sodium t-butoxide and 14 mg of palladium acetate were added in turn to 2 ml of degassed toluene, and the mixture was stirred at 80° C. for 15 minutes under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 122 mg of the objective compound as colorless oil. 
       Step 3 
     (S)-4-(Cyclopropylmethoxy)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [1076]    112 mg of (S)-6-chloro-4-(cyclopropylmethoxy)-N-[1-(4-fluorophenyl)ethyl]pyridine-2-amine, 43 mg of 2-aminopyrazine, 67 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 51 mg of sodium t-butoxide and 36 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 103 mg of the objective compound as brown powder. 
         [1077]    MS (ESI) m/z 380 (M+H) 
       Example 139 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 2 -methyl-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
     Step 1 
     (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]-N-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine 
       [1078]    92 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine was dissolved in 1.5 ml of tetrahydrofuran, and 17 mg of 60% sodium hydride was added thereto, and the mixture was stirred at room temperature for 10 minutes. 26 μl of methyl iodide was added thereto, and the reaction solution was subjected to microwave irradiation at 100° C. for 5 minutes. 8 mg of 60% sodium hydride and 26 μl of methyl iodide were added to the reaction solution, and the reaction solution was stirred at 130° C. for 10 minutes, and furthermore 17 mg of 60% sodium hydride and 26 μl of methyl iodide were added, and the mixture was stirred at 130° C. for 10 minutes. The reaction solution was added with water and subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 62 mg of the objective compound as pale yellow oil. 
       Step 2 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 2 -methyl-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
       [1079]    60 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-N-methyl-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine, 18 mg of 2-aminopyrazine, 16 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 24 mg of sodium t-butoxide and 9 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2 ml of degassed toluene, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 60 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 2 -methyl-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow oil. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 29 mg of the objective compound as pale yellow powder. 
         [1080]    MS (ESI) m/z 404 (M+H) 
         [1081]    Elemental analysis value (as C 22 H 22 FN 7  HCl+2.2H 2 O) 
         [1082]    Calculated value (%) C, 55.10; H, 5.76; N, 20.45. 
         [1083]    Found value (%) C, 55.27; H, 5.44; N, 20.09. 
       Example 140 
     (S)-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanol 
       [1084]    100 mg of methyl (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) isonicotinate was dissolved in 1 ml of tetrahydrofuran, 20 mg of lithium aluminum hydride was added by small portions, and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with tetrahydrofuran, and then cooled to 0° C., and 25 μl of water, 25 μl of 2N sodium hydroxide aqueous solution, and further 75 μl of water were added, and the reaction mixture was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 60 mg of the objective compound as pale yellow powder. 
         [1085]    MS (ESI) m/z 340 (M+H) 
       Example 141 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) isonicotinic acid 
       [1086]    To 500 mg of methyl (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) isonicotinate (Example 134), was added 5 ml of methanol, and 2.7 ml of 2N sodium hydroxide aqueous solution was added subsequently, and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with ethyl acetate and water, and subjected to extraction, and 2N hydrochloric acid was added to the aqueous layer. The precipitated solid was filtered, and dried under reduced pressure to obtain 160 mg of the objective compound as white powder. 
         [1087]    MS (ESI) m/z 354 (M+H) 
       Example 142 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(2-methoxyethoxy)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
       [1088]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(2-methoxyethoxy)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine was obtained by the same process as in Example 12 using 2-methoxyethanol instead of ethylene glycol. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [1089]    MS (ESI) m/z 384 (M+H) 
       Example 143 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) pyrimidine-4-carbonitrile 
       [1090]    To 500 mg of (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl) pyrimidine-2,4-diamine (Example 9), 197 mg of zinc cyanide, 66 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and 66 mg of tris(dibenzylideneacetone)dipalladium was added a mixed solution of dimethylformamide and water (99/1), and the solution was bubbled with argon gas for three minutes, and subjected to microwave irradiation at 150° C. for 15 minutes. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 323 mg of the objective compound as pale yellow powder. 
         [1091]    MS (ESI) m/z 336 (M+H) 
       Example 144 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) isonicotinonitrile 
       [1092]    The objective compound was obtained as pale yellow powder by the same process as in Example 143 using (S)-4-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine instead of (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 9). 
         [1093]    MS (ESI) m/z 335 (M+H) 
       Example 145 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) isonicotinamide 
       [1094]    To 500 mg of (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) isonicotinic acid (Example 141), was added 15 ml of 7N ammonia/methanol solution and the mixture was stirred at 100° C. for 3 days in a sealed tube. The solvent of the reaction solution was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 310 mg of the objective compound as pale yellow powder. 
         [1095]    MS (ESI) m/z 353 (M+H) 
       Example 146 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(1,2,4-oxadiazol-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
       [1096]    150 mg of (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) pyrimidine-4-carbonitrile (Example 143) was dissolved in 5 ml of anhydrous ethanol, and 156 mg of hydroxyamine hydrochloride and 309 μl of triethylamine were added, and the mixture was refluxed for 2 hours. The reaction solution was diluted with water, and the mixture was subjected to extraction with ethyl acetate, and the organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 140 mg of a brown amorphous solid. To the reaction solution, 5 ml of triethyl orthoformate and 7 mg of p-toluenesulfonic acid were added, and the mixture was stirred at 60° C. for 4 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 141 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(1,2,4-oxadiazol-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 67 mg of the objective compound as yellow powder. 
         [1097]    MS (ESI) m/z 379 (M+H) 
         [1098]    Elemental analysis value (as C 18 H 15 FN 8 O HCl) 
         [1099]    Calculated value (%) C, 52.12; H, 3.89; N, 27.01. 
         [1100]    Found value (%) C, 52.33; H, 3.97; N, 26.90. 
       Example 147 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(1,2,4-oxadiazol-3-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
       [1101]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(1,2,4-oxadiazol-3-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine was obtained by the same process as in Example 146 using (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) isonicotinonitrile instead of (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-carbonitrile. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [1102]    MS (ESI) m/z 378 (M+H) 
       Example 148 
     Methyl 
     (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) nicotinate 
     Step 1 
     Methyl 
     (S)-6-chloro-2-[1-(4-fluorophenyl)ethylamino]nicotinate 
       [1103]    5.0 g of methyl 2,6-dichloronicotinate was dissolved in 50 ml of dimethylformamide, and 4.39 g of (S)-(−)-1-(4-fluorophenyl)ethylamine, 6.27 g of diisopropylethylamine and 150 mg of 4-dimethylaminopyridine were added thereto, and the mixture was stirred at 60° C. for 24 hours. The reaction solution was cooled, and then diluted with ethyl acetate, and washed in turn with water and brine, and the organic layer was dried, over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 2.83 g of the objective compound as white powder. 
       Step 2 
     Methyl 
     (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) nicotinate 
       [1104]    2.83 g of methyl (S)-6-chloro-2-[1-(4-fluorophenyl)ethylamino]nicotinate, 870 mg of 2-aminopyrazine, 1.06 g of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 4.09 g of tripotassium phosphate and 475 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 15 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 3.14 g of the objective compound as orange powder. 
         [1105]    MS (ESI) m/z 368 (M+H) 
       Example 149 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)isonicotinamide 
       [1106]    70 mg of (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) isonicotinic acid (Example 141) was dissolved in 0.5 ml of dimethylformamide, 81 mg of dimethylamine hydrochloride, 37 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 32 mg of 1-hydroxy-7-azabenzotriazole, and 0.18 ml of diisopropylethylamine were added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off, and then the obtained residue was purified by silica gel column chromatography to obtain 45 mg of the objective compound as pale yellow powder. 
         [1107]    MS (ESI) m/z 381 (M+H) 
       Example 150 
     (S)—N-[2-(Dimethylamino)ethyl]-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide 
       [1108]    The objective compound was obtained as pale yellow powder by the same process as in Example 149 using N,N-dimethylethylenediamine instead of dimethylamine hydrochloride. 
         [1109]    MS (ESI) m/z 424 (M+H) 
       Example 151 
     (S)—N-t-Butyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide 
       [1110]    The objective compound was obtained as white powder by the same process as in Example 149 using t-butylamine instead of dimethylamine hydrochloride. 
         [1111]    MS (ESI) m/z 409 (M+H) 
       Example 152 
     (S)—N-Ethyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide 
       [1112]    To a dimethylformamide solution of 450 mg of (S)=2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) isonicotinic acid (Example 141) and 2.2 ml of diisopropylamine was added 1.32 g of 1H-benzotriazol-1-yloxy tripyrrolidinophosphonium hexafluorophosphate, and the mixture was stirred for 15 minutes. 520 mg of ethylamine hydrochloride was added thereto, and the mixture was stirred for 2 days. The reaction solution was diluted with ethyl acetate, and the organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off, and then the obtained residue was purified by silica gel column chromatography to obtain 390 mg of the objective compound as pale yellow powder. 
         [1113]    MS (ESI) m/z 381 (M+H) 
       Example 153 
     (S)-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}[4-(methanesulfonyl)piperazin-1-yl]methanone 
       [1114]    The objective compound was obtained as pale yellow powder by the same process as in Example 152 using 1-methanesulfonylpiperazine instead of ethylamine hydrochloride. 
         [1115]    MS (ESI) m/z 500 (M+H) −   
       Example 154 
     (S)-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}(pyrrolidin-1-yl)methanone 
       [1116]    As a by-product of Example 153, (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}(pyrrolidin-1-yl)methanone was obtained as pale yellow powder. 
         [1117]    MS (ESI) m/z 407 (M+H) 
       Example 155 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-N-isopropyl-6-(pyrazin-2-ylamino)isonicotinamide 
       [1118]    The objective compound was obtained as pale yellow powder by the same process as in Example 149 using isopropylamine instead of dimethylamine hydrochloride. 
         [1119]    MS (ESI) m/z 395 (M+H) 
       Example 156 
     (S)-1-{2-[(S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-2-carboxamide 
       [1120]    The objective compound was obtained as brown powder by the same process as in Example 1 using (S)-azetidine-2-carboxamide (synthesized according to the method described in Chem. Pharm. Bull., 1998, 787-796) instead of piperazin-2-one, and using 1,4-dioxane as a reaction solvent in Step 2. 
         [1121]    MS (ESI) m/z 409 (M+H) −   
       Example 157 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(tetrahydro-2H-pyran-4-yloxy)pyridine-2,6-diamine hydrochloride 
       [1122]    (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(tetrahydro-2H-pyran-4-yloxy)pyridine-2,6-diamine was obtained by the same process as in Example 138 using tetrahydro-2H-pyran-4-ol instead of cyclopropylcarbinol. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [1123]    MS (ESI) m/z 410 (M+H) +   
       Example 158 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide 
       [1124]    The objective compound was obtained as brown powder by the same process as in Example 1 using 3-azetidine carboxamide instead of piperazin-2-one, and using 1,4-dioxane as a reaction solvent in Step 2. 
         [1125]    MS (ESI) m/z 409 (M+H) −   
       Example 159 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-N-(2-hydroxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide 
       [1126]    The objective compound was obtained as red-brown powder by the same process as in Example 149 using 2-hydroxyethylamine instead of dimethylamine hydrochloride. 
         [1127]    MS (ESI) m/z 397 (M+H) 
       Example 160 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)isonicotinamide 
       [1128]    The objective compound was obtained as pale yellow powder by the same process as in Example 149 using methylamine hydrochloride instead of dimethylamine hydrochloride. 
         [1129]    MS (ESI) m/z 367 (M+H) 
       Example 161 
     (S)-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}(morpholino)methanone 
       [1130]    The objective compound was obtained as pale yellow powder by the same process as in Example 149 using morpholine instead of dimethylamine hydrochloride. 
         [1131]    MS (ESI) m/z 423 (M+H) 
       Example 162 
     (S)—N-Benzyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide hydrochloride 
       [1132]    (S)—N-Benzyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide was obtained by the same process as in Example 152 using benzylamine instead of ethylamine hydrochloride. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as yellow powder. 
         [1133]    MS (ESI) m/z 443 (M+H) 
       Example 163 
     (S)—N-Cyclopropyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide 
       [1134]    The objective compound was obtained as pale yellow powder by the same process as in Example 149 using cyclopropylamine instead of dimethylamine hydrochloride. 
         [1135]    MS (ESI) m/z 393 (M+H) 
       Example 164 
     (S)-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}(4-methylpiperazin-1-yl)methanone hydrochloride 
       [1136]    (S)-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}(4-methylpiperazin-1-yl)methanone was obtained by the same process as in Example 152 using 1-methylpiperazine instead of ethylamine hydrochloride. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as yellow powder. 
         [1137]    MS (ESI) m/z 436 (M+H) 
       Example 165 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-N-(2-methoxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide 
       [1138]    The objective compound was obtained as yellow powder by the same process as in Example 152 using methoxyethylamine instead of ethylamine hydrochloride. 
         [1139]    MS (ESI) m/z 411 (M+H) 
       Example 166 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-N-propyl-6-(pyrazin-2-ylamino)isonicotinamide 
       [1140]    The objective compound was obtained as pink powder by the same process as in Example 152 using 1-propylamine instead of ethylamine hydrochloride. 
         [1141]    MS (ESI) m/z 395 (M+H) 
       Example 167 
     (S)—N-Cyclopropylmethyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide 
       [1142]    The objective compound was obtained as pale yellow powder by the same process as in Example 152 using cyclopropylmethylamine instead of ethylamine hydrochloride. 
         [1143]    MS (ESI) m/z 407 (M+H) 
       Example 168 
     (S)—N-Cyclobutyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide 
       [1144]    The objective compound was obtained as red-brown powder by the same process as in Example 152 using cyclobutylamine instead of ethylamine hydrochloride. 
         [1145]    MS (ESI) m/z 407 (M+H) 
       Example 169 
     (S)—N-Butyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide 
       [1146]    The objective compound was obtained as yellow powder by the same process as in Example 152 using n-butylamine instead of ethylamine hydrochloride. 
         [1147]    MS (ESI) m/z 409 (M+H) 
       Example 170 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-N-isobutyl-6-(pyrazin-2-ylamino)isonicotinamide 
       [1148]    The objective compound was obtained as pale yellow powder by the same process as in Example 152 using isobutylamine instead of ethylamine hydrochloride. 
         [1149]    MS (ESI) m/z 409 (M+H) 
       Example 171 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)-N-(2,2,2-trifluoroethyl)isonicotinamide 
       [1150]    The objective compound was obtained as pale yellow powder by the same process as in Example 152 using 2,2,2-trifluoroethylamine instead of ethylamine hydrochloride. 
         [1151]    MS (ESI) m/z 435 (M+H) 
       Example 172 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-N-(3-hydroxypropyl)-6-(pyrazin-2-ylamino)isonicotinamide 
       [1152]    The objective compound was obtained as yellow powder by the same process as in Example 152 using 3-hydroxy propylamine instead of ethylamine hydrochloride. 
         [1153]    MS (ESI) m/z 411 (M+H) −   
       Example 173 
     (S)—N-(2-Ethoxyethyl)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide 
       [1154]    The objective compound was obtained as yellow powder by the same process as in Example 152 using 2-ethoxyethylamine instead of ethylamine hydrochloride. 
         [1155]    MS (ESI) m/z 425 (M+H) −   
       Example 174 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-methylazetidin-3-carboxamide 
     Step 1 
     1-Benzhydryl-N-methylazetidine-3-carboxamide 
       [1156]    400 mg of 1-benzhydrylazetidin-3-carboxylic acid (synthesized according to the method described in WO2005/49602) was dissolved in 4 ml of dimethylformamide, and 683 mg of triethylamine, 122 mg of methylamine hydrochloride, 304 mg of 1-hydroxybenzotriazole and 431 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 158 mg of the objective compound. 
       Step 2 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-methylazetidine-3-carboxamide 
       [1157]    150 mg of 1-benzhydryl-N-methylazetidin-3-carboxamide was dissolved in 6 ml of methanol, 535 μl of 4N hydrogen chloride ethyl acetate solution and 150 mg of 20% palladium hydroxide were added thereto, and the mixture was subjected to hydrogenation under 4 atmospheric pressures at room temperature overnight. Palladium hydroxide was filtered off, and the filtrate was concentrated under reduced pressure to obtain 150 mg of pale yellow oil. 81 mg of the obtained compound was dissolved in 5 ml of degassed 1,4-dioxane, and 81 mg of triethylamine, 184 mg of (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine, 51 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 103 mg of sodium t-butoxide and 55 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn thereto, and the mixture was stirred at 90° C. for 3.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate, and was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 24 mg of (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-methylazetidine-3-carboxamide as yellow powder. 
         [1158]    MS (ESI) m/z 423 (M+H) 
       Example 175 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(methoxymethyl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [1159]    20 mg of (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanol (Example 140) was dissolved in methylene chloride, and 59 mg of carbon tetrabromide and 47 mg of triphenylphosphine were added under ice-cooling, and the mixture was stirred for 30 minutes. Subsequently, 90 μl of 9.8M sodium methoxide/methanol solution was added thereto, and the mixture was stirred overnight. The reaction solution was diluted with ethyl acetate and was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled of f under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 7 mg of the objective compound as yellow powder. 
         [1160]    MS (ESI) m/z 354 (M+H) 
       Example 176 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N,N-dimethylazetidin-3-carboxamide 
       [1161]    The objective compound was obtained as white powder by the same process as in Example 174 using dimethylamine hydrochloride instead of methylamine hydrochloride. 
         [1162]    MS (ESI) m/z 437 (M+H) 
       Example 177 
     (S)—N-(1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-yl}azetidin-3-yl)methanesulfonamide 
       [1163]    100 mg of 1-(t-butoxycarbonyl)-3-aminoazetidine was dissolved in 5 ml of methylene chloride, and 225 mg of diisopropylethylamine was added thereto. Subsequently, 100 mg of methanesulfonyl chloride was added under ice-cooling, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with 5% citric acid aqueous solution and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 199 mg of colorless oil. The obtained oil was dissolved in 2.5 ml of methylene chloride, and 1 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure to obtain yellow oil. The obtained oil was dissolved in 6 ml of degassed 1,4-dioxane, and 200 mg of (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine, 55 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 111 mg of sodium t-butoxide, 294 mg of triethylamine and 60 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn, and the mixture was stirred at 90° C. for 3 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 12 mg of the objective compound as pale yellow powder. 
         [1164]    MS (ESI) m/z 459 (M+H) 
       Example 178 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carbonitrile 
       [1165]    216 mg of 1-(t-butoxycarbonyl)-3-cyanoazetidine was dissolved in 2.5 ml of methylene chloride, and 1 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure to obtain brown oil. The obtained oil was dissolved in 4 ml of degassed 1,4-dioxane, and 302 mg of triethylamine, 205 mg of (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine, 57 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 229 mg of sodium t-butoxide and 62 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn, and the mixture was stirred at 90° C. for 3 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 58 mg of the objective compound as pale yellow powder. 
         [1166]    MS (ESI) m/z 391 (M+H) 
       Example 179 
     2-(4-Fluorophenyl)-2-[4-(1-methyl-1H-pyrazol-4-yl)-6-(pyrazin-2-ylamino)pyridin-2-ylamino]ethanol 
     Step 1 
     4-(4-Fluorophenyl)oxazolidin-2-one 
       [1167]    600 mg of 2-amino-2-(4-fluorophenyl)ethan-1-ol and 80 mg of potassium carbonate were suspended in 914 mg of diethyl carbonate, and the mixture was stirred at 130° C. for 2.5 hours, and further stirred at 100° C. for 2.5 hours while removing the ethanol that was generated. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 610 mg of the objective compound as pale yellow oil. 
       Step 2 
     3-[6-Chloro-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]-4-(4-fluorophenyl)oxazolidin-2-one 
       [1168]    379 mg of 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine, 300 mg of 4-(4-fluorophenyl)oxazolidin-2-one, 192 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 705 mg of tripotassium phosphate and 172 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 10 ml of degassed 1,4-dioxane, and the mixture was stirred at 90° C. for 5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 212 mg of the objective compound as yellow powder. 
       Step 3 
     2-(4-Fluorophenyl)-2-[4-(1-methyl-1H-pyrazol-4-yl)-6-(pyrazin-2-ylamino)pyridin-2-ylamino]ethanol 
       [1169]    80 mg of 3-[6-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]-4-(4-fluorophenyl)oxazolidin-2-one, 20 mg of 2-aminopyrazine, 20 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, mg of sodium t-butoxide and 22 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2.5 ml of degassed 1,4-dioxane, and the mixture was stirred at 90° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 34 mg of the objective compound as white powder. 
         [1170]    MS (ESI) m/z 406 (M+H) 
       Example 180 
     (S)—N-Ethyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide 
       [1171]    The objective compound was obtained as pale yellow powder by the same process as in Example 174 using ethylamine hydrochloride instead of methylamine hydrochloride. 
         [1172]    MS (ESI) m/z 437 (M+H) 
       Example 181 
     (S)—N,N-Diethyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide 
       [1173]    The objective compound was obtained as white powder by the same process as in Example 174 using diethylamine instead of methylamine hydrochloride. 
         [1174]    MS (ESI) m/z 465 (M+H) −   
       Example 182 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}ethanone hydrochloride 
     Step 1 
     (S)-1-{2-Chloro-6-[1-(4-fluorophenyl)ethylamino]pyridin-4-yl}ethanone 
       [1175]    535 mg of 1-(2,6-dichloropyridin-4-yl)ethanone (Steps 1 and 2 of Example 29), 391 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 262 mg of (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1.28 g of cesium carbonate and 63 mg of palladium acetate were added in turn to 10 ml of degassed toluene, and the mixture was stirred at 100° C. for 3 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 132 mg of the objective compound as pale yellow powder. 
         [1176]    MS (ESI) m/z 293 (M+H) 
       Step 2 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}ethanone hydrochloride 
       [1177]    150 mg of (S)-1-{2-chloro-6-[1-(4-fluorophenyl)ethylamino]pyridin-4-yl}ethanone, 51 mg of 2-aminopyrazine, 49 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 59 mg of sodium t-butoxide and 23 mg of tris(dibenzylideneacetone)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 20 minutes under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 77 mg of (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}ethanone. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as yellow powder. 
         [1178]    MS (ESI) m/z 352 (M+H) 
         [1179]    Elemental analysis value (as C 19 H 18 FN 5 O HCl+0.8H 2 O) 
         [1180]    Calculated value (%) C, 56.73; H, 5.16; N, 17.41. 
         [1181]    Found value (%) C, 57.06; H, 5.20; N, 17.02. 
       Example 183 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(3-methoxyazetidin-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine hydrochloride 
       [1182]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(3-methoxyazetidin-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine was obtained by the same process as in Example 1 using 3-methoxyazetidine hydrochloride instead of piperazin-2-one. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [1183]    MS (ESI) m/z 396 (M+H) 
         [1184]    Elemental analysis value (as C 20 H 22 FN 7 O HCl+0.3H 2 O) 
         [1185]    Calculated value (%) C, 54.93; H, 5.44; N, 22.42. 
         [1186]    Found value (%) C, 55.14; H, 5.44; N, 22.16. 
       Example 184 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-methylazetidin-3-ol hydrochloride 
       [1187]    (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-methylazetidin-3-ol was obtained by the same process as in Example 1 using 3-methylazetidin-3-ol hydrochloride instead of piperazin-2-one. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [1188]    MS (ESI) m/z 396 (M+H) −   
       Example 185 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)nicotinamide 
     Step 1 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) nicotinic acid 
       [1189]    1.0 g of methyl (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) nicotinate was dissolved in 60 ml of methanol, and 20 ml of 10% sodium hydroxide aqueous solution was added thereto, and the reaction solution was heated at reflux for 4 hours. The reaction solution was distilled off under reduced pressure to remove methanol. The obtained aqueous layer was washed with diethyl ether, and the pH of the mixture was adjusted to 3 by 10% hydrochloric acid. The precipitated solid was filtered, and washed with water. The obtained solid was dried under reduced pressure to obtain 880 mg of the objective compound as pale yellow powder. 
       Step 2 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)nicotinamide 
       [1190]    80 mg of (S)-2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) nicotinic acid was dissolved in 1 ml of tetrahydrofuran, 86 mg of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate salt (HBTU) and 59 mg of triethylamine were added thereto. The mixture was stirred at room temperature for 30 minutes, and then 119 μl of 2M methylamine/tetrahydrofuran solution was added thereto, and the mixture was stirred for 5 hours. The reaction solution was purified by silica gel column chromatography to obtain 45 mg of the objective compound as white powder. 
         [1191]    MS (ESI) m/z 367 (M+H) 
       Example 186 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)nicotinamide 
       [1192]    The objective compound was obtained as white powder by the same process as in Example 185 using dimethylamine hydrochloride instead of 2M methylamine/tetrahydrofuran solution. 
         [1193]    MS (ESI) m/z 381 (M+H) 
       Example 187 
     (S)-2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) nicotinamide 
       [1194]    2 ml of oxalyl chloride was added to 82 mg of (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) nicotinic acid (Step 1 of Example 185), and the mixture was heated at reflux for 30 minutes. The reaction solution was concentrated under reduced pressure, and 5 ml of concentrated ammonia aqueous solution was added to the obtained residue, and the mixture was stirred at 100° C. for 30 minutes. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 13 mg of the objective compound as brown powder. 
         [1195]    MS (ESI) m/z 353 (M+H) 
       Example 188 
     (S)-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-3-yl}(morpholino)methanone dihydrochloride 
       [1196]    (S)-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-3-yl}(morpholino)methanone was obtained by the same process as in Example 185 using morpholine instead of 2M methylamine/tetrahydrofuran solution. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as white powder. 
         [1197]    MS (ESI) m/z 423 (M+H) 
         [1198]    Elemental analysis value (as C 22 H 23 FN 6 O 2  2HCl) 
         [1199]    Calculated value (%) C, 53.34; H, 5.09; N, 16.96. 
         [1200]    Found value (%) C, 53.18; H, 4.86; N, 16.99. 
       Example 189 
     (S)—N-(Cyclopropylmethyl)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)nicotinamide 
       [1201]    The objective compound was obtained as white powder by the same process as in Example 185 using cyclopropylmethylamine instead of 2M methylamine/tetrahydrofuran solution. 
         [1202]    MS (ESI) m/z 407 (M+H) 
       Example 190 
     (S)—N-(1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-yl}azetidin-3-yl)ethanesulfonamide 
       [1203]    The objective compound was obtained as pale orange powder by the same process as in Example 177 using ethanesulfonyl chloride instead of methanesulfonyl chloride. 
         [1204]    MS (ESI) m/z 473 (M+H) 
       Example 191 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-isopropylazetidine-3-carboxamide 
       [1205]    The objective compound was obtained as pale yellow powder by the same process as in Example 174 using isopropylamine instead of methylamine hydrochloride. 
         [1206]    MS (ESI) m/z 451 (M+H) 
       Example 192 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-(trifluoromethyl)azetidin-3-ol hydrochloride 
       [1207]    (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-(trifluoromethyl)azetidin-3-ol was obtained by the same process as in Example 1 using 3-(trifluoromethyl)azetidin-3-ol hydrochloride (synthesized according to the method described in US2007/275930) instead of piperazin-2-one. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder. 
         [1208]    MS (ESI) m/z 450 (M+H) 
         [1209]    Elemental analysis value (as C 20 H 19 F 4 N 7 O HCl+H 2 O) 
         [1210]    Calculated value (%) C, 47.67; H, 4.40; N, 19.46. 
         [1211]    Found value (%) C, 48.05; H, 4.11; N, 19.23. 
       Example 193 
     (S)-(1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)(pyrrolidin-1-yl)methanone 
       [1212]    The objective compound was obtained as white powder by the same process as in Example 174 using pyrrolidine instead of methylamine hydrochloride. 
         [1213]    MS (ESI) m/z 463 (M+H) 
       Example 194 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(2-methoxyethyl)azetidine-3-carboxamide 
       [1214]    The objective compound was obtained as white powder by the same process as in Example 174 using 2-methoxyethylamine instead of methylamine hydrochloride. 
         [1215]    MS (ESI) m/z 467 (M+H) −   
       Example 195 
     (S)-(1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)(piperidin-1-yl)methanone 
       [1216]    The objective compound was obtained as white powder by the same process as in Example 174 using piperidine instead of methylamine hydrochloride. 
         [1217]    MS (ESI) m/z 477 (M+H) 
       Example 196 
     (S)-(1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)(morpholino)methanone 
       [1218]    The objective compound was obtained as white powder by the same process as in Example 174 using morpholine instead of methylamine hydrochloride. 
         [1219]    MS (ESI) m/z 479 (M+H) 
       Example 197 
     (S)—N-(Cyclopropyl)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide 
       [1220]    The objective compound was obtained as white powder by the same process as in Example 174 using cyclopropylamine instead of methylamine hydrochloride. 
         [1221]    MS (ESI) m/z 449 (M+H) 
       Example 198 
     (S)—N-(Cyclopropylmethyl)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide 
       [1222]    The objective compound was obtained as white powder by the same process as in Example 174 using cyclopropylmethylamine instead of methylamine hydrochloride. 
         [1223]    MS (ESI) m/z 463 (M+H) 
       Example 199 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(2-hydroxyethyl)azetidine-3-carboxamide 
       [1224]    The objective compound was obtained as pale yellow powder by the same process as in Example 174 using 2-hydroxy ethylamine instead of methylamine hydrochloride. 
         [1225]    MS (ESI) m/z 453 (M+H) 
       Example 200 
     (S)-3-Cyclopropyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-ol hydrochloride 
       [1226]    (S)-3-Cyclopropyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-ol was obtained by the same process as in Example 1 using 3-cyclopropylazetidin-3-ol hydrochloride (synthesized according to the method described in US2007/275930) instead of piperazin-2-one. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [1227]    MS (ESI) m/z 422 (M+H) 
         [1228]    Elemental analysis value (as C 22 H 24 FN 7 O HCl+0.5H 2 O) 
         [1229]    Calculated value (%) C, 56.59; H, 5.61; N, 21.00. 
         [1230]    Found value (%) C, 56.35; H, 5.24; N, 20.97. 
       Example 201 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-isopropylazetidin-3-ol hydrochloride 
       [1231]    (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-isopropylazetidin-3-ol was obtained by the same process as in Example 1 using 3-isopropylazetidin-3-ol hydrochloride (synthesized according to the method described in US2007/275930) instead of piperazin-2-one. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [1232]    MS (ESI) m/z 424 (M+H) 
         [1233]    Elemental analysis value (as C 22 H 26 FN 7 O HCl+0.4H 2 O) 
         [1234]    Calculated value (%) C, 56.56; H, 6.00; N, 20.99. 
         [1235]    Found value (%) C, 56.81; H, 5.82; N, 20.94. 
       Example 202 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-ol hydrochloride 
       [1236]    100 mg of 3-hydroxyazetidine hydrochloride was dissolved in 2 ml of methanol, and 43 mg of sodium t-butoxide was added thereto, and the solvent was distilled off under reduced pressure. 4 ml of degassed 1,4-dioxane was added to the obtained residue, and subsequently 105 mg of (S)-4-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine (Reference Example 2), 57 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 96 mg of sodium t-butoxide and 32 mg of tris (dibenzylideneacetone)(chloroform)dipalladium were added in turn, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with a saturated aqueous solution of ammonium chloride and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 78 mg of (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-ol. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 60 mg of the objective compound as brown powder. 
         [1237]    MS (ESI) m/z 381 (M+H) 
       Example 203 
     (S)-3-Cyclopropyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-01 hydrochloride 
       [1238]    (S)-3-Cyclopropyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-ol was obtained by the same process as in Example 202 using 3-cyclopropylazetidin-3-ol hydrochloride instead of 3-hydroxyazetidine hydrochloride. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [1239]    MS (ESI) m/z 421 (M+H) 
       Example 204 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-isopropylazetidin-3-ol hydrochloride 
       [1240]    (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-isopropylazetidin-3-ol was obtained by the same process as in Example 202 using 3-isopropylazetidin-3-ol hydrochloride instead of 3-hydroxyazetidine hydrochloride, and using toluene instead of 1,4-dioxane as a solvent. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [1241]    MS (ESI) m/z 423 (M+H) 
       Example 205 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-methylazetidin-3-ol hydrochloride 
       [1242]    (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-methylazetidin-3-ol was obtained by the same process as in Example 202 using 3-methylazetidin-3-ol hydrochloride instead of 3-hydroxyazetidine hydrochloride, and using toluene instead of 1,4-dioxane as a solvent. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [1243]    MS (ESI) m/z 395 (M+H) −   
       Example 206 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-(trifluoromethyl)azetidin-3-ol hydrochloride 
       [1244]    (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-(trifluoromethyl)azetidin-3-ol was obtained by the same process as in Example 202 using 3-(trifluoromethyl)azetidin-3-ol hydrochloride instead of 3-hydroxyazetidine hydrochloride, and using toluene instead of 1,4-dioxane as a solvent. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [1245]    MS (ESI) m/z 449 (M+H) 
       Example 207 
     (S)-4-(3,3-Difluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
       [1246]    (S)-4-(3,3-Difluoroazetidin-1-yl)-N 7 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine was obtained by the same process as in Example 202 using 3,3-difluoroazetidine hydrochloride instead of 3-hydroxyazetidine hydrochloride, and using toluene instead of 1,4-dioxane as a solvent. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [1247]    MS (ESI) m/z 401 (M+H) 
       Example 208 
     (S)—N-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}acetamide 
     Step 1 
     t-Butyl 2,6-dichloropyridin-4-yl carbamate 
       [1248]    1.0 g of 2,6-dichloroisonicotinic acid was dissolved in 20 ml of t-butylalcohol, and 0.87 ml of triethylamine and 1.2 ml of diphenylphosphorylazide were added thereto, and the mixture was heated at reflux overnight. The solvent of the reaction mixture was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 969 mg of the objective compound as white powder. 
       Step 2 
       [1249]    t-Butyl 
       (S)-2-chloro-6-[1-(4-fluorophenyl)ethylamino]pyridin-4-yl carbamate 
       [1250]    390 mg of t-butyl 2,6-dichloropyridin-4-yl carbamate, 220 μl of (S)-(−)-1-(4-fluorophenyl)ethylamine, 243 mg of bis[2-(diphenylphosphino)phenyl]ethyl ether, 199 mg of sodium t-butoxide and 67 mg of palladium acetate were added in turn to 10 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 10 hours under argon atmosphere. 118 μl of acetic acid was added to the reaction solution, and then the mixture was diluted with ethyl acetate. The reaction mixture was filtrated by celite to remove precipitates, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 210 mg of the objective compound as a white amorphous solid. 
       Step 3 
       [1251]    t-Butyl 
       (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) pyridin-4-yl carbamate 
       [1252]    195 mg of t-butyl (S)-2-chloro-6-[1-(4-fluorophenyl)ethylamino]pyridin-4-yl carbamate, 61 mg of 2-aminopyrazine, 152 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 71 mg of sodium t-butoxide and 73 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 10 ml of degassed toluene, and the mixture was stirred at 100° C. overnight under argon atmosphere. 43 μl of acetic acid was added to the reaction solution, and then the mixture was diluted with ethyl acetate. The reaction mixture was filtrated by celite to remove precipitates, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 203 mg of the objective compound as a pale yellow amorphous solid. 
       Step 4 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,4,6-triamine 
       [1253]    210 mg of t-butyl (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) pyridin-4-yl carbamate was dissolved in 3 ml of methylene chloride, and 1 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into an ice-cooled saturated aqueous solution of sodium bicarbonate, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 151 mg of the objective compound as a pale yellow amorphous solid. 
       Step 5 
     (S)—N-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}acetamide 
       [1254]    50 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,4,6-triamine was dissolved in 1 ml of methylene chloride, and 43 μl of triethylamine, 22 μl of acetic anhydride and 1 mg of 4-dimethylaminopyridine were added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water. The solution was subjected to extraction with ethyl acetate, and the organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 32 mg of the objective compound as yellow powder. 
         [1255]    MS (ESI) m/z 367 (M+H) −   
       Example 209 
     (S)—N-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanesulfonamide hydrochloride 
       [1256]    (S)—N-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanesulfonamide was obtained by the same process as in Step 5 of Example 208, using methanesulfonic anhydride instead of acetic anhydride. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as yellow powder. 
         [1257]    MS (ESI) m/z 403 (M+H) +   
       Example 210 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}urea 
       [1258]    50 mg of (8)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,4,6-triamine was dissolved in 2 ml of methylene chloride, and 49 mg of N,N′-carbonyldiimidazole was added thereto, and the mixture was stirred at room temperature overnight. A saturated ammonia methanol solution was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 23 mg of the objective compound as pale yellow powder. 
         [1259]    MS (ESI) m/z 368 (M+H) 
       Example 211 
     (S)-4-(3-Cyclopropyl-3-methoxyazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
     Step 1 
     1-Benzhydryl-3-cyclopropylazetidin-3-ol 
       [1260]    300 mg of 1-benzhydrylazetidin-3-one dissolved in 3.8 ml of tetrahydrofuran was added to 2 ml of 1M cyclopropyl magnesium bromide/tetrahydrofuran solution under ice water cooling, and the mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction solution was poured into a saturated aqueous solution of sodium carbonate and the mixture was subjected to extraction with diethyl ether, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 334 mg of the objective compound. 
       Step 2 
     1-Benzhydryl-3-cyclopropyl-3-methoxyazetidine 
       [1261]    334 mg of 1-benzhydryl-3-cyclopropylazetidin-3-ol was dissolved in dimethylformamide, and 72 mg of 60% sodium hydride was added thereto, and the mixture was stirred at room temperature for 30 minutes. 112 μl of methyl iodide was added thereto, and the mixture was further stirred at room temperature for 2 hours. To the reaction solution was added water and the mixture was subjected to extraction with diethyl ether, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 280 mg of the objective compound. 
       Step 3 
     (S)-4-(3-Cyclopropyl-3-methoxyazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
       [1262]    275 mg of 1-benzhydryl-3-cyclopropyl-3-methoxyazetidine was dissolved in 15 ml of methanol, and 0.70 ml of 2N hydrochloric acid and 150 mg of 20% palladium hydroxide were added thereto, and the mixture was stirred at room temperature overnight under hydrogen pressure of 3.5 kgf/cm 2 . The reaction mixture was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure to obtain 146 mg of white powder. 62 mg of the obtained compound was dissolved in 2 ml of methanol, and 41 mg of sodium t-butoxide was added thereto, and the solvent was distilled off under reduced pressure. 4 ml of degassed toluene was added to the residue, and then 100 mg of (S)-4-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine (Reference Example 2), 55 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 41 mg of sodium t-butoxide and 27 mg of tris(dibenzylideneacetone) dipalladium were added in turn, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with a saturated aqueous solution of ammonium chloride and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 47 mg of (S)-4-(3-cyclopropyl-3-methoxyazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [1263]    MS (ESI) m/z 435 (M+H) −   
       Example 212 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(3-isopropyl-3-methoxyazetidin-1-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
       [1264]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(3-isopropyl-3-methoxyazetidin-1-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine was obtained by the same process as in Example 211, using 0.79M isopropyl magnesium bromide/tetrahydrofuran solution instead of 1M cyclopropyl magnesium bromide/tetrahydrofuran solution. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [1265]    MS (ESI) m/z 437 (M+H) −   
       Example 213 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(3-methoxy-3-methylazetidin-1-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride 
       [1266]    (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(3-methoxy-3-methylazetidin-1-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine was obtained by the same process as in Example 211, using 3M methyl magnesium bromide/tetrahydrofuran solution instead of 1M cyclopropyl magnesium bromide/tetrahydrofuran solution. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as brown powder. 
         [1267]    MS (ESI) m/z 409 (M+H) 
       Example 214 
     (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(5-methylpyrazin-2-yl)pyridine-2,6-diamine 
       [1268]    250 mg of 2-amino-5-bromopyrazine, 0.40 ml of trimethylboroxine, 794 mg of potassium carbonate and 166 mg of tetrakis(triphenylphosphine)palladium were added in turn to 4 ml of degassed dimethylformamide, and the mixture was stirred at 110° C. under argon atmosphere overnight. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 100 mg of pale yellow oil. The obtained residue was dissolved in 6 ml of degassed toluene, and 100 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine, 29 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 41 mg of sodium t-butoxide and 14 mg of tris(dibenzylideneacetone)dipalladium were added in turn, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 90 mg of the objective compound as pale yellow powder. 
         [1269]    MS (ESI) m/z 404 (M+H) 
       Example 215 
     (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[1-(methanesulfonyl)piperidin-4-yl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
     Step 1 
       [1270]    t-Butyl 
       4-(2,6-dichloropyridin-4-yl)-5,6-dihydropyridine-1(2H)-carbamate 
       [1271]    874 mg of 2,6-dichloro-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2-yl)pyridine, 1.06 g of t-butyl 4-(trifluoromethylsulfonyl oxy)-5,6-dihydropyridine-1(2H)-carbamate, 1.33 g of potassium carbonate and 26 mg of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex were added in turn to 16 ml of degassed dimethylformamide, and the mixture was stirred at 80° C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 631 mg of the objective compound. 
       Step 2 
     2,6-Dichloro-4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]pyridine 
       [1272]    327 mg of t-butyl 4-(2,6-dichloropyridin-4-yl)-5,6-dihydropyridine-1(2H)-carbamate was dissolved in 4 ml of methylene chloride, and 2 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 2N sodium hydroxide aqueous solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 221 mg of a brown solid. The obtained solid was dissolved in 10 ml of methylene chloride, and 270 μl of triethylamine, 251 mg of methanesulfonic anhydride and 1 mg of 4-dimethylaminopyridine were added thereto, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, and then the mixture was subjected to extraction with ethyl acetate, and the organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 236 mg of the objective compound as pale brown powder. 
       Step 3 
     (S)-6-Chloro-N-[1-(4-fluorophenyl)ethyl]-4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]pyridine-2-amine 
       [1273]    225 mg of 2,6-dichloro-4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]pyridine, 104 μl of (S)-(−)-1-(4-fluorophenyl)ethylamine, 68 mg of (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 359 mg of cesium carbonate and 17 mg of palladium acetate were added in turn to 5 ml of degassed tetrahydrofuran, and the mixture was stirred at 60° C. for 10 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate, and filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 118 mg of the objective compound as pale yellow powder. 
       Step 4 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [1274]    115 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]pyridine-2-amine, 40 mg of 2-aminopyrazine, 53 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 40 mg of sodium t-butoxide and 26 mg of tris(dibenzylideneacetone) dipalladium were added in turn to 5 ml of degassed toluene, and the mixture was stirred at 100° C. for 5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 89 mg of the objective compound as pale brown powder. 
       Step 5 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-[1-(methanesulfonyl)piperidin-4-yl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [1275]    88 mg of (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine was dissolved in 5 ml of methanol, and 599 mg of ammonium formate and 18 mg of palladium hydroxide 20% on carbon were added thereto, and the mixture was heated at reflux for 3 hours. 599 mg of ammonium formate and 18 mg of palladium hydroxide 20% on carbon were added to the reaction solution, and the reaction solution was further heated at reflux for 2 hours. The reaction solution was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate. The solution was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 34 mg of the objective compound as pale yellow powder. 
         [1276]    MS (ESI) m/z 471 (M+H) 
       Example 216 
     (S)—N-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}propionamide 
       [1277]    The objective compound was obtained as a yellow amorphous solid by the same process as in Step 5 of Example 208, using propionic anhydride instead of acetic anhydride. 
         [1278]    MS (ESI) m/z 381 (M+H) 
       Example 217 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-[1-(2-methoxyethyl)-1H-Pyrazol-4-yl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [1279]    The objective compound was obtained as pale yellow powder by the same process as in Example 37 using 2-bromoethyl methyl ether instead of 2-bromopropane. 
         [1280]    MS (ESI) m/z 434 (M+H) 
       Example 218 
     (S)-4-(1-Cyclopropyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
     Step 1 
     1-Cyclopropyl-4-iodo-1H-pyrazole 
       [1281]    100 mg of pyrazole, 253 mg of cyclopropylboronic acid, and 312 mg of sodium carbonate were added to 2.5 ml of 1,2-dichloroethane, and 5 ml of 1,2-dichloroethane suspension including 267 mg of copper acetate and 230 mg of 2,2-bipyridine was added dropwise thereto, and the mixture was stirred at 70° C. for 4 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with a saturated aqueous solution of ammonium chloride, water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 148 mg of yellow oil. The obtained oil was dissolved in 3 ml of acetonitrile, 209 mg of iodine and 451 mg of diammonium cerium(IV) nitrate were added thereto under ice water cooling, and the mixture was stirred at room temperature for 5 hours. 6 ml of 5% sodium hydrogensulfite aqueous solution was added thereto, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 167 mg of the objective compound as pale yellow oil. 
       Step 2 
     (S)-4-(1-Cyclopropyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [1282]    The objective compound was obtained as pale yellow powder by the same process as in Example 37, using 1-cyclopropyl-4-iodo-1H-pyrazole instead of 4-iodo-1-isopropyl-1H-pyrazole. 
         [1283]    MS (ESI) m/z 416 (M+H) 
       Example 219 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-[1-(methoxymethyl)-1H-pyrazol-4-yl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine 
       [1284]    The objective compound was obtained as brown powder by the same process as in Example 37 using bromomethyl methyl ether instead of 2-bromopropane. 
         [1285]    MS (ESI) m/z 420 (M+H) −   
       Example 220 
     (S)-6-[3-(Dimethylamino)azetidin-1-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
     Step 1 
     (S)-1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-one 
       [1286]    156 mg of (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-ol (Example 72) was dissolved in 1 ml of dimethyl sulfoxide, and 571 μl of triethylamine was added thereto and cooled to 15° C. 0.5 ml of dimethyl sulfoxide suspension including 388 mg of pyridine-trisulfur oxide complex was added thereto, and the mixture was stirred at room temperature overnight. Ice and saturated ammonium chloride aqueous solution were added to the reaction solution, and the mixture was stirred for 15 minutes, and diluted with ethyl acetate, and the organic layer was washed with saturated ammonium chloride aqueous solution and water in turn, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 50 mg of the objective compound as a brown amorphous solid. 
         [1287]    MS (ESI) m/z 380 (M+H) 
       Step 2 
     (S)-6-[3-(Dimethylamino)azetidin-1-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
       [1288]    300 mg of (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-one was dissolved in 5 ml of 1,2-dichloroethane, and 12 ml of 2M dimethylamine/tetrahydrofuran solution and 290 μl of acetic acid were added thereto, and the mixture was stirred at room temperature for 30 minutes. 340 mg of sodium triacetoxyborohydride was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with a saturated aqueous solution of sodium bicarbonate and brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 187 mg of the objective compound as brown powder. 
         [1289]    MS (ESI) m/z 409 (M+H) 
       Example 221 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-[3-(methylamino)azetidin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
       [1290]    The objective compound was obtained as white powder by the same process as in Example 220 using 2M methylamine/tetrahydrofuran solution instead of 2M dimethylamine/tetrahydrofuran solution. 
         [1291]    MS (ESI) m/z 395 (M+H) 
       Example 222 
     (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[3-(pyrrolidin-1-yl)azetidin-1-yl]pyrimidine-2,4-diamine 
       [1292]    The objective compound was obtained as white powder by the same process as in Example 220 using pyrrolidine instead of 2M dimethylamine/tetrahydrofuran solution. 
         [1293]    MS (ESI) m/z 435 (M+H) −   
       Example 223 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-(3-morpholinoazetidin-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
       [1294]    The objective compound was obtained as white powder by the same process as in Example 220 using morpholine instead of 2M dimethylamine/tetrahydrofuran solution. 
         [1295]    MS (ESI) m/z 451 (M+H) 
       Example 224 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-6-[3-(4-methylpiperazin-1-yl)azetidin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
       [1296]    The objective compound was obtained as brown powder by the same process as in Example 220 using N-methylpiperazine instead of 2M dimethylamine/tetrahydrofuran solution. 
         [1297]    MS (ESI) m/z 464 (M+H) −   
       Example 225 
     (S)-(1-{1-[2-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)piperidin-4-ol 
       [1298]    The objective compound was obtained as white powder by the same process as in Example 220 using 4-hydroxypiperidine instead of 2M dimethylamine/tetrahydrofuran solution. 
         [1299]    MS (ESI) m/z 465 (M+H) 
       Example 226 
     4-{2-[(1S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1λ 6 ,4-thiomorpholin-1,1-dione 
     Step 1 
     4-{6-Chloro-2-[(1S)-1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}-1λ 6 , 4-thiomorpholin-1,1-dione 
       [1300]    The objective compound was obtained as a colorless amorphous solid by the same process as in Step 1 of Example 1 using thiomorpholin-1,1-dioxide instead of piperazin-2-one. 
         [1301]    MS (ESI) m/z 385 (M+H) −   
       Step 2 
     4-{2-[(1S)-1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1λ 6 ,4-thiomorpholin-1,1-dione 
       [1302]    The objective compound was obtained as a brown amorphous solid by the same process as in Step 2 of Example 1 using 4-{6-chloro-2-[(1S)-1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}-1λ 6 ,4-thiomorpholin-1,1-dione as a starting material, and using a mixed solvent of toluene/1,4-dioxane instead of toluene as a reaction solvent. 
         [1303]    MS (ESI) m/z 444 (M+H) 
       Example 227 
     (S)-1-(1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-yl}azetidin-3-yl)urea 
     Step 1 
     (S)-1-(1-{6-Chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}azetidin-3-yl)urea 
       [1304]    105 mg of t-butyl 3-(carbamoylamino)azetidin-1-carboxylate was dissolved in 2 ml of methylene chloride, and 0.5 ml of trifluoroacetic acid was added thereto, and the mixture solution was stirred at room temperature for 30 min. The solvent was distilled off under reduced pressure and then the obtained residue was dissolved in 3 ml of 1-butanol. 108 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine and 331 μl of N,N-diisopropylethylamine were added to the mixture, and the mixture was stirred at 60° C. for 20 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 89 mg of the objective compound as white powder. 
       Step 2 
     (S)-1-(1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyrimidin-4-yl}azetidin-3-yl)urea 
       [1305]    73 mg of (S)-1-(1-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}azetidin-3-yl)urea, 25 mg of 2-aminopyrazine, 38 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 29 mg of sodium t-butoxide and 18 mg of tris(dibenzylideneacetone)dipalladium were added in turn to of a degassed mixed solvent of toluene/1,4-dioxane (1/1), and the mixture was stirred at 90° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with a saturated aqueous solution of ammonium chloride and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 31 mg of the objective compound as brown powder. 
         [1306]    MS (ESI) m/z 424 (M+H) 
       Example 228 
     (S)-(1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methanol 
     Step 1 
     (S)-(1-{6-Chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}azetidin-3-yl)methanol 
       [1307]    The objective compound was obtained as white powder by the same process as in Step 1 of Example 1 using azetidin-3-yl-methanol instead of piperazin-2-one. 
         [1308]    MS (ESI) m/z 323 (M+H) 
       Step 2 
     (S)-(1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methanol 
       [1309]    The objective compound was obtained as a brown amorphous solid by the same process as in Step 2 of Example 1 using (S)-(1-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}azetidin-3-yl)methanol as a starting material, and using 1,4-dioxane instead of toluene as a reaction solvent. 
         [1310]    MS (ESI) m/z 396 (M+H) −   
       Example 229 
       [1311]    t-Butyl 
       (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methyl carbamate 
       [1312]    The objective compound was obtained as a brown amorphous solid by the same process as in Example 1 using t-butyl azetidin-3-ylmethyl carbamate instead of piperazin-2-one. 
         [1313]    MS (ESI) m/z 495 (M+H) −   
       Example 230 
     (S)-6-[3-(Aminomethyl)azetidin-1-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine 
       [1314]    80 mg of t-butyl (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methylcarbamate was dissolved in 4 ml of dichloromethane, and 0.8 ml of trifluoroacetic acid was added thereto, and the mixture solution was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 63 mg of the objective compound as a brown amorphous solid. 
         [1315]    MS (ESI) m/z 395 (M+H) 
       Example 231 
     (S)—N-[(1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methyl]ethane sulfonamide 
       [1316]    23 mg of (S)-6-[3-(aminomethyl)azetidin-1-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine was dissolved in 2 ml of 1,2-dichloroethane, and 8.1 mg of ethanesulfonyl chloride and 22 μl of N,N-diisopropylethylamine were added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 15 mg of the objective compound as a brown amorphous solid. 
         [1317]    MS (ESI) m/z 487 (M+H) 
       Example 232 
     (S)—N-[(1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methyl]acetamide 
       [1318]    23 mg of (S)-6-[3-(aminomethyl)azetidin-1-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine was dissolved in 2 ml of 1,2-dichloroethane, and 7 μl of acetic anhydride and 11 μl of pyridine were added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 20 mg of the objective compound as a brown amorphous solid. 
         [1319]    MS (ESI) m/z 437 (M+H) −   
       Example 233 
     (S)—N 2 -[1-(4-Fluorophenyl)ethyl]-4-[3-morpholinoazetidin-1-yl]-N 6 -(pyrazin-2-yl)Pyridine-2,6-diamine 
       [1320]    The objective compound was obtained as brown powder by the same process as in Example 38 using 4-(azetidin-3-yl)morpholine dihydrochloride instead of (S)—N-(pyrrolidin-3-yl)acetamide. 
         [1321]    MS (ESI) m/z 450 (M+H) 
       Example 234 
     (S)-1-(1-{2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-yl amino)pyridin-4-yl}azetidin-3-yl)piperidin-4-ol 
       [1322]    The objective compound was obtained as brown powder by the same process as in Example 38 using 1-(3-azetidinyl)-4-piperidinol dihydrochloride instead of (S)—N-(pyrrolidin-3-yl)acetamide. 
         [1323]    MS (ESI) m/z 464 (M+H) 
         [1324]    The formula of Example 1 to Example 234 is shown in Table 1 to Table 12. 
         [0000]    
       
         
               
               
             
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Example 
                 Structural formula 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 21 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Example 
                 Structural formula 
               
               
                   
               
             
             
               
                 22 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 26 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 28 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 29 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 30 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 31 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 32 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 33 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 34 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 35 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 36 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 37 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 38 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 39 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 40 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 41 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 42 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Example 
                 Structural formula 
               
               
                   
               
             
             
               
                 43 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 44 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 45 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 46 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 47 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 48 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 49 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 50 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 51 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 52 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 53 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 54 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 55 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 56 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 57 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 58 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 59 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 60 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 61 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 62 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 63 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                 Example 
                 Structural Formula 
               
               
                   
               
             
             
               
                 64 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 65 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 66 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 67 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 68 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 69 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 70 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 71 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 72 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 73 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 74 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 75 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 76 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 77 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 78 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 79 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 80 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 81 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 82 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 83 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 84 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                 Example 
                 Structural formula 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 85 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 86 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 87 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 88 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 89 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 90 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 91 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 92 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 93 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 94 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 95 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 96 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 97 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 98 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 99 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 100 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 101 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 102 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 103 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 104 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 105 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
           
               
                 TABLE 6 
               
               
                   
               
               
                 Example 
                 Structural formula 
               
               
                   
               
             
             
               
                 106 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 107 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 108 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 109 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 110 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 111 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 112 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 113 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 114 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 115 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 116 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 117 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 118 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 119 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 120 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 121 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 122 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 123 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 124 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 125 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 126 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
           
               
                 TABLE 7 
               
               
                   
               
               
                 Example 
                 Structural formula 
               
               
                   
               
             
             
               
                 127 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 128 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 129 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 130 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 131 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 132 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 133 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 134 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 135 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 136 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 137 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 138 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 139 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 140 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 141 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 142 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 143 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 144 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 145 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 146 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 147 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
           
               
                 TABLE 8 
               
               
                   
               
               
                 Example 
                 Structural formula 
               
               
                   
               
             
             
               
                 148 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 149 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 150 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 151 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 152 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 153 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 154 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 155 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 156 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 157 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 158 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 159 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 160 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 161 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 162 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 163 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 164 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 165 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 166 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 167 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 168 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
           
               
                 TABLE 9 
               
               
                   
               
               
                 Example 
                 Structural formula 
               
               
                   
               
             
             
               
                 169 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 170 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 171 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 172 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 173 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 174 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 175 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 176 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 177 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 178 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 179 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 180 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 181 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 182 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 183 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 184 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 185 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 186 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 187 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 188 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 189 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
           
               
                 TABLE 10 
               
               
                   
               
               
                 Example 
                 Structural formula 
               
               
                   
               
             
             
               
                 190 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 191 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 192 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 193 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 194 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 195 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 196 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 197 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 198 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 199 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 200 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 201 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 202 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 203 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 204 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 205 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 206 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 207 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 208 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 209 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 210 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
           
               
                 TABLE 11 
               
               
                   
               
               
                 Example 
                 Structural formula 
               
               
                   
               
             
             
               
                   
               
               
                 211 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 212 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 213 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 214 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 215 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 216 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 217 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 218 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 219 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 220 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 221 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 222 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 223 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 224 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 225 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 226 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 227 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 228 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 229 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 230 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 231 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
           
               
                 TABLE 12 
               
               
                   
               
               
                 Example 
                 Structural formula 
               
               
                   
               
             
             
               
                 232 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 233 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 234 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
       Test 1: Test for Inhibitory Activity to JAK2 and JAK3 Tyrosine Kinases 
     1. Preparation of Test Material 
       [1325]    The test material was dissolved in dimethylsulfoxide (DMSO) to be 10 mM, and further diluted with DMSO to be 100-fold concentrations for measurement (1000, 300, 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01 μm). In addition, solutions diluted with an assay buffer up to 20 times were used as solutions of the test material. As a negative control, a solution of DMSO diluted 20 times with an assay buffer was used. As the assay buffer, 15 mM Tris-Cl (pH 7.5), 0.01 v/v % Tween-20, and 1 mM dithiothreitol were used. 
       2. Measurement of the Activities of JAK2 and JAK3 Tyrosine Kinases 
       [1326]    The activity was determined by ELISA. The solution of the test material (10 μl each; n=2) was placed in a streptavidine-coated 96 well plate (DELFIA Strip Plate 8×12 wells; Perkin Elmer), to which 20 μl each of substrate solution (625 nM biotin-labeled peptide substrate, 25 μM ATP, 25 mM MgCl 2 , mM Tris-Cl (pH 7.5), 0.01 v/v % Tween-20, and 1 mM dithiothreitol) was added and stirred. Finally, 20 μl each of JAK2 tyrosine kinase (Carnabioscience Co.) (diluted to 0.75 nM with assay buffer) or JAK3 tyrosine kinase (Carnabioscience Co.) (diluted to 0.75 nM with assay buffer) was added, stirred and allowed to stand at 30° C. for 1 hour. The plate was washed 4 times with a washing buffer (50 mM Tris-Cl, pH 7.5, 150 mM NaCl, 0.02 v/v % Tween-20), and then a blocking buffer (0.1% Bovine Serum Albumin, 50 mM Tris-Cl, pH 7.5, 150 mM NaCl, 0.02 v/v % Tween-20) (150 μl each) was added for blocking at 30° C. for 30 minutes. Blocking buffer was removed, and there was added 100 μl each of horse radish peroxidase-labeled anti-phosphorylated tyrosin kinase antibody (BD Bioscience Co.) (diluted 10,000 times with blocking buffer). The plate was incubated at 30° C. for 30 minutes and then washed 4 times with a washing buffer, and 100 μl each of 3,3′,5,5′-tetramethylbenzidine (Sigma-Aldrich Co.) was added to develop color for 10 minutes. 0.1 M sulfuric acid (100 μl each) was added to stop the reaction. The absorbance was measured by means of a micro-plate reader (BIO-RAD; Model 3550) at 450 nm. 
       3. Analysis of the Results of the Measurement 
       [1327]    The measured absorbance was subjected to a non-linear regression analysis by means of a SAS system (SAS Institute Inc.), and the concentration (IC 50 ) of the test material which inhibited 50% of the activity of each tyrosine kinase was estimated. Tables 13 to 18 show the results. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE 13 
               
               
                   
                   
               
               
                   
                   
                 inhibitory activity to 
                 inhibitory activity to 
               
               
                   
                   
                 JAK2 tyrosine kinase 
                 JAK3 tyrosine kinase 
               
               
                   
                 test material 
                 (IC 50 , nM) 
                 (IC 50 , nM) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Example 1 
                 0.94 
                 45 
               
               
                   
                 Example 2 
                 0.49 
                 43 
               
               
                   
                 Example 3 
                 1.2 
                 130 
               
               
                   
                 Example 4 
                 0.59 
                 44 
               
               
                   
                 Example 5 
                 0.62 
                 62 
               
               
                   
                 Example 6 
                 5.7 
                 500 
               
               
                   
                 Example 7 
                 0.42 
                 39 
               
               
                   
                 Example 8 
                 1.1 
                 82 
               
               
                   
                 Example 9 
                 16 
                 360 
               
               
                   
                 Example 10 
                 0.89 
                 95 
               
               
                   
                 Example 11 
                 0.82 
                 36 
               
               
                   
                 Example 12 
                 0.92 
                 79 
               
               
                   
                 Example 13 
                 1.3 
                 71 
               
               
                   
                 Example 14 
                 1.9 
                 120 
               
               
                   
                 Example 15 
                 1.3 
                 72 
               
               
                   
                 Example 16 
                 8.0 
                 630 
               
               
                   
                 Example 17 
                 4.4 
                 340 
               
               
                   
                 Example 18 
                 3.0 
                 130 
               
               
                   
                 Example 19 
                 2.6 
                 59 
               
               
                   
                 Example 20 
                 0.69 
                 21 
               
               
                   
                 Example 21 
                 8.7 
                 950 
               
               
                   
                 Example 22 
                 1.6 
                 88 
               
               
                   
                 Example 23 
                 4.2 
                 210 
               
               
                   
                 Example 24 
                 1.1 
                 53 
               
               
                   
                 Example 25 
                 0.97 
                 100 
               
               
                   
                 Example 26 
                 0.27 
                 28 
               
               
                   
                 Example 27 
                 0.52 
                 42 
               
               
                   
                 Example 28 
                 1.2 
                 110 
               
               
                   
                 Example 29 
                 2.0 
                 160 
               
               
                   
                 Example 30 
                 1.5 
                 75 
               
               
                   
                 Example 31 
                 0.41 
                 26 
               
               
                   
                 Example 32 
                 0.50 
                 68 
               
               
                   
                 Example 33 
                 0.40 
                 30 
               
               
                   
                 Example 34 
                 0.51 
                 59 
               
               
                   
                 Example 35 
                 2.5 
                 440 
               
               
                   
                 Example 36 
                 2.8 
                 200 
               
               
                   
                 Example 37 
                 3.2 
                 130 
               
               
                   
                 Example 38 
                 2.3 
                 85 
               
               
                   
                 Example 39 
                 0.93 
                 90 
               
               
                   
                 Example 40 
                 3.4 
                 310 
               
               
                   
                 Example 41 
                 1.1 
                 51 
               
               
                   
                 Example 42 
                 1.0 
                 66 
               
               
                   
                 Example 43 
                 1.2 
                 130 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE 14 
               
               
                   
                   
               
               
                   
                   
                 inhibitory activity to 
                 inhibitory activity to 
               
               
                   
                   
                 JAK2 tyrosine kinase 
                 JAK3 tyrosine kinase 
               
               
                   
                 test material 
                 (IC 50 , nM) 
                 (IC 50 , nM) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Example 44 
                 2.1 
                 140 
               
               
                   
                 Example 45 
                 9.0 
                 2300 
               
               
                   
                 Example 46 
                 3.7 
                 93 
               
               
                   
                 Example 47 
                 12 
                 1300 
               
               
                   
                 Example 48 
                 6.0 
                 140 
               
               
                   
                 Example 49 
                 2.3 
                 170 
               
               
                   
                 Example 50 
                 0.84 
                 29 
               
               
                   
                 Example 51 
                 3.1 
                 51 
               
               
                   
                 Example 52 
                 2.0 
                 160 
               
               
                   
                 Example 53 
                 5.9 
                 390 
               
               
                   
                 Example 54 
                 22 
                 1800 
               
               
                   
                 Example 55 
                 2.0 
                 190 
               
               
                   
                 Example 56 
                 0.79 
                 24 
               
               
                   
                 Example 57 
                 1.3 
                 82 
               
               
                   
                 Example 58 
                 0.69 
                 26 
               
               
                   
                 Example 59 
                 1.7 
                 60 
               
               
                   
                 Example 60 
                 0.71 
                 28 
               
               
                   
                 Example 61 
                 6.0 
                 150 
               
               
                   
                 Example 62 
                 2.2 
                 65 
               
               
                   
                 Example 63 
                 1.0 
                 36 
               
               
                   
                 Example 64 
                 7.0 
                 220 
               
               
                   
                 Example 65 
                 0.27 
                 8.9 
               
               
                   
                 Example 66 
                 1.8 
                 37 
               
               
                   
                 Example 67 
                 11 
                 470 
               
               
                   
                 Example 68 
                 1.5 
                 34 
               
               
                   
                 Example 69 
                 2.6 
                 83 
               
               
                   
                 Example 70 
                 1.5 
                 65 
               
               
                   
                 Example 71 
                 0.72 
                 26 
               
               
                   
                 Example 72 
                 0.96 
                 31 
               
               
                   
                 Example 73 
                 1.3 
                 48 
               
               
                   
                 Example 74 
                 3.8 
                 230 
               
               
                   
                 Example 75 
                 12 
                 630 
               
               
                   
                 Example 76 
                 2.5 
                 57 
               
               
                   
                 Example 77 
                 0.73 
                 37 
               
               
                   
                 Example 78 
                 1.4 
                 35 
               
               
                   
                 Example 79 
                 4.3 
                 140 
               
               
                   
                 Example 80 
                 1.1 
                 60 
               
               
                   
                 Example 81 
                 5.6 
                 480 
               
               
                   
                 Example 82 
                 1.7 
                 99 
               
               
                   
                 Example 83 
                 3.7 
                 58 
               
               
                   
                 Example 84 
                 2.0 
                 170 
               
               
                   
                 Example 85 
                 0.51 
                 20 
               
               
                   
                 Example 86 
                 2.4 
                 87 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE 15 
               
               
                   
                   
               
               
                   
                   
                 inhibitory activity to 
                 inhibitory activity to 
               
               
                   
                   
                 JAK2 tyrosine kinase 
                 JAK3 tyrosine kinase 
               
               
                   
                 test material 
                 (IC 50 , nM) 
                 (IC 50 , nM) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Example 87 
                 14 
                 450 
               
               
                   
                 Example 88 
                 13 
                 200 
               
               
                   
                 Example 89 
                 3.8 
                 150 
               
               
                   
                 Example 90 
                 6.1 
                 380 
               
               
                   
                 Example 91 
                 1.4 
                 97 
               
               
                   
                 Example 92 
                 9.8 
                 460 
               
               
                   
                 Example 93 
                 3.0 
                 220 
               
               
                   
                 Example 94 
                 1.7 
                 77 
               
               
                   
                 Example 95 
                 2.2 
                 110 
               
               
                   
                 Example 96 
                 1.4 
                 33 
               
               
                   
                 Example 97 
                 37 
                 610 
               
               
                   
                 Example 98 
                 19 
                 1300 
               
               
                   
                 Example 99 
                 2.4 
                 200 
               
               
                   
                 Example 100 
                 0.52 
                 47 
               
               
                   
                 Example 101 
                 11 
                 600 
               
               
                   
                 Example 102 
                 2.6 
                 140 
               
               
                   
                 Example 103 
                 4.1 
                 310 
               
               
                   
                 Example 104 
                 1.0 
                 39 
               
               
                   
                 Example 105 
                 0.55 
                 27 
               
               
                   
                 Example 106 
                 1.9 
                 110 
               
               
                   
                 Example 107 
                 0.77 
                 56 
               
               
                   
                 Example 108 
                 1.1 
                 56 
               
               
                   
                 Example 109 
                 2.4 
                 130 
               
               
                   
                 Example 110 
                 0.67 
                 44 
               
               
                   
                 Example 111 
                 1.6 
                 110 
               
               
                   
                 Example 112 
                 0.69 
                 67 
               
               
                   
                 Example 113 
                 4.9 
                 200 
               
               
                   
                 Example 114 
                 4.8 
                 66 
               
               
                   
                 Example 115 
                 2.3 
                 210 
               
               
                   
                 Example 116 
                 5.3 
                 340 
               
               
                   
                 Example 117 
                 2.7 
                 190 
               
               
                   
                 Example 118 
                 1.6 
                 290 
               
               
                   
                 Example 119 
                 28 
                 1600 
               
               
                   
                 Example 120 
                 23 
                 1700 
               
               
                   
                 Example 121 
                 2.7 
                 170 
               
               
                   
                 Example 122 
                 0.40 
                 30 
               
               
                   
                 Example 123 
                 5.4 
                 330 
               
               
                   
                 Example 124 
                 1.3 
                 66 
               
               
                   
                 Example 125 
                 1.6 
                 130 
               
               
                   
                 Example 126 
                 8.8 
                 630 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE 16 
               
               
                   
                   
               
               
                   
                   
                 inhibitory activity to 
                 inhibitory activity to 
               
               
                   
                   
                 JAK2 tyrosine kinase 
                 JAK3 tyrosine kinase 
               
               
                   
                 test material 
                 (IC 50 , M) 
                 (IC 50 , nM) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Example 127 
                 2.9 
                 200 
               
               
                   
                 Example 128 
                 0.65 
                 46 
               
               
                   
                 Example 129 
                 3.4 
                 380 
               
               
                   
                 Example 130 
                 7.7 
                 570 
               
               
                   
                 Example 131 
                 2.8 
                 180 
               
               
                   
                 Example 132 
                 7.8 
                 350 
               
               
                   
                 Example 133 
                 3.0 
                 230 
               
               
                   
                 Example 134 
                 9.2 
                 620 
               
               
                   
                 Example 135 
                 2.6 
                 320 
               
               
                   
                 Example 136 
                 1.1 
                 170 
               
               
                   
                 Example 137 
                 2.2 
                 160 
               
               
                   
                 Example 138 
                 3.4 
                 420 
               
               
                   
                 Example 139 
                 5.0 
                 290 
               
               
                   
                 Example 140 
                 1.4 
                 61 
               
               
                   
                 Example 141 
                 14 
                 440 
               
               
                   
                 Example 142 
                 1.2 
                 66 
               
               
                   
                 Example 143 
                 14 
                 2100 
               
               
                   
                 Example 144 
                 2.1 
                 210 
               
               
                   
                 Example 145 
                 0.34 
                 36 
               
               
                   
                 Example 146 
                 9.5 
                 1400 
               
               
                   
                 Example 147 
                 9.2 
                 920 
               
               
                   
                 Example 148 
                 21 
                 810 
               
               
                   
                 Example 149 
                 2.6 
                 690 
               
               
                   
                 Example 150 
                 1.7 
                 150 
               
               
                   
                 Example 151 
                 7.4 
                 490 
               
               
                   
                 Example 152 
                 0.71 
                 93 
               
               
                   
                 Example 153 
                 8.4 
                 300 
               
               
                   
                 Example 154 
                 16 
                 340 
               
               
                   
                 Example 155 
                 2.4 
                 390 
               
               
                   
                 Example 156 
                 6.7 
                 580 
               
               
                   
                 Example 157 
                 2.0 
                 150 
               
               
                   
                 Example 158 
                 0.65 
                 39 
               
               
                   
                 Example 159 
                 1.0 
                 170 
               
               
                   
                 Example 160 
                 1.0 
                 100 
               
               
                   
                 Example 161 
                 12 
                 230 
               
               
                   
                 Example 162 
                 3.4 
                 370 
               
               
                   
                 Example 163 
                 0.74 
                 170 
               
               
                   
                 Example 164 
                 12 
                 470 
               
               
                   
                 Example 165 
                 3.1 
                 360 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE 17 
               
               
                   
                   
               
               
                   
                   
                 inhibitory activity to 
                 inhibitory activity to 
               
               
                   
                   
                 JAK2 tyrosine kinase 
                 JAK3 tyrosine kinase 
               
               
                   
                 test material 
                 (IC 50 , nM) 
                 (IC 50 , nM) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Example 166 
                 2.2 
                 380 
               
               
                   
                 Example 167 
                 1.6 
                 350 
               
               
                   
                 Example 168 
                 17 
                 1300 
               
               
                   
                 Example 169 
                 3.0 
                 500 
               
               
                   
                 Example 170 
                 1.2 
                 180 
               
               
                   
                 Example 171 
                 1.9 
                 570 
               
               
                   
                 Example 172 
                 0.85 
                 150 
               
               
                   
                 Example 173 
                 1.5 
                 200 
               
               
                   
                 Example 174 
                 0.99 
                 47 
               
               
                   
                 Example 175 
                 4.9 
                 400 
               
               
                   
                 Example 176 
                 0.96 
                 35 
               
               
                   
                 Example 177 
                 0.74 
                 87 
               
               
                   
                 Example 178 
                 1.0 
                 82 
               
               
                   
                 Example 179 
                 2.6 
                 330 
               
               
                   
                 Example 180 
                 2.5 
                 52 
               
               
                   
                 Example 181 
                 2.2 
                 56 
               
               
                   
                 Example 182 
                 6.4 
                 440 
               
               
                   
                 Example 183 
                 1.8 
                 59 
               
               
                   
                 Example 184 
                 0.92 
                 45 
               
               
                   
                 Example 185 
                 4.2 
                 380 
               
               
                   
                 Example 186 
                 5.5 
                 240 
               
               
                   
                 Example 187 
                 2.4 
                 400 
               
               
                   
                 Example 188 
                 3.7 
                 120 
               
               
                   
                 Example 189 
                 12 
                 1500 
               
               
                   
                 Example 190 
                 1.2 
                 58 
               
               
                   
                 Example 191 
                 1.4 
                 31 
               
               
                   
                 Example 192 
                 1.9 
                 120 
               
               
                   
                 Example 193 
                 0.80 
                 35 
               
               
                   
                 Example 194 
                 0.79 
                 84 
               
               
                   
                 Example 195 
                 1.2 
                 50 
               
               
                   
                 Example 196 
                 0.64 
                 35 
               
               
                   
                 Example 197 
                 1.6 
                 58 
               
               
                   
                 Example 198 
                 1.6 
                 60 
               
               
                   
                 Example 199 
                 1.6 
                 64 
               
               
                   
                 Example 200 
                 0.39 
                 26 
               
               
                   
                 Example 201 
                 0.41 
                 35 
               
               
                   
                 Example 202 
                 4.7 
                 470 
               
               
                   
                 Example 203 
                 4.5 
                 120 
               
               
                   
                 Example 204 
                 8.1 
                 220 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE 18 
               
               
                   
                   
               
               
                   
                   
                 inhibitory activity to 
                 inhibitory activity to 
               
               
                   
                   
                 JAK2 tyrosine kinase 
                 JAK3 tyrosine kinase 
               
               
                   
                 test material 
                 (IC 50 , nM) 
                 (IC 50 , nM) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Example 205 
                 2.8 
                 170 
               
               
                   
                 Example 206 
                 10 
                 360 
               
               
                   
                 Example 207 
                 7.0 
                 300 
               
               
                   
                 Example 208 
                 1.4 
                 100 
               
               
                   
                 Example 209 
                 7.1 
                 440 
               
               
                   
                 Example 210 
                 3.2 
                 180 
               
               
                   
                 Example 211 
                 5.6 
                 86 
               
               
                   
                 Example 212 
                 15 
                 160 
               
               
                   
                 Example 213 
                 3.2 
                 130 
               
               
                   
                 Example 214 
                 5.5 
                 380 
               
               
                   
                 Example 215 
                 2.3 
                 210 
               
               
                   
                 Example 216 
                 1.4 
                 49 
               
               
                   
                 Example 217 
                 1.5 
                 36 
               
               
                   
                 Example 218 
                 2.2 
                 85 
               
               
                   
                 Example 219 
                 2.6 
                 69 
               
               
                   
                 Example 220 
                 0.98 
                 24 
               
               
                   
                 Example 221 
                 1.5 
                 59 
               
               
                   
                 Example 222 
                 0.75 
                 18 
               
               
                   
                 Example 223 
                 0.65 
                 11 
               
               
                   
                 Example 224 
                 1.1 
                 16 
               
               
                   
                 Example 225 
                 0.69 
                 13 
               
               
                   
                 Example 226 
                 1.1 
                 24 
               
               
                   
                 Example 227 
                 1.1 
                 20 
               
               
                   
                 Example 228 
                 1.1 
                 19 
               
               
                   
                 Example 229 
                 3.9 
                 180 
               
               
                   
                 Example 230 
                 1.2 
                 63 
               
               
                   
                 Example 231 
                 0.59 
                 33 
               
               
                   
                 Example 232 
                 0.55 
                 32 
               
               
                   
                 Example 233 
                 5.8 
                 140 
               
               
                   
                 Example 234 
                 5.4 
                 170 
               
               
                   
                   
               
             
          
         
       
     
         [1328]    As mentioned above, the compounds of the invention or pharmaceutically acceptable salts thereof exhibit a high JAK2 tyrosine kinase inhibitory activity with a low JAK3 tyrosine kinase inhibitory activity; thus, pharmaceutical compositions containing the compounds of the invention or pharmaceutically acceptable salts thereof can be used as preventives or therapeutics for cancers (e.g. hematic cancers (e.g. polycythemia vera, essential thrombocythemia, myeloidproliferative neoplasms such as idiopathic myelofibrosis (chronic myeloid proliferative diseases), osteomyelodysplasia syndrome, acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma), solid cancers (e.g. prostatic cancer, breast cancer)), inflammatory diseases (e.g. rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis), and angiopathy (e.g., pulmonary hypertension, arteriosclerosis, aneurysm, varicose vein). Further, the compounds of the invention or pharmaceutically acceptable salts thereof are excellent also from the viewpoint of adverse effects, since their inhibitory activity to other families of tyrosine kinases is weak. 
       Test 2: Growth Inhibitory Action Against Variant JAK2 Expressed Cells 
       [1329]    BaF3 cells into which JAK2 V617F gene was introduced (BaF3/JAK2 V617F cells) were inoculated on a 96-well plate in an amount of 1×10 3  cells/well and allowed to stand in a CO 2  incubator. Next day, the test material was added to the cells. The test material was serially diluted with DMSO to give 10 mM, 6 mM, 3 mM, 1 mM, 600 μM, 300 μM, 100 μm, 60 μm, 30 μM, or 10 μm solution. This was diluted 100 times with distilled water to give 100 μM, 60 μm, 30 μm, 10 μM, 6 μM, 3 μm, 1 μm, 600 nM, 300 nM, or 100 nM solution. This solution of test material was added to the well in an amount of 10 μl/well. As a negative control, 1% DMSO solution was added to the well in an amount of 10 μl/well. In the above operation, the final concentration of the test material became 10 μm, 6 μM, 3 μm, 1 μm, 600 nM, 300 nM, 100 nM, 60 nM, 30 nM, 10 nM, or 0 nM (0.1% DMSO solution). The addition of the test material solution to each well was made in triplicate. 
         [1330]    After continuous incubation for 3 days, the viable count was determined by an MTT method. The MTT method was carried out as follows. First, 10 μl each of solution containing 5 mg/ml of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was added to each well. The plate was allowed to stand in a CO 2  incubator for 4 hours, and then 100 μl of 0.04N HCl/2-propanol solution was added to each well to stop the reaction. The generated MTT-formazan was dissolved well with a multi-channel pipette, and the absorbance at 595 nm was measured with reference to that at 655 nm (Thermo Co.; Multiskan FC). Non-linear regression analysis was made by means of a SAS system (SAS Institute Inc.), and the concentration (IC 50 ) of the test material which inhibited 50% of the cell growth was estimated. Table 19 shows the results. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 19 
               
               
                   
                   
               
               
                   
                 test material 
                 (IC 50 , nM) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Example 1 
                 83 
               
               
                   
                 Example 2 
                 70 
               
               
                   
                 Example 4 
                 71 
               
               
                   
                 Example 7 
                 90 
               
               
                   
                 Example 11 
                 100 
               
               
                   
                 Example 20 
                 55 
               
               
                   
                 Example 24 
                 100 
               
               
                   
                 Example 27 
                 89 
               
               
                   
                 Example 28 
                 94 
               
               
                   
                 Example 30 
                 60 
               
               
                   
                 Example 31 
                 87 
               
               
                   
                 Example 50 
                 53 
               
               
                   
                 Example 56 
                 81 
               
               
                   
                 Example 60 
                 80 
               
               
                   
                 Example 65 
                 93 
               
               
                   
                 Example 71 
                 100 
               
               
                   
                 Example 105 
                 60 
               
               
                   
                 Example 112 
                 64 
               
               
                   
                 Example 152 
                 100 
               
               
                   
                 Example 166 
                 64 
               
               
                   
                 Example 167 
                 63 
               
               
                   
                 Example 170 
                 77 
               
               
                   
                 Example 200 
                 70 
               
               
                   
                 Example 220 
                 64 
               
               
                   
                 Example 222 
                 66 
               
               
                   
                 Example 223 
                 57 
               
               
                   
                 Example 224 
                 94 
               
               
                   
                 Example 225 
                 64 
               
               
                   
                 Example 228 
                 89 
               
               
                   
                 Example 231 
                 97 
               
               
                   
                 Example 232 
                 88 
               
               
                   
                   
               
             
          
         
       
     
       Formulation Example 1 
       [1331]    Tablets (for oral administration)
 
Formulation: Each tablet (80 mg) contains the following
 
         [0000]                                                Compound of Example 1   5.0 mg           Corn starch   46.6 mg            Crystalline cellulose   24.0 mg            Methyl cellulose   4.0 mg           Magnesium stearate   0.4 mg                        
The mixed powder in the above ratio is made into tablets by a conventional method to prepare tablets for oral administration.
 
       Formulation Example 2 
       [1332]    Tablets (for oral administration)
 
Formulation: Each tablet (80 mg) contains the following
 
         [0000]                                                Compound of Example 2   5.0 mg           Corn starch   46.6 mg            Crystalline cellulose   24.0 mg            Methyl cellulose   4.0 mg           Magnesium stearate   0.4 mg                        
The mixed powder in the above ratio is made into tablets by a conventional method to prepare tablets for oral administration.
 
         [1333]    As mentioned above, the compounds of the invention or pharmaceutically acceptable salts thereof exhibit a high JAK2 tyrosine kinase inhibitory activity; thus, pharmaceutical compositions containing the compounds of the invention or pharmaceutically acceptable salts thereof can be used as preventives or therapeutics for cancers (e.g. hematic cancers (e.g. polycythemia vera, essential thrombocythemia, myeloidproliferative neoplasms such as idiopathic myelofibrosis (chronic myeloid proliferative diseases), osteomyelodysplasia syndrome, acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma), solid cancers (e.g. prostatic cancer, breast cancer)), inflammatory diseases (e.g. rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis), and angiopathy (e.g., pulmonary hypertension, arteriosclerosis, aneurysm, varicose vein).