JPWO2012020786A1 - Pharmaceutical composition - Google Patents

Abstract

Rectal cancer containing the compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof as an active ingredient in any of the following (I) or (II) as the present invention And a therapeutic or prophylactic agent for diseases such as colon cancer, colon cancer, melanoma, pancreatic cancer, ovarian cancer, bladder cancer and the like. (I) X represents CH or N, R1 represents halogen, R2 represents halogen, H, cyano, a group represented by the following general formula [9], an optionally substituted heteroaryl, or the like. , R3 represents H or hydroxy, R4 represents H or alkyl, and R5 represents H or alkyl. (II) X represents -CRA, RA represents -CORB, RB represents an optionally substituted amino, alkoxy or saturated cyclic amino group, R1 represents halogen, R2 represents H, R3 represents H or hydroxy is represented, R4 represents H or alkyl, and R5 represents H or alkyl.

Description

  The present invention relates to a novel pharmaceutical composition having an inhibitory action on Src family tyrosine kinases.

Src family tyrosine kinases are non-receptor tyrosine kinases and are involved in various intracellular signal transduction systems. Src family tyrosine kinases are activated by various cell surface receptors (receptor-type tyrosine kinases and G proteins) and stimuli via exogenous stress (ultraviolet rays and pathogens), and the growth, survival, migration and invasion of cancer cells In addition to enhancing the activity of inflammatory cells, it is involved in activation of inflammatory cells and increased permeability of vascular endothelial cells.
c-Src tyrosine kinase has been discovered as a proto-oncogene, and its overexpression and abnormal activity control are involved in the onset and malignancy of many types of cancer.
The activation of c-Src tyrosine kinase is notably rectal cancer, colon cancer, colon cancer, melanoma, pancreatic cancer, ovarian cancer, bladder cancer, gastric cancer, head and neck cancer, esophageal cancer, lung cancer, neuroblastoma, retinoblast It has been clarified that it is involved in the progression of tumors (see, for example, Non-Patent Document 1).
In addition, abnormal control of c-Src tyrosine kinase activity is caused by cancer (eg, prostate cancer, breast cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, testicular cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer). Involved in bone metastasis from primary lesions (eg, detachment from primary lesions, bone infiltration and proliferation), and also involved in bone loss by disturbing bone resorption / bone formation balance in bone metastases (For example, refer nonpatent literature 2).
Src family tyrosine kinases are also involved in the activation of inflammatory cells and increased permeability of vascular endothelial cells, in addition to their involvement in the cancer region. For example, regarding the Fyn tyrosine kinase, Yes tyrosine kinase, Lyn tyrosine kinase, Fgr tyrosine kinase, and Lck tyrosine kinase belonging to the Src family tyrosine kinase, there are the following reports.
Fyn tyrosine kinase is a squamous cell carcinoma (for example, Non-patent Document 3), oral squamous cell carcinoma (for example, Non-Patent Document 4), mesothelioma (for example, Non-Patent Document 5), systemic lupus erythematosus (for example, Non-patent document). 11), diseases caused by allergic reactions (for example, allergic rhinitis, atopic dermatitis, atopic asthma) (for example, non-patent document 10), bronchial asthma (for example, non-patent document 9), Alzheimer's disease (for example, Involved in the onset and progress of Non-Patent Document 17).
Yes tyrosine kinase is skin cancer (for example, non-patent document 7), oral cancer (for example, non-patent document 8), bronchial asthma (for example, non-patent document 9), age-related macular degeneration (for example, non-patent document 18). ) Is involved in the onset and progression.
Lyn tyrosine kinase is used, for example, for glomerulonephritis (for example, Non-Patent Document 12), rejection at the time of organ transplantation (for example, heart transplantation) (for example, Non-Patent Document 13), diseases caused by allergic reactions (for example, allergy). Rhinitis, atopic dermatitis, atopic asthma (for example, Non-Patent Document 10), atherosclerosis (for example, Non-Patent Document 14), diseases caused by leukocyte accumulation during vascular disorders (for example, transdermal) Is involved in the onset and progress of restenosis after coronary intervention (for example, Non-Patent Document 14), bronchial asthma (for example, Non-Patent Document 9), and AIDS (for example, Non-Patent Document 16).
Fgr tyrosine kinase is atherosclerosis (eg, non-patent document 14), a disease caused by leukocyte accumulation during vascular injury (eg, restenosis after percutaneous coronary intervention) (eg, non-patent document 14). ), Involved in the onset and progression of bronchial asthma (eg, Non-Patent Document 9).
Lck tyrosine kinase is a thymic tumor (for example, non-patent document 6), rejection during organ transplantation (for example, heart transplantation) (for example, non-patent document 13), autoimmune disease (for example, systemic lupus erythematosus, type I diabetes) , Psoriasis, glomerulonephritis) (for example, Non-Patent Documents 11 and 12), bronchial asthma (for example, Non-Patent Document 9), acute coronary syndrome (for example, Non-Patent Document 15), Alzheimer's disease (for example, Non-Patent Document 17). ) Is involved in the onset and progression.
However, in the above diseases, there are many cases where treatment with existing therapies is insufficient, relapse cases, and intractable cases, and new therapeutic agents are being sought.
On the other hand, the aminopyrazine derivative according to the present invention has a high JAK2 tyrosine kinase inhibitory action, such as cancer (eg, blood cancer (eg, polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis, etc.) Myeloproliferative tumors (chronic myeloproliferative disorders), myelotypic syndrome, acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, multiple myeloma), solid cancer (eg, prostate cancer, breast cancer)) , Used as a prophylactic or therapeutic agent for inflammatory diseases (eg, rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis), vascular disorders (eg, pulmonary hypertension, arteriosclerosis, aneurysm, varicose veins) (For example, Patent Document 1).

Justin M.J. Summy, et al. , Cancer and Metastasis, 22, 337-358, 2003. Fred Saad, British Journal of Urology International, 103, 434-440, 2008 Mariotti A. et al. , The Journal of Cell Biology, 155, 447-458, 2001. Lewin B. et al, Anticancer Research, 30, 2591-2596, 2010 Menges CW. et al. Genes and Cancer, 1,493-505, 2010. Abraham KM. et al. , Proceedings of the National Academy of Sciences of the United States of America, 88, 3777-3981, 1991. Lee JH. et al. , Journal of Experimental and Clinical Cancer Research, 29, 116, 2010. Chen JY. et al. , Neoplasia, 10, 1393-11401, 2008. Sakai H.M. et al. , Peptides, 312, 2162-1221, 2010 Samayawardhena LA. et al. , Journal of Immunology, 185, 5993-6002, 2010. Kamens JS. et al. , Current Opinion in Investigative Drugs, 2, 1213-1219, 2001. Hibbs ML. et al. The Journal of Experimental Medicine, 196, 1593-1604, 2002, The Journal of Experimental Medicine. Zhang Q. , Transplantation, 80, 1112-1120, 2005 Evangelista V.D. et al. , Blood, 109, 2461-2469, 2007 Pryshchep S. et al. , Circulation Research, 106, 769-778, 2009. Triple RP. et al, The Journal of Biological Chemistry, 281, 27029-27038, 2006 Scales TM. et al. , Molecular Neurogeneration, 6, 12, 2011 Palanki MS. et al. , Journal of Medicinal Chemistry, 51, 1545-1559, 2008.

International Publication WO2010 / 090290A

  The main object of the present invention is to provide a novel pharmaceutical composition having an inhibitory action on Src family tyrosine kinases.

The present inventor has found that the aminopyrazine derivative according to the present invention has an inhibitory action on Src family tyrosine kinase, and thus completed the present invention.
As the present invention, a compound represented by the following general formula [1] (hereinafter referred to as “the compound of the present invention”) or a pharmaceutically acceptable salt thereof, which is the case of either of the following (I) or (II): Rectal cancer, colon cancer, colon cancer, melanoma, pancreatic cancer, ovarian cancer, bladder cancer, gastric cancer, head and neck cancer, esophageal cancer, lung cancer, neuroblastoma, retinoblastoma, Squamous cell carcinoma, oral squamous cell carcinoma, mesothelioma, thymic tumor, skin cancer, oral cancer, retinoblastoma, cancer bone metastasis, bronchial asthma, disease caused by allergic reaction, autoimmune disease, vascular injury A therapeutic agent or a preventive agent for a disease selected from the group consisting of diseases caused by leukocyte accumulation, rejection at the time of organ transplantation, acute coronary syndrome, AIDS, Alzheimer's disease, and age-related macular degeneration.

（Ｉ）
Ｘは、ＣＨ又はＮを表す。
Ｒ^１は、ハロゲンを表す。
Ｒ^２は、
（１）Ｈ、
（２）ハロゲン、
（３）シアノ、
（４）次の一般式［２］で表される基、

（式中、＊は、結合位置を表す。Ｒ^Ｃ、Ｒ^Ｄ、Ｒ^Ｅは、同一又は異なって、（ａ）Ｈ、若しくは（ｂ）ヒドロキシ若しくはアルコキシで置換されていてもよいアルキルを表すか、又は、Ｒ^Ｃ、Ｒ^Ｄ、Ｒ^Ｅのうち２つの基が隣接するＣと一緒になって１個のＮを含む飽和複素環式基を表す。残り１つの基はＨを表す。かかる飽和複素環式基は、アルキルスルホニルで置換されていてもよい。）、
（５）次の一般式［３］で表される基、

(I)
X represents CH or N.
R ¹ represents halogen.
R ² is
(1) H,
(2) halogen,
(3) Cyano,
(4) a group represented by the following general formula [2],

(In the formula, * represents a bonding position. R ^C , R ^D and R ^E are the same or different and each represents (a) H or (b) alkyl optionally substituted with hydroxy or alkoxy. Or two of R ^C , R ^D and R ^E together with adjacent C represent a saturated heterocyclic group containing one N. The remaining one represents H. Such saturation The heterocyclic group may be substituted with alkylsulfonyl),
(5) a group represented by the following general formula [3],

（式中、＊は、前記と同義である。Ｒ^Ｆ、Ｒ^Ｇは、同一又は異なって、（ａ）Ｈ、（ｂ）ヒドロキシ、アミノ、ジアルキルアミノ、飽和環状アミノ基、アルキルカルボニルアミノ、アルキルスルホニルアミノ、アリール、アルキルで置換されていてもよいヘテロアリール、テトラヒドロフラニル、及びカルバモイルからなる群から選択される１若しくは２個の基で置換されていてもよいアルキル、（ｃ）アルキルカルボニル、（ｄ）アルキルスルホニル、（ｅ）カルバモイル、若しくは（ｆ）アルキルで置換されていてもよいヘテロアリールを表すか、又は、Ｒ^ＦとＲ^Ｇが隣接するＮと一緒になって、飽和環状アミノ基を表す。かかる飽和環状アミノ基は、（ａ）ハロゲン、（ｂ）シアノ、（ｃ）ヒドロキシ、（ｄ）ヒドロキシ、アルコキシ、アミノ、アルコキシカルボニルアミノ、アルキルスルホニルアミノ、及びアルキルカルボニルアミノからなる群から選択される１若しくは２個の基で置換されていてもよいアルキル、（ｅ）シクロアルキル、（ｆ）ハロアルキル、（ｇ）アルコキシ、（ｈ）オキソ、（ｉ）次の一般式［４］で表される基、

(In the formula, * is as defined above. R ^F and R ^G are the same or different, and (a) H, (b) hydroxy, amino, dialkylamino, saturated cyclic amino group, alkylcarbonylamino, alkyl (C) alkylcarbonyl, (c) alkyl optionally substituted with one or two groups selected from the group consisting of sulfonylamino, aryl, heteroaryl optionally substituted with alkyl, tetrahydrofuranyl, and carbamoyl d) represents alkylsulfonyl, (e) carbamoyl, or (f) heteroaryl optionally substituted with alkyl, or R ^F and R ^G together with adjacent N to form a saturated cyclic amino group Such saturated cyclic amino groups include (a) halogen, (b) cyano, (c) hydroxy, (d) hydroxy, alcohol Alkyl optionally substituted with one or two groups selected from the group consisting of cis, amino, alkoxycarbonylamino, alkylsulfonylamino, and alkylcarbonylamino, (e) cycloalkyl, (f) haloalkyl, ( g) alkoxy, (h) oxo, (i) a group represented by the following general formula [4],

（式中、＊は、前記と同義である。Ｒ^Ｈは、アルキル又はアリールを表す）、（ｊ）次の一般式［５］で表される基、

(Wherein, * is as defined above, R ^H represents alkyl or aryl), (j) a group represented by the following general formula [5],

（式中、＊は、前記と同義である。Ｒ^Ｉ、Ｒ^Ｊは、同一又は異なって、Ｈ、アルキル、カルバモイル、アルキルカルボニル、又はアルキルスルホニルを表す。）、（ｋ）次の一般式［６］で表される基、

(Wherein * is as defined above. R ^I and R ^J are the same or different and represent H, alkyl, carbamoyl, alkylcarbonyl, or alkylsulfonyl), (k) the following general formula [ 6],

（式中、＊は、前記と同義である。Ｒ^Ｋは、アルキル、ヒドロキシ、アミノ、アルキルアミノ、ジアルキルアミノ、シクロアルキルアミノ、（シクロアルキル）アルキルアミノ、（ヒドロキシアルキル）アミノ、（アルコキシアルキル）アミノ、アルコキシ、アルキルスルホニルアミノ、又は飽和環状アミノ基を表す）、及び（ｌ）ヒドロキシで置換されていてもよい飽和環状アミノ基からなる群から選択される１若しくは２個の基で置換されていてもよく、次の一般式［７Ａ］若しくは［７Ｂ］で表される基とスピロ結合していてもよい。

(Wherein * has the same meaning as defined above .R ^K is alkyl, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, (cycloalkyl) alkylamino, (hydroxyalkyl) amino, (alkoxyalkyl) (Represents an amino, alkoxy, alkylsulfonylamino, or saturated cyclic amino group), and (l) substituted with one or two groups selected from the group consisting of a saturated cyclic amino group optionally substituted with hydroxy Or may be spiro-bonded to a group represented by the following general formula [7A] or [7B].

（式中、＊は、前記と同義である。））、
（６）次の一般式［８］で表される基、

(Wherein * is as defined above)),
(6) a group represented by the following general formula [8],

（式中、＊は、前記と同義である。Ｒ^Ｌは、（ａ）アルキル、（ｂ）ヒドロキシ、（ｃ）アルコキシ、（ｄ）アルキル若しくはアルキルスルホニルで置換されていてもよい飽和環状アミノ基、又は（ｅ）アルキル、シクロアルキル、（シクロアルキル）アルキル、アラルキル、ハロアルキル、ジアルキルアミノアルキル、アルコキシアルキル、及びヒドロキシアルキルからなる群から選択される１若しくは２個の基で置換されていてもよいアミノを表す。）、
（７）次の一般式［９］で表される基、

(Wherein * is as defined above. R ^L is a saturated cyclic amino group optionally substituted with (a) alkyl, (b) hydroxy, (c) alkoxy, (d) alkyl or alkylsulfonyl. Or (e) optionally substituted with one or two groups selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, alkoxyalkyl, and hydroxyalkyl Represents amino).
(7) a group represented by the following general formula [9],

（式中、＊は、前記と同義である。Ｒ^Ｍ、Ｒ^Ｎ、Ｒ^Ｏは、同一又は異なって、Ｈ、ハロゲ
ン、シアノ、アルコキシ、カルバモイル、スルファモイル、モノアルキルアミノスルホニル、若しくは、アルキルスルホニルを表すか、又はＲ^Ｍ、Ｒ^Ｎ、Ｒ^Ｏのうち２つの基が一緒になってメチレンジオキシを表す。残り１つの基はＨを表す。）、

(In the formula, * is as defined above. R ^M , R ^N and R ^O are the same or different and represent H, halogen, cyano, alkoxy, carbamoyl, sulfamoyl, monoalkylaminosulfonyl, or alkylsulfonyl. Or two groups of R ^M , R ^N and R ^O together represent methylenedioxy, the other one represents H).

(8) —OR ^P (R ^P may be alkyl substituted with a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl, or may be substituted with hydroxy Often represents a saturated cyclic group optionally containing one O), or

(9) substituted with one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl Represents an optionally heteroaryl.
R ³ represents H or hydroxy.
R ⁴ represents H or alkyl.
R ⁵ represents H or alkyl.

(II)
X represents a -CR ^A.
R ^A represents a group represented by the following general formula [10].

（式中、＊は、前記と同義である。Ｒ^Ｂは、（ａ）アルキル、シクロアルキル、（シクロアルキル）アルキル、及びアルコキシアルキルからなる群から選択される１若しくは２個の基で置換されていてもよいアミノ、（ｂ）アルコキシ、（ｃ）ヒドロキシ、又は（ｄ）飽和環状アミノ基を表す。）
Ｒ^１は、ハロゲンを表す。
Ｒ^２は、Ｈを表す。
Ｒ^３は、Ｈ又はヒドロキシを表す。
Ｒ^４は、Ｈ又はアルキルを表す。
Ｒ^５は、Ｈ又はアルキルを表す。

好ましくは、一般式［１］で表される化合物であって、次の［ｉ］又は［ｉｉ］のいずれかの場合である化合物、又はその医薬上許容される塩を有効成分として含有する、直腸癌、結腸癌、大腸癌、黒色腫、膵癌、卵巣癌、膀胱癌、胃癌、頭頸部癌、食道癌、肺癌、神経芽細胞腫、網膜芽細胞腫、扁平上皮癌、口腔扁平上皮癌、中皮腫、胸腺腫瘍、皮膚癌、口腔癌、網膜芽細胞腫、がんの骨転移、気管支喘息、アレルギー反応に起因する疾患、自己免疫疾患、血管傷害時の白血球集積に起因する疾患、臓器移植時の拒絶反応、急性冠症候群、エイズ、アルツハイマー病及び加齢黄斑変性症からなる群から選択される疾患の治療剤又は予防剤を挙げることができる。

［ｉ］
ＸがＣＨ又はＮ、
Ｒ^２が、
（１）次の一般式［１１］で表される基、

(Wherein * is as defined above, R ^B is substituted with 1 or 2 groups selected from the group consisting of (a) alkyl, cycloalkyl, (cycloalkyl) alkyl, and alkoxyalkyl). Which may represent amino, (b) alkoxy, (c) hydroxy, or (d) a saturated cyclic amino group.)
R ¹ represents halogen.
R ² represents H.
R ³ represents H or hydroxy.
R ⁴ represents H or alkyl.
R ⁵ represents H or alkyl.

Preferably, the compound represented by the general formula [1], which is a compound according to any of the following [i] or [ii], or a pharmaceutically acceptable salt thereof as an active ingredient, Rectal cancer, colon cancer, colon cancer, melanoma, pancreatic cancer, ovarian cancer, bladder cancer, gastric cancer, head and neck cancer, esophageal cancer, lung cancer, neuroblastoma, retinoblastoma, squamous cell carcinoma, oral squamous cell carcinoma, Mesothelioma, thymic tumor, skin cancer, oral cancer, retinoblastoma, bone metastasis of cancer, bronchial asthma, disease caused by allergic reaction, autoimmune disease, disease caused by leukocyte accumulation during vascular injury, organ The therapeutic agent or preventive agent of the disease selected from the group which consists of rejection at the time of a transplant, acute coronary syndrome, AIDS, Alzheimer's disease, and age-related macular degeneration can be mentioned.

[I]
X is CH or N,
R ² is
(1) a group represented by the following general formula [11],

（式中、＊は、前記と同義である。Ｒ^Ｆ１、Ｒ^Ｇ１は、同一又は異なって、（ａ）Ｈ、（ｂ）ヒドロキシ、アミノ、ジアルキルアミノ、飽和環状アミノ基、アルキルカルボニルアミノ、アルキルスルホニルアミノ、アリール、アルキルで置換されていてもよいヘテロアリール、テトラヒドロフラニル、及びカルバモイルからなる群から選択される１若しくは２個の基で置換されていてもよいアルキル、（ｃ）アルキルカルボニル、（ｄ）アルキルスルホニル、（ｅ）カルバモイル、若しくは（ｆ）アルキルで置換されていてもよいヘテロアリールを表すか、又は、Ｒ^Ｆ１とＲ^Ｇ１とが隣接するＮと一緒になって、飽和環状アミノ基を表す。かかる飽和環状アミノ基は、（ａ）ハロゲン、（ｂ）シアノ、（ｃ）ヒドロキシ、（ｄ）ヒドロキシ、アルコキシ、アミノ、アルコキシカルボニルアミノ、アルキルスルホニルアミノ、及びアルキルカルボニルアミノからなる群から選択される１若しくは２個の基で置換されていてもよいアルキル、（ｅ）シクロアルキル、（ｆ）ハロアルキル、（ｇ）アルコキシ、（ｈ）オキソ、（ｉ）次の一般式［４］で表される基、

(In the formula, * is as defined above. R ^F1 and R ^G1 are the same or different and (a) H, (b) hydroxy, amino, dialkylamino, saturated cyclic amino group, alkylcarbonylamino, alkyl (C) alkylcarbonyl, (c) alkyl optionally substituted with one or two groups selected from the group consisting of sulfonylamino, aryl, heteroaryl optionally substituted with alkyl, tetrahydrofuranyl, and carbamoyl d) represents alkylsulfonyl, (e) carbamoyl, or (f) heteroaryl optionally substituted with alkyl, or R ^F1 and R ^G1 together with adjacent N to form a saturated cyclic amino group Such saturated cyclic amino groups are (a) halogen, (b) cyano, (c) hydroxy, (d) hydroxy. , Alkyl optionally substituted with one or two groups selected from the group consisting of alkoxy, amino, alkoxycarbonylamino, alkylsulfonylamino, and alkylcarbonylamino, (e) cycloalkyl, (f) haloalkyl, (G) alkoxy, (h) oxo, (i) a group represented by the following general formula [4],

（式中、＊、Ｒ^Ｈは、前記と同義である。）、（ｊ）次の一般式［５］で表される基、

(Wherein, * and ^RH are as defined above), (j) a group represented by the following general formula [5],

（式中、＊、Ｒ^Ｉ、Ｒ^Ｊは、前記と同義である。）、（ｋ）次の一般式［６］で表される基、

(Wherein, *, R ^I and R ^J are as defined above), (k) a group represented by the following general formula [6],

（式中、＊、Ｒ^Ｋは、前記と同義である。）、及び（ｌ）ヒドロキシで置換されていてもよい飽和環状アミノ基からなる群から選択される１又は２個の基で置換されていてもよい。）、
（２）次の一般式［８］で表される基、

(Wherein, *, R ^K are the same as defined above.), And (l) substituted with 1 or 2 groups selected from the group consisting of may also be a saturated cyclic amino group optionally substituted by hydroxy It may be. ),
(2) a group represented by the following general formula [8],

（式中、＊、Ｒ^Ｌは、前記と同義である。）、
（３）次の一般式［９］で表される基、

(Wherein, * and ^RL are as defined above),
(3) a group represented by the following general formula [9],

（式中、＊、Ｒ^Ｍ、Ｒ^Ｎ、Ｒ^Ｏは、前記と同義である。）、

(Wherein, *, R ^M , R ^N and R ^O are as defined above),

(4) -OR ^P1 (wherein R ^P1 represents alkyl optionally substituted with a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl), or

(5) substituted with one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl Optionally heteroaryl.

[Ii]
X is -CR ^A ,
R ^A is a group represented by the following general formula [10]:

（式中、＊、Ｒ^Ｂは、前記と同義である。）
Ｒ^２がＨ。

より好ましくは、
ＸがＣＨであり、
Ｒ^２が、
（１）次の一般式［１１］で表される基、

(Wherein, *, ^{R B} are the same as defined above.)
R ² is H.

More preferably,
X is CH,
R ² is
(1) a group represented by the following general formula [11],

（式中、＊、Ｒ^Ｆ１、Ｒ^Ｇ１は、前記と同義である。）、
（２）次の一般式［８］で表される基、

(Wherein, *, R ^F1 and R ^G1 are as defined above),
(2) a group represented by the following general formula [8],

（式中、＊、Ｒ^Ｌは、前記と同義である。）、
（３）次の一般式［９］で表される基、

(Wherein, * and ^RL are as defined above),
(3) a group represented by the following general formula [9],

（式中、＊、Ｒ^Ｍ、Ｒ^Ｎ、Ｒ^Ｏは、前記と同義である。）、

(Wherein, *, R ^M , R ^N and R ^O are as defined above),

(4) -OR ^P1 (wherein R ^P1 has the same ^meaning as described above), or

(5) substituted with one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl A compound containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, which may be a heteroaryl. Cancer, esophageal cancer, lung cancer, neuroblastoma, retinoblastoma, squamous cell carcinoma, oral squamous cell carcinoma, mesothelioma, thymic tumor, skin cancer, oral cancer, retinoblastoma, bone metastasis of cancer , Bronchial asthma, disease caused by allergic reaction, autoimmune disease, disease caused by leukocyte accumulation during vascular injury, rejection at organ transplantation, acute coronary disease Mention may be made of the group, AIDS, a therapeutic agent or prophylactic agent for disease selected from the group consisting of Alzheimer's disease and age-related macular degeneration.

Specifically, rectal cancer, colon cancer, colon cancer, melanoma, pancreatic cancer, ovarian cancer, bladder cancer containing the following compounds (1) to (229) or a pharmaceutically acceptable salt thereof as an active ingredient Gastric cancer, head and neck cancer, esophageal cancer, lung cancer, neuroblastoma, retinoblastoma, squamous cell carcinoma, oral squamous cell carcinoma, mesothelioma, thymic tumor, skin cancer, oral cancer, retinoblastoma, Bone metastases, bronchial asthma, diseases caused by allergic reactions, autoimmune diseases, diseases caused by leukocyte accumulation during vascular injury, rejection during organ transplantation, acute coronary syndrome, AIDS, Alzheimer's disease and age-related macular degeneration The therapeutic agent or preventive agent of the disease selected from the group which consists of symptoms can be mentioned.
(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] pyrrolidine -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) pyrimidin-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) pyrimidin-2,4-diamine,
(14) (S) -N ² -[1- (4-Fluorophenyl) ethyl] -N ⁴ -(Pyrazin-2-yl) -6- (pyridin-2-yl) pyrimidin-2,4-diamine,
(15) (S) -N ² -[1- (4-Fluorophenyl) ethyl] -N ⁴ -(Pyrazin-2-yl) -6- (pyridin-4-yl) pyrimidin-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) pyrimidin-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-pyrazol-3-yl) pyrimidin-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} pyrrolidine-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] pyrrolidine -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-ylamino) 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-Fluorophenyl) 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) pyrimidin-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) pyrimidin-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-ylamino) pyrimidin-4-yl} pyrrolidin-3-yl) methane Sulfonamide,
(56) (S) -2-({2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} (2-hydroxyethyl) amino) ethane -1-ol,
(57) (S) -N ⁴ -[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) pyrimidin-2,4-diamine,
(62) (R) -1- {2-[(S) -1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} -4-hydroxypyrrolidine- 2-on,
(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) pyrimidin-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-ylamino) pyrimidin-4-ylamino} ethyl) methanesulfonamide,
(73) (S) -N- (2- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) 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-phenylpropane- 1-ol,
(83) (R) -2- {2-[(S) -1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-ylamino} -4-methylpentane- 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-methylbutane-1 -All,
(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-ylmethyl) -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) piperidine-4 -All,
(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) pyrimidin-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-Fluorophenyl) 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) piperidine-4 -All,
(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-thiomorpholine-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-ylamino) pyridin-4-yl} -1,4-diazepane- 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) (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinic acid methyl ester,
(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) -Nt-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) methane Sulfonamide,
(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-methoxyazetidin-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-ylamino) pyrimidin-4-yl} azetidin-3-yl) ethane Sulfonamide,
(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) azetidine- 3-ol,
(188) (S)-(1- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} azetidin-3-yl) (pyrrolidine- 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) (piperidine- 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) ethylamino] -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) azetidine- 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) -N ² -[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] pyrimidin-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) piperidine-4 -All,
(221) 4- {2-[(1S) -1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} -1λ ⁶ , 4-thiomorpholine-1,1-dione,
(222) (S) -1- (1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) 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) (S)-(1- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} azetidin-3-yl) methylcarbamic acid t -Butyl,
(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,
(229) (S) -1- (1- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} azetidin-3-yl) piperidine -4-ol.

Each term in this specification is explained in full detail below.
“Src family tyrosine kinase” is a general term for various tyrosine kinases such as c-Src tyrosine kinase, Fyn tyrosine kinase, Yes tyrosine kinase, Lyn tyrosine kinase, Fgr tyrosine kinase, and Lck tyrosine kinase.
Examples of “halogen” include fluorine, chlorine, bromine and iodine.

  Examples of the “alkyl” include linear or branched alkyl having 1 to 8 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Examples thereof include tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl and n-octyl. Especially, a C1-C6 alkyl is preferable and a C1-C3 alkyl is more preferable.

  “Alkylsulfonyl”, “alkylcarbonylamino”, “hydroxyalkyl”, “(cycloalkyl) alkyl”, “alkoxyalkyl”, “alkylamino”, “(hydroxyalkyl) amino”, “(alkoxyalkyl) amino”, Alkyl part of “dialkylamino”, “dialkylaminoalkyl” “(cycloalkyl) alkylamino”, “alkylcarbonyl”, “alkylcarbonylamino”, “alkylsulfonyl”, “alkylsulfonylamino”, “monoalkylaminosulfonyl” Can be the same as the above-mentioned “alkyl”.

  “Haloalkyl” includes, for example, linear or branched alkyl having 1 to 8 carbon atoms substituted at any position where one or more halogen atoms can be substituted. Examples of the alkyl part and the halogen part of “haloalkyl” include those similar to the above “alkyl” and “halogen”, respectively.

  Examples of “cycloalkyl” include cycloalkyl having 3 to 8 carbon atoms, specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

  Examples of the cycloalkyl moiety of “(cycloalkyl) alkyl”, “cycloalkylamino”, and “(cycloalkyl) alkylamino” include those similar to the above “cycloalkyl”.

  The “alkoxy” is, for example, linear or branched alkoxy having 1 to 8 carbon atoms, specifically methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy. , T-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, and n-octyloxy.

  Examples of the alkoxy moiety of “alkoxyalkyl” and “(alkoxyalkyl) amino” include those similar to the above “alkoxy”.

  Examples of “aryl” include aryl having 6 to 10 carbon atoms, such as phenyl, 1-naphthyl, and 2-naphthyl. Of these, phenyl is preferred.

  The “aralkyl” includes, for example, linear or branched alkyl having 1 to 8 carbon atoms substituted at any position where aryl having 6 to 10 carbon atoms can be substituted, such as benzyl, phenylethyl ( For example, 1-phenylethyl, 2-phenylethyl), phenylpropyl (1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, etc.), naphthylmethyl (eg, 1-naphthylmethyl, 2-naphthylmethyl, etc.) Can be mentioned.

  The “saturated cyclic amino group” includes, for example, a 4-membered to 7-membered saturated cyclic amino group having one or two N, which may have one O or S as a ring atom, Examples include 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, piperidino, 1-piperazinyl, 1-tetrahydropyrimidinyl, morpholino, thiomorpholino, 1-homopiperazinyl.

  As the “saturated heterocyclic group containing 1 N”, for example, a 5-membered or 6-membered saturated heterocyclic group having 1 N as a ring-constituting atom, specific examples include 2-pyrrolidinyl, Examples include 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl.

As the “saturated cyclic group optionally containing one O”, for example, a 5-membered or 6-membered saturated cyclic group optionally having 1 O as a ring-constituting atom, specifically, Can include, for example, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl.

  “Heteroaryl” is, for example, a 5- or 6-membered heteroaryl having 1 to 4 N, O, or S as ring-constituting atoms. Specific examples include furyl (for example, 2-furyl, 3 -Furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl) , Pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (eg 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2, 4-triazol-4-yl), tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (eg -Oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (eg 1,3,4-oxadiazol-2-yl), thiazolyl ( For example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (eg, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl) , Pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), and pyrazinyl (eg, 2-pyrazinyl).

  Examples of “tetrahydrofuranyl” include 2-tetrahydrofuranyl and 3-tetrahydrofuranyl.

Examples of “tetrahydropyranyl” include 2-tetrahydropyranyl, 3-tetrahydropyranyl, and 4-tetrahydropyranyl.

The compound of the present invention can be produced from a known compound or an easily synthesizeable intermediate, for example, according to the following method. In the production of the compound of the present invention, when the raw material has a substituent that affects the reaction, the reaction is generally carried out after the raw material is protected with a suitable protecting group by a known method in advance. The protecting group can be removed after the reaction by a known method.

Production method 1 When R ² is halogen

（Ｒ^１、Ｒ^５は、前記と同義である。Ｘ^１は、ＣＨ又はＮを表す。Ｈａｌ^１、Ｈａｌ^２は、同一又は異なって、ハロゲンを表す。）
本反応は、化合物［１２］と化合物［１３］とのパラジウム触媒を用いた縮合反応であって、それ故、縮合反応としてそれ自体公知の方法によって行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、１，４−ジオキサン、テトラヒドロフランなどのエーテル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。反応は塩基の存在下、２０℃〜２００℃の範囲内で行う。使用しうるパラジウム触媒としては、例えば、トリス（ジベンジリデンアセトン）（クロロホルム）ジパラジウム（０）、トリス（ジベンジリデンアセトン）ジパラジウム（０）、酢酸パラジウム（ＩＩ）が挙げられる。使用しうるパラジウム触媒の量は、ハロゲン化アリール１モルに対して、０．００１〜０．１モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、１，１’−ビス（ジフェニルホスフィノ）フェロセン、４，５−ビス（ジフェニルホスフィノ）−９，９’−ジメチルキサンテン、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル、（±）−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル、２−（ジ−ｔ−ブチルホスフィノ）ビフェニル、ビス［２−（ジフェニルホスフィノ）フェニル］エーテル、トリｔ−ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムｔ−ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、１０分〜２４時間の範囲内が適当である。

原料化合物である化合物［１２］は、公知の方法（Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．，１４，２００４，４２４９−４２５２、Ｏｒｇ．Ｌｅｔｔ．，６，２００４，３６７１−３６７４など）に準じて製造することができる。

製法２ Ｒ ^２ が−ＯＲ ^Ｐ の場合（式中、Ｒ^Ｐは、前記と同義である。）
製法２−１

(R ¹ and R ⁵ are as defined above. X ¹ represents CH or N. Hal ¹ and Hal ² are the same or different and represent halogen.)
This reaction is a condensation reaction of the compound [12] and the compound [13] using a palladium catalyst, and therefore can be performed by a method known per se as a condensation reaction. Solvents that can be used are not particularly limited as long as they are not involved in the reaction. For example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N, N-dimethylformamide, N, Examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof. The reaction is carried out in the range of 20 ° C. to 200 ° C. in the presence of a base. Examples of the palladium catalyst that can be used include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate. The amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide. Examples of the ligand of the palladium catalyst that can be used include 1,1′-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, and 2-dicyclohexylphosphino- 2 ′, 4 ′, 6′-triisopropylbiphenyl, (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis Mention may be made of [2- (diphenylphosphino) phenyl] ether and tri-t-butylphosphine. Examples of the base that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.

Compound [12], which is a raw material compound, is produced according to a known method (Bioorg. Med. Chem. Lett., 14, 2004, 4249-4252, Org. Lett., 6, 2004, 3671-3675, etc.). be able to.

If method 2 ^{R 2} is -OR ^P (wherein, ^{R P} has the same meaning as defined above.)
Manufacturing method 2-1

（Ｘ^１、Ｒ^１、Ｒ^５、Ｈａｌ^２は、前記と同義である。Ｒ^Ｐは、ヒドロキシ、ジアルキルアミノ、アルコキシ、テトラヒドロフラニル、及びシクロアルキルからなる群から選択される基で置換されていてもよいアルキル、又は、ヒドロキシで置換されていてもよく、１個のＯを含んでいてもよい飽和環式基を表す。）

本反応は、化合物［１ａ］とアルコール化合物［１４］とのパラジウム触媒を用いた縮合反応により行われる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、１，４−ジオキサン、テトラヒドロフランなどのエーテル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。本反応は塩基の存在下、２０℃〜２００℃の範囲内で行うことができる。パラジウム触媒としては、例えば、トリス（ジベンジリデンアセトン）（クロロホルム）ジパラジウム（０）、トリス（ジベンジリデンアセトン）ジパラジウム（０）、酢酸パラジウム（ＩＩ）が挙げられる。使用しうるパラジウム触媒の量は、ハロゲン化アリール１モルに対して、０．００１〜０．１モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、４，５−ビス（ジフェニルホスフィノ）−９，９’−ジメチルキサンテン、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル、（±）−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル、２−（ジ−ｔ−ブチルホスフィノ）ビフェニル、ビス［２−（ジフェニルホスフィノ）フェニル］エーテルを挙げることができる。使用しうる塩基としては、例えば、ナトリウムｔ−ブトキシド、リン酸三カリウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、１０分〜２４時間の範囲内が適当である。

製法２−２

(X ¹ , R ¹ , R ⁵ , Hal ² are as defined above. R ^P is substituted with a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl. And represents a saturated cyclic group which may be substituted with alkyl or hydroxy and may contain one O.)

This reaction is carried out by a condensation reaction of compound [1a] and alcohol compound [14] using a palladium catalyst. Solvents that can be used are not particularly limited as long as they are not involved in the reaction. For example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N, N-dimethylformamide, N, Examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof. This reaction can be carried out in the range of 20 ° C. to 200 ° C. in the presence of a base. Examples of the palladium catalyst include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate. The amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide. Examples of palladium catalyst ligands that can be used include 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 be able to. Examples of the base that can be used include sodium t-butoxide and tripotassium phosphate. The reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.

Manufacturing method 2-2

（Ｘ^１、Ｒ^１、Ｒ^５、Ｒ^Ｐ、Ｈａｌ^１は、前記と同義である。）
本反応は、化合物［１５］と化合物［１３］とのパラジウム触媒を用いた縮合反応であって、前記製法１と同様の方法によって行うことができる。

(X ¹ , R ¹ , R ⁵ , R ^P , and Hal ¹ are as defined above.)
This reaction is a condensation reaction of compound [15] and compound [13] using a palladium catalyst, and can be carried out by the same method as in Production Method 1.

Compound [15], which is a raw material compound, can be produced, for example, according to the following method.

（Ｘ^１、Ｒ^１、Ｒ^Ｐ、Ｈａｌ^１、Ｈａｌ^２は、前記と同義である。）

工程１
化合物［１８］は、化合物［１６］とアルコール化合物［１７］とを適当な溶媒中、塩基の存在下、−２０℃〜１００℃の範囲内で反応させることにより製造することができる。使用しうる塩基としては、例えば、水素化ナトリウム、水酸化ナトリウム等を挙げることができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、１，４−ジオキサン、テトラヒドロフランなどのエーテル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドンなどのアミド類、水、又はこれらの混合溶媒を挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常３０分から２４時間が適当である。

(X ¹ , R ¹ , R ^P , Hal ¹ and Hal ² are as defined above.)

Process 1
Compound [18] can be produced by reacting compound [16] with alcohol compound [17] in the presence of a base in the range of −20 ° C. to 100 ° C. Examples of the base that can be used include sodium hydride and sodium hydroxide. Solvents that can be used are not particularly limited as long as they are not involved in the reaction. For example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N, N-dimethylformamide, N, Examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, water, or a mixed solvent thereof. The reaction time varies depending on the type of raw materials used and the reaction temperature, but usually 30 minutes to 24 hours is appropriate.

Process 2
This reaction is a condensation reaction of the compound [18] and the compound [19] using a palladium catalyst, and therefore can be performed by a method known per se as a condensation reaction. Solvents that can be used are not particularly limited as long as they are not involved in the reaction. For example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N, N-dimethylformamide, N, Examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof. This reaction can be carried out in the range of 20 ° C. to 200 ° C. in the presence of a base. Examples of the palladium catalyst that can be used include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate. The amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide. Examples of the palladium catalyst ligand that can be used include 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, (±) -2,2′-bis (diphenylphosphino) -1,1. Examples include '-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis [2- (diphenylphosphino) phenyl] ether, and tri-t-butylphosphine. Examples of the base that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.

Production Method 3 R ² is a group represented by the following general formula [9],

(Wherein R ^M , R ^N , R ^O , * Is as defined above. ) Or
Substituted with one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl In the case of a good heteroaryl (provided that the bond is from C)

Production method 3-1

（Ｘ^１、Ｒ^１、Ｒ^５、Ｈａｌ^２は、前記と同義である。Ｒ^６、Ｒ^７は、いずれもヒドロキシを表すか、又は、Ｒ^６とＲ^７とが一緒になって、−Ｏ−Ｃ（ＣＨ_３）_２−Ｃ（ＣＨ_３）_２−Ｏ−、−Ｏ−（ＣＨ_２）_３−Ｏ−、又は、−Ｏ−ＣＨ_２−Ｃ（ＣＨ_３）_２−ＣＨ_２−Ｏ−を表す。
Ｒ^８は、次の一般式［９］で表される基、

(X ¹ , R ¹ , R ⁵ and Hal ² are as defined above. R ⁶ and R ⁷ both represent hydroxy, or R ⁶ and R ⁷ together 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- Represents.
R ⁸ is a group represented by the following general formula [9],

（式中、Ｒ^Ｍ、Ｒ^Ｎ、Ｒ^Ｏ、＊は、前記と同義である。）、又は、
シアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、（シクロアルキル）アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される１若しくは２個の基で置換されていてもよいヘテロアリール（但し、結合手がＣから出ているものに限る。）を表す。）

本反応は、化合物［１ａ］と有機ホウ素化合物［２０］とを用いたクロスカップリング反応であり、それ自体公知の方法によって行うことができる。本反応は、例えばパラジウム触媒と塩基の存在下、適当な溶媒中、２０〜２００℃で行うことができる。使用しうるパラジウム触媒としては、例えば、テトラキス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（ＩＩ）ジクロリド−ジクロロメタン錯体を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール１モルに対して、０．００１〜０．１モルの範囲内が適当である。使用しうる反応溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、１，４−ジオキサン、１，２−ジメトキシエタンなどのエーテル類、メタノール、エタノールなどのアルコール類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、水、又はこれらの混合溶媒を挙げることができる。また、使用しうる塩基としては、例えば、水酸化ナトリウム、炭酸カリウム、炭酸ナトリウムを挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、３０分〜２４時間の範囲内が適当である。

製法３−２

(Wherein R ^M , R ^N , R ^O and * are as defined above), or
Substituted with one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl Represents a good heteroaryl (provided that the bond is from C). )

This reaction is a cross-coupling reaction using the compound [1a] and the organoboron compound [20], and can be performed by a method known per se. This reaction can be performed at 20-200 degreeC in a suitable solvent, for example in presence of a palladium catalyst and a base. Examples of palladium catalysts that can be used include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex. Can do. The amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide. The reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction. For example, ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, N, Examples thereof include amides such as N-dimethylformamide and N, N-dimethylacetamide, hydrocarbons such as benzene and toluene, water, or a mixed solvent thereof. Examples of the base that can be used include sodium hydroxide, potassium carbonate, and sodium carbonate. The reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 30 minutes to 24 hours.

Manufacturing method 3-2

（Ｘ^１、Ｒ^１、Ｒ^５、Ｒ^８、Ｈａｌ^１は、前記と同義である。）

本反応は、化合物［２１］と化合物［１３］とのパラジウム触媒を用いた縮合反応であって、それ自体公知の方法によって行われる。使用しうる溶媒は、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、１，４−ジオキサン、テトラヒドロフランなどのエーテル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。本反応は塩基の存在下、２０℃〜２００℃の範囲内で反応を行うことができる。使用しうるパラジウム触媒としては、例えば、トリス（ジベンジリデンアセトン）（クロロホルム）ジパラジウム（０）、トリス（ジベンジリデンアセトン）ジパラジウム（０）、酢酸パラジウム（ＩＩ）が挙げられる。使用しうるパラジウム触媒の量は、ハロゲン化アリール１モルに対して、０．００１〜０．１モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、１，１’−ビス（ジフェニルホスフィノ）フェロセン、４，５−ビス（ジフェニルホスフィノ）−９，９’−ジメチルキサンテン、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル、（±）−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル、２−（ジ−ｔ−ブチルホスフィノ）ビフェニル、ビス［２−（ジフェニルホスフィノ）フェニル］エーテル、トリｔ−ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムｔ−ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、１０分〜２４時間の範囲内が適当である。

原料化合物である化合物［２１］は、例えば次の３つの方法に従って製造することができる。

(X ¹ , R ¹ , R ⁵ , R ⁸ , and Hal ¹ are as defined above.)

This reaction is a condensation reaction of compound [21] and compound [13] using a palladium catalyst, and is performed by a method known per se. Solvents that can be used are not particularly limited as long as they are not involved in the reaction. For example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N, N-dimethylformamide, N, N -Amides such as dimethylacetamide and N-methyl-2-pyrrolidone, or a mixed solvent thereof. This reaction can be carried out in the range of 20 ° C. to 200 ° C. in the presence of a base. Examples of the palladium catalyst that can be used include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate. The amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide. Examples of the ligand of the palladium catalyst that can be used include 1,1′-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, and 2-dicyclohexylphosphino- 2 ′, 4 ′, 6′-triisopropylbiphenyl, (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis Mention may be made of [2- (diphenylphosphino) phenyl] ether and tri-t-butylphosphine. Examples of the base that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.

Compound [21], which is a raw material compound, can be produced, for example, according to the following three methods.

（Ｘ^１、Ｒ^１、Ｒ^６、Ｒ^７、Ｒ^８、Ｈａｌ^１、Ｈａｌ^２は、前記と同義である。Ｈａｌ^３は、ハロゲンを表す。）

工程１
本反応は、化合物［２２］と有機ホウ素化合物［２０］とを用いたクロスカップリング反応であり、それ自体公知の方法によって行うことができる。本反応は、例えばパラジウム触媒と塩基の存在下、適当な溶媒中、２０〜２００℃の範囲内で行うことができる。使用しうるパラジウム触媒としては、例えば、テトラキス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（ＩＩ）ジクロリド−ジクロロメタン錯体を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール１モルに対して、０．００１〜０．１モルの範囲内が適当である。使用しうる反応溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、１，４−ジオキサン、１，２−ジメトキシエタンなどのエーテル類、メタノール、エタノールなどのアルコール類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、水、又はこれらの混合溶媒を挙げることができる。使用しうる塩基としては、例えば、水酸化ナトリウム、炭酸カリウム、炭酸ナトリウムを挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、３０分〜２４時間の範囲内が適当である。

工程２
本反応は、化合物［２３］と化合物［１９］とのパラジウム触媒を用いた縮合反応であって、それ故、縮合反応としてそれ自体公知の方法によって行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、１，４−ジオキサン、テトラヒドロフランなどのエーテル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。本反応は、塩基の存在下、２０℃〜２００℃の範囲内で反応を行うことができる。使用しうるパラジウム触媒としては、例えば、トリス（ジベンジリデンアセトン）（クロロホルム）ジパラジウム（０）、トリス（ジベンジリデンアセトン）ジパラジウム（０）、酢酸パラジウム（ＩＩ）を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール１モルに対して、０．００１〜０．１モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、４，５−ビス（ジフェニルホスフィノ）−９，９’−ジメチルキサンテン、（±）−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル、２−（ジ−ｔ−ブチルホスフィノ）ビフェニル、ビス［２−（ジフェニルホスフィノ）フェニル］エーテル、トリｔ−ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムｔ−ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、１０分〜２４時間の範囲内が適当である。

方法Ｂ Method A

(X ¹ , R ¹ , R ⁶ , R ⁷ , R ⁸ , Hal ¹ , Hal ² are as defined above. Hal ³ represents halogen.)

Process 1
This reaction is a cross-coupling reaction using compound [22] and organoboron compound [20], and can be performed by a method known per se. This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent within a range of 20 to 200 ° C. Examples of palladium catalysts that can be used include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex. Can do. The amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide. The reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction. For example, ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, N, Examples thereof include amides such as N-dimethylformamide and N, N-dimethylacetamide, hydrocarbons such as benzene and toluene, water, or a mixed solvent thereof. Examples of the base that can be used include sodium hydroxide, potassium carbonate, and sodium carbonate. The reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 30 minutes to 24 hours.

Process 2
This reaction is a condensation reaction of the compound [23] and the compound [19] using a palladium catalyst, and therefore can be performed by a method known per se as a condensation reaction. Solvents that can be used are not particularly limited as long as they are not involved in the reaction. For example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N, N-dimethylformamide, N, Examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof. This reaction can be carried out in the range of 20 ° C. to 200 ° C. in the presence of a base. Examples of the palladium catalyst that can be used include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate. The amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide. Examples of the palladium catalyst ligand that can be used include 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, (±) -2,2′-bis (diphenylphosphino) -1,1. Examples include '-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis [2- (diphenylphosphino) phenyl] ether, and tri-t-butylphosphine. Examples of the base that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.

Method B

（Ｘ^１、Ｒ^１、Ｒ^８、Ｈａｌ^１、Ｈａｌ^２は、前記と同義である。Ｒ^９、Ｒ^１０、Ｒ^１１は、同一又は異なって、アルキルを表す。）

本反応は、化合物［１２］と有機スズ化合物［２４］とを用いたクロスカップリング反応で、それ自体公知の方法によって行うことができる。本反応は、例えばパラジウム触媒存在下、適当な溶媒中、２０〜２００℃で行うことができる。使用しうるパラジウム触媒としては、例えば、テトラキス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（ＩＩ）ジクロリド−ジクロロメタン錯体、酢酸パラジウムを挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール１モルに対して、０．００１〜０．１モルの範囲内が適当である。使用しうる反応溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、１，４−ジオキサン、１，２−ジメトキシエタンなどのエーテル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、又はこれらの混合溶媒を挙げることができる。また酸化銅や酸化銀のような添加剤を加えることも出来る。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、１〜２４時間の範囲内が適当である。

方法Ｃ

(X ¹ , R ¹ , R ⁸ , Hal ¹ and Hal ² are as defined above. R ⁹ , R ¹⁰ and R ¹¹ are the same or different and represent alkyl.)

This reaction is a cross-coupling reaction using compound [12] and organotin compound [24] and can be carried out by a method known per se. This reaction can be performed at 20 to 200 ° C. in a suitable solvent, for example, in the presence of a palladium catalyst. Examples of the palladium catalyst that can be used include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex, and palladium acetate. Can be mentioned. The amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide. The reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction. For example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, N, N -Amides such as dimethylacetamide, hydrocarbons such as benzene and toluene, or a mixed solvent thereof. Additives such as copper oxide and silver oxide can also be added. The reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 1 to 24 hours.

Method C

（Ｘ^１、Ｒ^１、Ｒ^６、Ｒ^７、Ｒ^８、Ｈａｌ^１、Ｈａｌ^２は、前記と同義である。）

本反応は、化合物［１２］と有機ホウ素化合物［２０］とを用いたクロスカップリング反応であり、それ自体公知の方法によって行うことができる。本反応は、例えばパラジウム触媒と塩基の存在下、適当な溶媒中、２０〜２００℃の範囲内で行うことができる。使用しうるパラジウム触媒としては、例えば、テトラキス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（ＩＩ）ジクロリド−ジクロロメタン錯体を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール１モルに対して、０．００１〜０．１モルの範囲内が適当である。使用しうる反応溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、１，４−ジオキサン、１，２−ジメトキシエタンなどのエーテル類、メタノール、エタノールなどのアルコール類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、水、又はこれらの混合溶媒を挙げることができる。使用しうる塩基としては、例えば、水酸化ナトリウム、炭酸カリウム、炭酸ナトリウムを挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、３０分〜２４時間の範囲内が適当である。

製法４ Ｒ ^２ が次の一般式［３］で表される基

(X ¹ , R ¹ , R ⁶ , R ⁷ , R ⁸ , Hal ¹ , Hal ² are as defined above.)

This reaction is a cross-coupling reaction using compound [12] and organoboron compound [20], and can be carried out by a method known per se. This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent within a range of 20 to 200 ° C. Examples of palladium catalysts that can be used include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex. Can do. The amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide. The reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction. For example, ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, N, Examples thereof include amides such as N-dimethylformamide and N, N-dimethylacetamide, hydrocarbons such as benzene and toluene, water, or a mixed solvent thereof. Examples of the base that can be used include sodium hydroxide, potassium carbonate, and sodium carbonate. The reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 30 minutes to 24 hours.

Production Method 4 R ² is a group represented by the following general formula [3]

(Wherein R ^F , R ^G Is as defined above. )in the case of

Manufacturing method 4-1

（Ｘ^１、Ｒ^１、Ｒ^５、Ｈａｌ^２は、前記と同義である。Ｒ^１２は、次の一般式［３］で表される基を表す。

(X ¹ , R ¹ , R ⁵ and Hal ² are as defined above. R ¹² represents a group represented by the following general formula [3].

（式中、Ｒ^Ｆ、Ｒ^Ｇは、前記と同義である。））

本反応は、化合物［１ａ］と化合物［２５］とを用いたクロスカップリング反応であり、それ自体公知の方法によって行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、１，４−ジオキサン、テトラヒドロフランなどのエーテル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。本反応は、例えばパラジウム触媒と塩基の存在下、適当な溶媒中、２０〜２００℃の範囲内で行うことができる。使用しうるパラジウム触媒としては、例えば、トリス（ジベンジリデンアセトン）（クロロホルム）ジパラジウム（０）、トリス（ジベンジリデンアセトン）ジパラジウム（０）、酢酸パラジウム（ＩＩ）を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール１モルに対して、０．００１〜０．１モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、１，１’−ビス（ジフェニルホスフィノ）フェロセン、４，５−ビス（ジフェニルホスフィノ）−９，９’−ジメチルキサンテン、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル、（±）−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル、２−（ジ−ｔ−ブチルホスフィノ）ビフェニル、ビス［２−（ジフェニルホスフィノ）フェニル］エーテル、トリｔ−ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムｔ−ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、３０分〜２４時間の範囲内が適当である。

製法４−２

(Wherein R ^F and R ^G are as defined above.)

This reaction is a cross-coupling reaction using compound [1a] and compound [25] and can be carried out by a method known per se. Solvents that can be used are not particularly limited as long as they are not involved in the reaction. For example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N, N-dimethylformamide, N, Examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof. This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent within a range of 20 to 200 ° C. Examples of the palladium catalyst that can be used include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate. The amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide. Examples of the ligand of the palladium catalyst that can be used include 1,1′-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, and 2-dicyclohexylphosphino- 2 ′, 4 ′, 6′-triisopropylbiphenyl, (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis Mention may be made of [2- (diphenylphosphino) phenyl] ether and tri-t-butylphosphine. Examples of the base that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 30 minutes to 24 hours.

Manufacturing method 4-2

（Ｘ^１、Ｒ^１、Ｒ^５、Ｒ^１２、Ｈａｌ^１は、前記と同義である。）

本反応は、化合物［２６］と化合物［１３］とのパラジウム触媒を用いた縮合反応であって、それ自体公知の方法によって行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、１，４−ジオキサン、テトラヒドロフランなどのエーテル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。本反応は塩基の存在下、２０℃〜２００℃の範囲内で反応を行うことができる。使用しうるパラジウム触媒としては、例えば、トリス（ジベンジリデンアセトン）（クロロホルム）ジパラジウム（０）、トリス（ジベンジリデンアセトン）ジパラジウム（０）、酢酸パラジウム（ＩＩ）を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール１モルに対して、０．００１〜０．１モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、１，１’−ビス（ジフェニルホスフィノ）フェロセン、４，５−ビス（ジフェニルホスフィノ）−９，９’−ジメチルキサンテン、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル、（±）−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル、２−（ジ−ｔ−ブチルホスフィノ）ビフェニル、ビス［２−（ジフェニルホスフィノ）フェニル］エーテル、トリｔ−ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムｔ−ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、１０分〜２４時間の範囲内が適当である。

原料化合物である化合物［２６］は、例えば、次の２つの方法に従って製造することができる。

(X ¹ , R ¹ , R ⁵ , R ¹² and Hal ¹ are as defined above.)

This reaction is a condensation reaction of compound [26] and compound [13] using a palladium catalyst and can be carried out by a method known per se. Solvents that can be used are not particularly limited as long as they are not involved in the reaction. For example, hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N, N-dimethylformamide, N, Examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, and mixed solvents thereof. This reaction can be carried out in the range of 20 ° C. to 200 ° C. in the presence of a base. Examples of the palladium catalyst that can be used include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate. The amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide. Examples of the ligand of the palladium catalyst that can be used include 1,1′-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, and 2-dicyclohexylphosphino- 2 ′, 4 ′, 6′-triisopropylbiphenyl, (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis Mention may be made of [2- (diphenylphosphino) phenyl] ether and tri-t-butylphosphine. Examples of the base that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.

Compound [26], which is a raw material compound, can be produced, for example, according to the following two methods.

（Ｘ^１、Ｒ^１、Ｒ^１２、Ｈａｌ^１、Ｈａｌ^２は、前記と同義である。）
方法ａ
化合物［２６］は、化合物［１２］と化合物［２５］とを適当な溶媒中、塩基の存在下、２０℃〜２００℃の範囲内で反応させることにより製造することができる。使用しうる塩基は、例えば、ピリジン、トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、炭酸カリウム、炭酸水素ナトリウムを挙げることができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、１−ブタノール、２−メトキシエタノールなどのアルコール類、テトラヒドロフラン、１，４−ジオキサンなどのエーテル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、アセトニトリル、又はこれらの混合溶媒を挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、１〜２４時間の範囲内が適当である。

方法ｂ
化合物［２６］は、化合物［１２］と化合物［２５］とのパラジウム触媒を用いた縮合反応であって、それ自体公知の方法によって行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、１，４−ジオキサン、テトラヒドロフランなどのエーテル類、又はこれらの混合溶媒を挙げることができる。本反応は塩基の存在下、２０℃〜２００℃の範囲内で反応を行うことができる。使用しうるパラジウム触媒としては、例えば、トリス（ジベンジリデンアセトン）（クロロホルム）ジパラジウム（０）、トリス（ジベンジリデンアセトン）ジパラジウム（０）、酢酸パラジウム（ＩＩ）を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール１モルに対して、０．００１〜０．１モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、１，１’−ビス（ジフェニルホスフィノ）フェロセン、４，５−ビス（ジフェニルホスフィノ）−９，９’−ジメチルキサンテン、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル、（±）−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル、２−（ジ−ｔ−ブチルホスフィノ）ビフェニル、ビス［２−（ジフェニルホスフィノ）フェニル］エーテル、トリｔ−ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムｔ−ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、１０分〜２４時間の範囲内が適当である。

製法５ Ｒ ^２ がシアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、（シクロアルキル）アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される１若しくは２個の基で置換されていてもよいヘテロアリール（但し、結合手がＮから出ているものに限る。）の場合

(X ¹ , R ¹ , R ¹² , Hal ¹ , Hal ² are as defined above.)
Method a
Compound [26] can be produced by reacting compound [12] and compound [25] in a suitable solvent in the presence of a base within the range of 20 ° C to 200 ° C. Examples of the base that can be used include pyridine, triethylamine, N, N-diisopropylethylamine, potassium carbonate, and sodium hydrogen carbonate. Solvents that can be used are not particularly limited as long as they are not involved in the reaction, but alcohols such as 1-butanol and 2-methoxyethanol, ethers such as tetrahydrofuran and 1,4-dioxane, N, N-dimethylformamide, Examples thereof include amides such as N, N-dimethylacetamide, hydrocarbons such as benzene and toluene, acetonitrile, and a mixed solvent thereof. The reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 1 to 24 hours.

Method b
Compound [26] is a condensation reaction of compound [12] and compound [25] using a palladium catalyst and can be carried out by a method known per se. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples thereof include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, and mixed solvents thereof. it can. This reaction can be carried out in the range of 20 ° C. to 200 ° C. in the presence of a base. Examples of the palladium catalyst that can be used include tris (dibenzylideneacetone) (chloroform) dipalladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate. The amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide. Examples of the ligand of the palladium catalyst that can be used include 1,1′-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene, and 2-dicyclohexylphosphino- 2 ′, 4 ′, 6′-triisopropylbiphenyl, (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 2- (di-t-butylphosphino) biphenyl, bis Mention may be made of [2- (diphenylphosphino) phenyl] ether and tri-t-butylphosphine. Examples of the base that can be used include sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.

Production Method 5 R ² is one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl. In the case of optionally substituted heteroaryl (provided that the bond is from N)

（Ｘ^１、Ｒ^１、Ｒ^５、Ｈａｌ^１は、前記と同義である。Ｒ^１３は、シアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、（シクロアルキル）アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される又は２個の基で置換されていてもよいヘテロアリール（但し、結合手がＮから出ているものに限る。）を表す。）
本反応は、化合物［２７］と化合物［１３］とのパラジウム触媒を用いた縮合反応であって、前記製法４−２と同様の方法により行うことができる。

原料化合物である化合物［２７］は、次の方法に従って製造することができる。

(X ¹ , R ¹ , R ⁵ , Hal ¹ are as defined above. R ¹³ is cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, Heteroaryl selected from the group consisting of hydroxycarbonyl and alkoxyalkyl or optionally substituted with two groups (provided that the bond is from N)
This reaction is a condensation reaction of compound [27] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in the above production method 4-2.

Compound [27], which is a raw material compound, can be produced according to the following method.

（Ｘ^１、Ｒ^１、Ｒ^１３、Ｈａｌ^１、Ｈａｌ^２は、前記と同義である。）
本反応は、化合物［１２］と化合物［２８］とを用いたクロスカップリング反応であり、それ自体公知の方法によって行うことができる。本反応は、例えば、銅触媒の存在又は非存在下に、適当な溶媒中、２０〜２００℃の範囲内で行うことができる。使用しうる銅触媒としては、例えば、ヨウ化銅、酢酸銅などを挙げることができる。使用しうる銅触媒の量は、ハロゲン化アリール１モルに対して、０．０１〜０．２モルの範囲内が適当である。また、銅の配位子として、トランス−Ｎ，Ｎ’−ジメチルシクロヘキサン−１，２−ジアミン、トランス−１，２−シクロヘキサンジアミン、１，１０−フェナントロリンなどを挙げることができる。使用しうる反応溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、１，４−ジオキサン、１，２−ジメトキシエタンなどのエーテル類、メタノール、エタノールなどのアルコール類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、又はこれらの混合溶媒を挙げることができる。使用しうる塩基としては、例えば、リン酸三カリウム、炭酸カリウム、炭酸ナトリウム、炭酸セシウムなどを挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、３０分〜２４時間の範囲内が適当である。

製法６ Ｒ ^２ がアルコキシカルボニルの場合

(X ¹ , R ¹ , R ¹³ , Hal ¹ , and Hal ² are as defined above.)
This reaction is a cross-coupling reaction using compound [12] and compound [28] and can be carried out by a method known per se. This reaction can be performed, for example, in the range of 20 to 200 ° C. in a suitable solvent in the presence or absence of a copper catalyst. Examples of the copper catalyst that can be used include copper iodide and copper acetate. The amount of the copper catalyst that can be used is suitably in the range of 0.01 to 0.2 mol with respect to 1 mol of the aryl halide. Examples of copper ligands include trans-N, N′-dimethylcyclohexane-1,2-diamine, trans-1,2-cyclohexanediamine, and 1,10-phenanthroline. The reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction. For example, ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, N, Examples thereof include amides such as N-dimethylformamide and N, N-dimethylacetamide, hydrocarbons such as benzene and toluene, and mixed solvents thereof. Examples of the base that can be used include tripotassium phosphate, potassium carbonate, sodium carbonate, cesium carbonate and the like. The reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 30 minutes to 24 hours.

Production Method 6 When R ² is Alkoxycarbonyl

（Ｘ^１、Ｒ^１、Ｒ^５、Ｈａｌ^１は、前記と同義である。Ｒ^１４は、アルキルを表す。）
本反応は、化合物［２９］と化合物［１３］とのパラジウム触媒を用いた縮合反応であって、前記製法４−２と同様の方法により行うことができる。

原料化合物である化合物［２９］は、次の方法に従って製造することができる。

(X ¹ , R ¹ , R ⁵ and Hal ¹ are as defined above. R ¹⁴ represents alkyl.)
This reaction is a condensation reaction of compound [29] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in the above production method 4-2.

Compound [29], which is a raw material compound, can be produced according to the following method.

（Ｘ^１、Ｒ^１、Ｒ^１４、Ｈａｌ^１、Ｈａｌ^３は、前記と同義である。）
本反応は、化合物［３０］と化合物［１９］とのパラジウム触媒を用いた縮合反応であって、前記原料化合物である化合物［１５］の製法の工程２と同様の方法により行うことができる。

製法７ Ｒ ^２ がヒドロキシカルボニルの場合

(X ¹ , R ¹ , R ¹⁴ , Hal ¹ , Hal ³ are as defined above.)
This reaction is a condensation reaction of the compound [30] and the compound [19] using a palladium catalyst, and can be performed by the same method as in Step 2 of the production method of the compound [15] as the raw material compound.

Production Method 7 When R ² is Hydroxycarbonyl

（Ｘ^１、Ｒ^１、Ｒ^５、Ｒ^１４は、前記と同義である。）
本反応は、化合物［１ｆ］の加水分解反応であって、それ自体公知の方法によって行うことができる。通常、酸又は塩基存在下において、化合物［１ｆ］を加水分解することにより化合物［１ｇ］を製造することができる。本反応に使用される酸としては、例えば、塩酸、硫酸のような無機酸、塩基としては、例えば、水酸化ナトリウム、水酸化カリウムなどの無機塩基を挙げることができる。本反応に使用しうる反応溶媒としては、例えば、メタノール、エタノールなどのアルコール類、テトラヒドロフラン、１，４−ジオキサンなどのエーテル類、水、又はこれらの混合溶媒を挙げることができる。反応温度は、０℃〜１００℃で行われ、反応時間は通常３０分〜２４時間である。

製法８ Ｒ ^２ が（ａ）アルキル若しくはアルキルスルホニルで置換されていてもよい飽和環状アミノ基、又は、（ｂ）アルキル、シクロアルキル、（シクロアルキル）アルキル、アラルキル、ハロアルキル、ジアルキルアミノアルキル、アルコキシアルキル、及びヒドロキシアルキルからなる群から選択される１若しくは２個の基を置換されていてもよいアミノカルボニルの場合

(X ¹ , R ¹ , R ⁵ and R ¹⁴ have the same meanings as described above.)
This reaction is a hydrolysis reaction of the compound [1f] and can be carried out by a method known per se. Usually, compound [1g] can be produced by hydrolyzing compound [1f] in the presence of an acid or a base. Examples of the acid used in this reaction include inorganic acids such as hydrochloric acid and sulfuric acid, and examples of the base include inorganic bases such as sodium hydroxide and potassium hydroxide. Examples of the reaction solvent that can be used in this reaction include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and 1,4-dioxane, water, and a mixed solvent thereof. The reaction temperature is 0 ° C to 100 ° C, and the reaction time is usually 30 minutes to 24 hours.

Production Method 8 R ² is (a) a saturated cyclic amino group optionally substituted with alkyl or alkylsulfonyl, or (b) alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, alkoxyalkyl In the case of aminocarbonyl optionally substituted with one or two groups selected from the group consisting of hydroxyalkyl

（Ｘ^１、Ｒ^１、Ｒ^５は、前記と同義である。Ｒ^１５、Ｒ^１６は、同一又は異なって、Ｈ、アルキル、シクロアルキル、（シクロアルキル）アルキル、アラルキル、ハロアルキル、ジアルキルアミノアルキル、アルコキシアルキル、若しくは、ヒドロキシアルキルを表すか、又は隣接するＮと一緒になって、飽和環状アミノ基を表す。かかる飽和環状アミノ基は、アルキル又はアルキルスルホニルで置換されていてもよい。）

本反応は、化合物［１ｇ］と化合物［３１］との縮合反応であって、縮合反応としてそれ自体公知の方法によって行うことができる。化合物［１ｇ］で表されるカルボン酸又はその反応性誘導体と、化合物［３１］を反応させることにより、化合物［１ｈ］を合成することができる。化合物［１ｇ］の反応性誘導体としては、例えば、酸ハライド（例えば、酸クロリド、酸ブロミド）、混合酸無水物、イミダゾリド、活性アミド等、アミド縮合形成反応に通常用いられるものを挙げることができる。化合物［１ｇ］を用いる場合には、塩基の存在又は非存在下において、縮合剤を使用して、−２０〜１００℃で反応を行うことができる。本反応に使用しうる縮合剤としては、例えば、１，１’−オキサリルジイミダゾール、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド、ジシクロヘキシルカルボジイミド、シアノホスホン酸ジエチル、Ｏ−（ベンゾトリアゾール−１−イル）−Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチルウロニウムヘキサフルオロリン酸塩、１Ｈ−ベンゾトリアゾール−１−イルオキシトリピロリジノホスホニウムヘキサフルオロホスファートを挙げることができる。本反応に使用しうる塩基としては、例えば、トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、Ｎ，Ｎ−ジメチルアニリン、ピリジン、１，８−ジアザビシクロ［５，４，０］−７−ウンデセンの有機塩基を挙げることができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、１，４−ジオキサン、ジエチルエーテルなどのエーテル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド類、アセトニトリル、プロピオンニトリルなどのニトリル類、ベンゼン、トルエンなどの炭化水素類、クロロホルム、塩化メチレンなどのハロゲン化炭化水素類、又はこれらの混合溶媒を挙げることができる。また、必要に応じて、添加剤を使用することができる。使用しうる添加剤としては、例えば、１−ヒドロキシベンゾトリアゾール、１−ヒドロキシ−７−アザベンゾトリアゾールを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、１０分〜２４時間の範囲内が適当である。化合物［３１］及び縮合剤の使用量としては、例えば、化合物［１ｇ］１モルに対して１〜３モルの範囲内が適当である。

製法９ Ｒ ^２ がＨ、アルキルカルボニル、アルキルスルホニルで置換されていてもよい１個のＮを含む飽和複素環式基、又は、ヒドロキシ若しくはアルコキシで置換されていてもよいアルキルである場合

(X ¹ , R ¹ , R ⁵ are as defined above. R ¹⁵ , R ¹⁶ are the same or different, and H, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, Represents alkoxyalkyl or hydroxyalkyl, or together with the adjacent N represents a saturated cyclic amino group, which may be substituted with alkyl or alkylsulfonyl)

This reaction is a condensation reaction between compound [1g] and compound [31] and can be carried out by a method known per se as a condensation reaction. Compound [1h] can be synthesized by reacting carboxylic acid represented by compound [1g] or a reactive derivative thereof with compound [31]. Examples of the reactive derivative of the compound [1g] include acid halides (for example, acid chloride, acid bromide), mixed acid anhydrides, imidazolides, active amides, and the like that are commonly used in amide condensation formation reactions. . When using the compound [1 g], the reaction can be performed at −20 to 100 ° C. using a condensing agent in the presence or absence of a base. Examples of the condensing agent that can be used in this reaction include 1,1′-oxalyldiimidazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphonate, O- (benzotriazole). -1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate. Examples of the base that can be used in this reaction include triethylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, pyridine, and an organic base of 1,8-diazabicyclo [5,4,0] -7-undecene. Can be mentioned. Solvents that can be used are not particularly limited as long as they are not involved in the reaction. For example, ethers such as tetrahydrofuran, 1,4-dioxane and diethyl ether, N, N-dimethylformamide, N, N-dimethylacetamide and the like. Examples thereof include amides, nitriles such as acetonitrile and propiononitrile, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and methylene chloride, and mixed solvents thereof. Moreover, an additive can be used as needed. Examples of additives that can be used include 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole. The reaction time varies depending on the type of raw materials used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours. The amount of the compound [31] and the condensing agent used is, for example, in the range of 1 to 3 mol relative to 1 mol of the compound [1g].

Production Method 9 In the case where R ² is H, a saturated heterocyclic group containing 1 N which may be substituted with alkylcarbonyl or alkylsulfonyl, or alkyl which may be substituted with hydroxy or alkoxy

（Ｘ^１、Ｒ^１、Ｒ^５、Ｈａｌ^１は、前記と同義である。Ｒ^１７は、Ｈ、アルキルカルボニル、アルキルスルホニルで置換されていてもよい１個のＮを含む飽和複素環式基、又は、ヒドロキシ若しくはアルコキシで置換されていてもよいアルキルを表す）
本反応は、化合物［３２］と化合物［１３］とのパラジウム触媒を用いた縮合反応であって、前記製法１と同様の方法によって行うことができる。

製法１０ Ｒ ^２ がシアノである場合

(X ¹ , R ¹ , R ⁵ , Hal ¹ are as defined above. R ¹⁷ is a saturated heterocyclic group containing 1 N optionally substituted with H, alkylcarbonyl, or alkylsulfonyl, Or represents an alkyl optionally substituted with hydroxy or alkoxy)
This reaction is a condensation reaction of compound [32] and compound [13] using a palladium catalyst, and can be carried out by the same method as in Production Method 1.

Production Method 10 When R ² is Cyano

（Ｘ^１、Ｒ^１、Ｒ^５、Ｈａｌ^２は、前記と同義である。）

本反応は、化合物［１ａ］のシアノ化反応であって、それ自体公知の方法によって行うことができる。本反応は、例えばパラジウム触媒の存在又は非存在下に、適当な溶媒中、シアノ化合物と２０〜２００℃の範囲内で、必要であればマイクロウエーブを用いて行うことができる。使用しうるパラジウム触媒としては、例えば、テトラキス（トリフェニルホスフィン）パラジウム、１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（ＩＩ）ジクロリド−ジクロロメタン錯体、トリス（ジベンジリデンアセトン）ジパラジウム（０）を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール１モルに対して、０．００１〜０．１モルの範囲内が適当である。必要であればパラジウムのリガンドとして、４，５−ビス（ジフェニルホスフィノ）−９，９’−ジメチルキサンテン、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル、２−ジシクロヘキシルホスフィノ−２’，６’−ジメトキシビフェニルなどを用いることができる。使用しうるシアノ化合物としては、シアン化銅（Ｉ）、シアン化亜鉛（ＩＩ）、シアン化カリウム、シアン化ナトリウムを挙げることができる。使用しうる反応溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、１，４−ジオキサンなどのエーテル類、メタノール、エタノールなどのアルコール類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドンなどのアミド類、ベンゼン、トルエンなどの炭化水素類、ジメチルスルホキシド、水、又はこれらの混合溶媒を挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、３０分〜２４時間の範囲内が適当である。

製法１１ Ｘが−ＣＲ ^Ａ であって、Ｒ ^Ａ がアルコキシカルボニルの場合

(X ¹ , R ¹ , R ⁵ and Hal ² are as defined above.)

This reaction is a cyanation reaction of compound [1a] and can be carried out by a method known per se. This reaction can be carried out, for example, in the presence or absence of a palladium catalyst, in a suitable solvent, in the range of 20 to 200 ° C. with a cyano compound, if necessary, using a microwave. Examples of the palladium catalyst that can be used include tetrakis (triphenylphosphine) palladium, 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex, tris (dibenzylideneacetone) dipalladium (0 ). The amount of the palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mole per mole of aryl halide. If necessary, as a ligand of palladium, 4,5-bis (diphenylphosphino) -9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, 2-dicyclohexyl Phosphino-2 ′, 6′-dimethoxybiphenyl and the like can be used. Examples of cyano compounds that can be used include copper (I) cyanide, zinc (II) cyanide, potassium cyanide, and sodium cyanide. The reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction. For example, ethers such as tetrahydrofuran and 1,4-dioxane, alcohols such as methanol and ethanol, N, N-dimethylformamide, N, Examples thereof include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, hydrocarbons such as benzene and toluene, dimethyl sulfoxide, water, and a mixed solvent thereof. The reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 30 minutes to 24 hours.

Production Method 11 When X is —CR ^A and R ^A is Alkoxycarbonyl

（Ｒ^１、Ｒ^５、Ｈａｌ^１は、前記と同義である。Ｒ^１８は、アルキルを表す。）
本反応は、化合物［３３］と化合物［１３］とのパラジウム触媒を用いた縮合反応であって、前記製法４−２と同様の方法により行うことができる。

原料化合物である化合物［３３］は、次の方法に従って製造することができる。

(R ¹ , R ⁵ , and Hal ¹ are as defined above. R ¹⁸ represents alkyl.)
This reaction is a condensation reaction of the compound [33] and the compound [13] using a palladium catalyst, and can be carried out by the same method as in the above production method 4-2.

Compound [33], which is a raw material compound, can be produced according to the following method.

（Ｒ^１、Ｒ^１８、Ｈａｌ^１、Ｈａｌ^３は、前記と同義である。）

本反応は、化合物［３４］と化合物［１９］とのパラジウム触媒を用いた縮合反応であって、前記製法３−２、方法Ａの工程２と同様の方法により行うことができる。

製法１２ Ｘが−ＣＲ ^Ａ であって、Ｒ ^Ａ がヒドロキシカルボニルの場合

(R ¹ , R ¹⁸ , Hal ¹ , Hal ³ are as defined above.)

This reaction is a condensation reaction of compound [34] and compound [19] using a palladium catalyst, and can be carried out by the same method as in production method 3-2 and method A, step 2.

Production Method 12 When X is —CR ^A and R ^A is Hydroxycarbonyl

（Ｒ^１、Ｒ^５、Ｒ^１８は、前記と同義である。）
本反応は、化合物［１ｋ］の加水分解反応であり、前記製法７と同様の方法によって行うことができる。

製法１３ Ｘが−ＣＲ ^Ａ であって、Ｒ ^Ａ が次の一般式［３５］で表される基の場合

(R ¹ , R ⁵ and R ¹⁸ are as defined above.)
This reaction is a hydrolysis reaction of the compound [1k] and can be carried out by the same method as in Production Method 7.

Production Method 13 When X is —CR ^A and R ^A is a Group Represented by the General Formula [35]

(In the formula, * is as defined above. R ¹⁹ , R ²⁰ Are the same or different and each represents H, alkyl, cycloalkyl, (cycloalkyl) alkyl or alkoxyalkyl, or together with the adjacent N represents a saturated cyclic amino group. )

（Ｒ^１、Ｒ^５、Ｒ^１９、Ｒ^２０は、前記と同義である。）
本反応は、化合物［１ｊ］と化合物［３６］との縮合反応であって、前記製法８と同様の方法によって行うことができる。

製法１４ Ｒ ^４ がアルキルの場合

(R ¹ , R ⁵ , R ¹⁹ , R ²⁰ have the same meanings as described above.)
This reaction is a condensation reaction between compound [1j] and compound [36] and can be carried out in the same manner as in Production Method 8.

Process 14 When R ⁴ is alkyl

（Ｘ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、Ｈａｌ^１は、前記と同義である。Ｒ^２１は、アルキルを表す。）
本反応は、化合物［３７］と化合物［１３］とのパラジウム触媒を用いた縮合反応であって、前記製法４−２と同様の方法により行うことができる。

原料化合物である化合物［３７］は、次の方法に従って製造することができる。

(X, R ¹ , R ² , R ³ , R ⁵ and Hal ¹ are as defined above. R ²¹ represents alkyl.)
This reaction is a condensation reaction of compound [37] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in the above production method 4-2.

Compound [37], which is a raw material compound, can be produced according to the following method.

（Ｘ^１、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^２１、Ｈａｌ^１は、前記と同義である。Ｈａｌ^４はハロゲンを表す。）

本工程は、化合物［３８］と化合物［３９］を適当な溶媒中、塩基の存在下、２０℃〜２００℃で、必要であればマイクロウエーブを用いて、反応させることにより製造することができる。使用しうる塩基は、例えば、水素化ナトリウム、リチウムジイソプロピルアミド、ｎ−ブチルリチウムなどを挙げることができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、１，４−ジオキサンなどのエーテル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、アセトニトリル、又はこれらの混合溶媒を挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、１０分〜２４時間の範囲内が適当である。

製法１５ Ｒ ^３ がヒドロキシである場合

(X ¹ , R ¹ , R ² , R ³ , R ²¹ , and Hal ¹ are as defined above. Hal ⁴ represents halogen.)

This step can be produced by reacting compound [38] and compound [39] in an appropriate solvent at 20 ° C. to 200 ° C. in the presence of a base, if necessary, using a microwave. . Examples of the base that can be used include sodium hydride, lithium diisopropylamide, and n-butyllithium. Solvents that can be used are not particularly limited as long as they are not involved in the reaction. Examples thereof include ethers such as tetrahydrofuran and 1,4-dioxane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, Examples thereof include hydrocarbons such as benzene and toluene, acetonitrile, or a mixed solvent thereof. The reaction time varies depending on the type of raw material used and the reaction temperature, but it is usually within the range of 10 minutes to 24 hours.

Process 15 When R ³ is hydroxy

（Ｘ^１、Ｒ^１、Ｒ^２、Ｒ^５、Ｈａｌ^１は、前記と同義である。）
本反応は、化合物［４０］と化合物［１３］とのパラジウム触媒を用いた縮合反応であって、前記製法１と同様の方法によって行うことができる。本反応に使用しうる塩基としては、ナトリウムｔ−ブトキシドが適当である。

原料化合物である化合物［４０］は、次の方法に従って製造することができる。

(X ¹ , R ¹ , R ² , R ⁵ and Hal ¹ are as defined above.)
This reaction is a condensation reaction of compound [40] and compound [13] using a palladium catalyst, and can be carried out by the same method as in Production Method 1. Sodium t-butoxide is suitable as a base that can be used in this reaction.

Compound [40], which is a raw material compound, can be produced according to the following method.

（Ｘ^１、Ｒ^１、Ｒ^２、Ｈａｌ^１、Ｈａｌ^３は、前記と同義である。）

工程１
化合物［４２］は、化合物［４１］を用いて公知の方法（Ｊ．Ｏｒｇ．Ｃｈｅｍ．，６５，２０００，９０５９−９０６８など）に準じて製造することができる。

工程２
本工程は、化合物［４２］と化合物［４３］とのパラジウム触媒を用いた縮合反応であって、例えば、前記製法１と同様の方法によって行うことができる。

(X ¹ , R ¹ , R ² , Hal ¹ , Hal ³ have the same meanings as described above.)

Process 1
Compound [42] can be produced according to a known method (J. Org. Chem., 65, 2000, 9059-9068, etc.) using compound [41].

Process 2
This step is a condensation reaction of the compound [42] and the compound [43] using a palladium catalyst, and can be performed, for example, by the same method as the production method 1.

  The compound of the present invention can be used, for example, as a medicine as it is, but can also be used in the form of a pharmaceutically acceptable salt by a known method. Such salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, Mention may be made of salts of organic acids such as methanesulfonic acid.

  For example, the hydrochloride of the compound of the present invention can be obtained by dissolving the compound of the present invention in an alcohol solution, an ethyl acetate solution or a diethyl ether solution of hydrogen chloride.

  Although some of the compounds of the present invention have asymmetric carbon, each optical isomer and a mixture thereof are included in the present invention. The optical isomer is known from, for example, the racemate obtained as described above, using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) using its basicity. The optical resolution can be carried out by the above method, or an optically active compound prepared in advance can be used as a raw material. In addition, it can also be produced by optical resolution using a chiral column or asymmetric synthesis.

In addition, when a geometric isomer or tautomer exists in the compound of the present invention, not only one isomer but also a mixture thereof is also included in the compound of the present invention.

The compounds of the present invention and pharmaceutically acceptable salts thereof are useful as pharmaceuticals because they have high inhibitory activity against Src family tyrosine kinases as shown in the following test examples.
The pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is not limited as long as it is a disease involving Src family tyrosine kinase. Since each Src family tyrosine kinase is known to be involved in the onset and progression, it can be used as a therapeutic or prophylactic agent for those diseases.

The activation of c-Src tyrosine kinase is, for example, rectal cancer, colon cancer, colon cancer, melanoma, pancreatic cancer, ovarian cancer, bladder cancer, stomach cancer, head and neck cancer, esophageal cancer, lung cancer, neuroblastoma, retinoblastoma. Involved in the development of cytomas. In addition, abnormal control of c-Src tyrosine kinase activity is exemplified by cancer (eg, prostate cancer, breast cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, testicular cancer, cervical cancer, stomach cancer, colon cancer, bladder Cancer) involved in bone metastasis from the primary lesion (eg, detachment from the primary lesion, bone infiltration and proliferation), and also involved in bone loss by disturbing the bone resorption / bone formation balance in the bone metastasis To do.
Fyn tyrosine kinase is, for example, squamous cell carcinoma, oral squamous cell carcinoma, mesothelioma, systemic lupus erythematosus, diseases caused by allergic reactions (eg allergic rhinitis, atopic dermatitis, atopic asthma), bronchial asthma, Involved in the development and development of Alzheimer's disease.
Yes tyrosine kinase is involved, for example, in the development and progression of skin cancer, oral cancer, bronchial asthma, age-related macular degeneration.
Lyn tyrosine kinase is, for example, glomerulonephritis, diseases caused by allergic reaction (for example, allergic rhinitis, atopic dermatitis, atopic asthma), rejection during organ transplantation (for example, heart transplantation), atherosclerotic artery It is involved in the onset and progression of sclerosis, diseases caused by leukocyte accumulation during vascular injury (for example, restenosis after percutaneous coronary intervention), bronchial asthma, and AIDS.
Fgr tyrosine kinase is involved in, for example, the onset and progression of atherosclerosis, diseases caused by leukocyte accumulation during vascular injury (eg, restenosis after percutaneous coronary intervention), bronchial asthma.
Lck tyrosine kinases are, for example, thymic tumors, rejection during organ transplantation (eg heart transplantation), autoimmune diseases (eg systemic lupus erythematosus, type I diabetes, psoriasis, glomerulonephritis), bronchial asthma, acute coronary syndrome Involved in the development and development of Alzheimer's disease.

  When the compound of the present invention and a pharmaceutically acceptable salt thereof are administered as a pharmaceutical, the compound of the present invention or a pharmaceutically acceptable salt thereof is used as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, A pharmaceutical composition containing 0.001% to 99.5%, preferably 0.1% to 90%, is administered to mammals including humans.

  As the carrier, a solid, semi-solid, or liquid diluent, filler, and one or more auxiliary agents for formulation are used. The pharmaceutical composition according to the present invention is desirably administered in a dosage unit form. The pharmaceutical composition can be administered intra-tissue, oral, intravenous, topical (transdermal, ophthalmic, etc.) or rectally. Of course, it is administered in a dosage form suitable for these administration methods.

It is desirable that the dosage as a pharmaceutical is adjusted in consideration of the patient's condition such as age, weight, type of disease, degree of administration, etc., and the route of administration. The amount of the active ingredient in the salt to be administered is suitably in the range of 0.1 mg to 5 g / adult, preferably 1 mg to 500 mg / adult, per day for oral administration. In some cases, less than this may be sufficient, and vice versa. Usually, it is administered once or divided into several times a day, or can be continuously administered intravenously over 1 to 24 hours.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, Test Examples and Formulation Examples, but the present invention is not limited to these.

Reference Example 1 (S) -4,6-dichloro-N- [1- (4-fluorophenyl) ethyl] pyrimidin-2-amine 2,4,6-trichloropyrimidine (2.4 g ) was dissolved in tetrahydrofuran (24 ml) at room temperature. Then, 2.0 ml of triethylamine was added thereto, followed by dropwise addition of 12 ml of a tetrahydrofuran solution of 2.0 g of (S)-(−)-1- (4-fluorophenyl) ethylamine, followed by stirring at room temperature for 9.5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.77 g of the title compound.
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 7.2 g of 2,4,6-trichloropyridine and (S)-(-)- 1.74 g of 1- (4-fluorophenyl) ethylamine was dissolved in 25 ml of 1-butanol, 13.7 ml of N, N-diisopropylethylamine was added, and the mixture was stirred at 120 ° C. for 42 hours. After allowing to cool, the reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 2.57 g of the title compound as a yellow oil.
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 (S)-4,6- Dichloro-N- [1- (4-fluorophenyl) ethyl] pyridin-2-amine 734 mg, 2-aminopyrazine 343 mg, tripotassium phosphate 1.39 g, 4,5-bis (diphenylphosphino) -9, 9 17 ml of 1,4-dioxane was added to 190 mg of '-dimethylxanthene and 170 mg of tris (dibenzylideneacetone) (chloroform) dipalladium, deaerated and purged with argon, and stirred at 100 ° C. for 19 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 654 mg of the title compound as a brown powder.
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 1 (S) -4- {6-chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl} piperazin-2-one (S) -4,6-dichloro-N- [ 1- (4-Fluorophenyl) ethyl] pyrimidin-2-amine 150 mg and piperazin-2-one 58 mg are dissolved in 1-butanol 1.5 ml, N, N-diisopropylethylamine 183 μl is added, and the mixture is stirred at 60 ° C. for 20 hours. did. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, 196 mg of the title compound was obtained as a white powder.
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 To 6 ml of degassed toluene , (S) -4- {6-chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl} piperazin-2-one 196 mg, 2-aminopyrazine 55 mg, 2-dicyclohexylphosphino -2 ′, 4 ′, 6′-triisopropylbiphenyl 50 mg, sodium t-butoxide 101 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 27 mg were sequentially added, and the mixture was stirred at 100 ° C. for 2 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 196 mg of the title compound as a light brown powder.
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] pyrrolidine -3-yl} acetamide hydrochloride In the same manner as in Example 1, using (S) -N- (pyrrolidin-3-yl) acetamide instead of piperazin-2-one, N-{(S) -1- [2-{[(S) -1- (4-Fluorophenyl) ethyl] amino} -6- (pyrazin-2-ylamino) pyrimidin-4-yl] pyrrolidin-3-yl} acetamide was prepared. . This was dissolved in methanol, 1N hydrochloric acid was added in an equal amount, and then the solvent was distilled off to obtain the title compound as a white powder.
MS (ESI) m / z 437 (M + H) ⁺

Example 3 (S) -6- (3,3- ^{difluoro-1-yl)} -N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidine - 2, 4
-Diamine hydrochloride In the same manner as in Example 1, using 3,3-difluoroazetidine hydrochloride instead of piperazin-2-one, (S) -6- (3,3-difluoroazetidine- ^1-yl) -N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (prepared pyrazin-2-yl) pyrimidine-2,4-diamine. This was dissolved in methanol, 1N hydrochloric acid was added in an equal amount, and then the solvent was distilled off to obtain the title compound as a white powder.
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 7.5 ml of degassed 1,4-dioxane and water To a mixed solution of 5 ml, 500 mg of 2,6-dichloro-4-iodopyridine, 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H -379 mg of pyrazole, 753 mg of potassium carbonate and 74 mg of 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex were sequentially added, and the mixture was stirred at 90 ° C for 2 hours under an argon atmosphere. It was. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 257 mg of the title compound.
MS (ESI) m / z 228 (M + H) ⁺

Step 2 (S) -6-Chloro-N- [1- (4-fluorophenyl) ethyl] -4- (1-methyl-1H-pyrazol-4-yl) pyridin-2-amine To 6 ml of degassed toluene , 257 mg of 2,6-dichloro-4- (1-methyl-1H-pyrazol-4-yl) pyridine obtained in 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 sequentially added, and the mixture was stirred at 85 ° C. for 2 hours under an argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 240 mg of the title compound as a pale yellow powder.
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) pyridin-2 , 6-diamine hydrochloride To 6 ml of degassed toluene, (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -4- (1-methyl-1H-pyrazol-4-yl) Pyridin-2-amine 235 mg, 2-aminopyrazine 74 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 68 mg, sodium t-butoxide 95 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 37 mg was sequentially added, and the mixture was stirred at 100 ° C. for 1.5 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (S) -N ^2- [1- (4-fluorophenyl) ethyl] -4- (1-methyl-1H) was purified. - pyrazol-4-yl) -N ⁶ - (pyrazine-2-yl) pyridine-2,6-diamine 204mg as a pale yellow powder. This was dissolved in ethanol, 1N hydrochloric acid was added in an equal amount, and then the solvent was distilled off to obtain the title compound as a pale yellow powder.
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 Hydrochloric acid In the same manner as in Example 4, instead of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole, 3- Using (1,3,2-dioxaborinan-2-yl) pyridine, (S) —N ^{2 ′} -[1- (4-fluorophenyl) ethyl] —N ^{6 ′} -(pyrazin-2-yl) -3 , 4′-bipyridine-2 ′, 6′-diamine was prepared. This was dissolved in ethanol, 1N hydrochloric acid was added in an equal amount, and then the solvent was distilled off to obtain the title compound as a yellow powder.
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 In the same manner as in Example 4, instead of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole, Using 2-methoxy-5-pyridineboronic acid, the title compound was obtained as a pale yellow powder.
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 (S) — N ^{2 ′} -[1- (4-fluorophenyl) ethyl] -6-methoxy-N ^{6 ′} -(pyrazin-2-yl) -3,4′-bipyridine-2 ′, 6′-diamine (108 mg) was added to 3 ml of acetonitrile. Then, 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 an argon atmosphere. The reaction mixture was diluted with ethyl acetate and water, and adjusted to pH 9 with saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (S) -2 ′-[1- (4-fluorophenyl) ethylamino] -6 ′-(pyrazine-2). 78 mg of -ylamino) -3,4'-bipyridin-6-ol were obtained as a pale yellow powder. This was dissolved in methanol, 1N hydrochloric acid was added in an equal amount, and then the solvent was distilled off to obtain the title compound as a pale yellow powder.
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 2,6-Dichloroisonicotinaldehyde (J. Chem. Soc., Chem. Commun., 1998, 1567-1568) 528 mg was dissolved in 10 ml of methanol, 586 mg of p-toluenesulfonylmethyl isocyanide and 415 mg of potassium carbonate were added, and the mixture was stirred at 50 ° C. for 30 minutes. The reaction mixture was concentrated, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, 630 mg of the desired product was obtained as a white powder.
MS (ESI) m / z 215 (M + H) ⁺

Step ^{2 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -4- (5-oxazol-yl) -N ⁶ - (pyrazin-2-yl) pyridine-2,6-diamine degassing To 30 ml of toluene, 630 mg of 5- (2,6-dichloropyridin-4-yl) oxazole obtained in Step 1, 408 mg of (S)-(−)-1- (4-fluorophenyl) ethylamine, 2,2 182 mg of '-bis (diphenylphosphino) -1,1'-binaphthyl, 1.9 g of cesium carbonate and 66 mg of palladium acetate were sequentially added, and the mixture was stirred at 100 ° C. for 1.5 hours under an argon atmosphere. The reaction solution was purified by silica gel column chromatography, and 600 mg of (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -4- (oxazol-5-yl) pyridin-2-amine was lightly added. Obtained as a yellow powder. To this was added 10 ml of degassed toluene, followed by 180 mg 2-aminopyrazine, 180 mg 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 254 mg sodium t-butoxide and tris (dibenzylideneacetone). 98 mg of dipalladium was sequentially added, and the mixture was stirred at 100 ° C. for 2 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 390 mg of the title compound as a pale yellow powder.
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 (S)-4,6 -Dichloro-N- [1- (4-fluorophenyl) ethyl] pyrimidin-2-amine 1.37 g (Reference Example 1), 2-aminopyrazine 460 mg, 4,5-bis (diphenylphosphino) -9, 9 '-Dimethylxanthene (277 mg), tripotassium phosphate (2.04 g) and tris (dibenzylideneacetone) (chloroform) dipalladium (248 mg) were added with 30 ml of 1,4-dioxane, purged with argon, and stirred at 100 ° C for 2 hours. did. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 960 mg of the title compound as a pale yellow powder.
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 was degassed 1,4-dioxane 3ml of water 1.2ml, (S) -6- chloro ^-N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2 Yl) pyrimidine-2,4-diamine 100 mg, 4- (methylsulfonyl) phenylboronic acid 145 mg, sodium carbonate 123 mg and tetrakis (triphenylphosphine) palladium 17 mg were sequentially added, and the mixture was stirred at 100 ° C. for 3 hours under an argon atmosphere. . The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (S) -N ^2- [1- (4-fluorophenyl) ethyl] -6- [4- (methylsulfonyl) was obtained. ) phenyl] -N ⁴ - a (pyrazin-2-yl) pyrimidine-2,4-diamine 124mg was obtained as a white powder. This was dissolved in methanol, 1N hydrochloric acid was added in an equal amount, and then the solvent was distilled off to obtain the title compound as a white powder.
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 In the same manner as in Example 10, instead of 4- (methylsulfonyl) phenylboronic acid, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl )-1H-pyrazole -1-carbamic acid t- ^{butyl, (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) -6- ( 1H-pyrazol-4-yl) pyrimidine-2,4-diamine was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a white powder.
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 (S) -4-Chloro -N ² - [1- (4- fluorophenyl) ethyl] -N ⁶ - (pyrazin-2-yl) pyridine-2,6-diamine 150mg, tripotassium phosphate 187 mg, 2-dicyclohexyl phosphino-2 ', To 84 mg of 4 ′, 6′-triisopropylbiphenyl and 46 mg of tris (dibenzylideneacetone) (chloroform) dipalladium, 3 ml of ethylene glycol and 1.5 ml of 1,4-dioxane were added, degassed and purged with argon, and 100 ° C. Stir for 13 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (S) -2- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazine- 62 mg of 2-ylamino) pyridin-4-yloxy} ethanol was obtained as a light brown powder. Further, the hydrochloride was obtained according to a conventional method to obtain 52 mg of the title compound as a yellow powder.
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) pyrimidin-2-amine 15 ml of degassed toluene, 7 ml of ethanol and In a mixed solvent of 10 ml of water, 500 mg of (S) -4,6-dichloro-N- [1- (4-fluorophenyl) ethyl] pyrimidin-2-amine (Reference Example 1), 3- (1, 3, 2 -Dioxaborinan-2-yl) pyridine (314 mg), sodium carbonate (927 mg) and tetrakis (triphenylphosphine) palladium (202 mg) were sequentially added, and the mixture was stirred at 110 ° C for 3 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 218 mg of the title compound as a white powder.

Step ^{2 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) -6- (pyridin-3-yl) pyrimidine-2,4-diamine (S ) -4-chloro-N- [1- (4-fluorophenyl) ethyl] -6- (pyridin-3-yl) pyrimidin-2-amine 100 mg, 2-aminopyrazine 35 mg, 4,5-bis (diphenylphos) Fino) -9,9′-dimethylxanthene 18 mg, tripotassium phosphate 129 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 16 ml were added with 2 ml of 1,4-dioxane, degassed and purged with argon, 100 ° C. For 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 54 mg of the title compound as a white powder.
MS (ESI) m / z 388 (M + H) ⁺
Specific rotation [α] _D ²⁰ = −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) pyrimidin-2-amine To degassed toluene, (S) -4,6-dichloro-N- [1- (4-fluorophenyl) ethyl] pyrimidin-2-amine 200 mg (Reference Example 1), 2- (tributylstannyl) pyridine 0.22 ml, copper oxide 55 mg and tetrakis ( Triphenylphosphine) palladium (81 mg) was sequentially added, and the mixture was stirred at 110 ° C. for 4 hours under an argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 63 mg of the title compound as a colorless oil.

Step ^{2 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) -6- (pyridin-2-yl) pyrimidine-2,4-diamine (S ) -4-chloro-N- [1- (4-fluorophenyl) ethyl] -6- (pyridin-2-yl) pyrimidin-2-amine 62 mg, 2-aminopyrazine 22 mg, 4,5-bis (diphenylphos) Fino) -9,9′-dimethylxanthene 22 mg, tripotassium phosphate 80 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 2 ml were added with 2 ml of 1,4-dioxane, deaerated and purged with argon. For 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 25 mg of the title compound as a white powder.
MS (ESI) m / z 388 (M + H) ⁺
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 [ In the same manner as in Example 14, 4- (tributylstannyl) pyridine was used instead of 2- (tributylstannyl) pyridine to give the title compound as a pale yellow powder.
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 1 (S) -1- {6-Chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl} pyrrolidin-2-one To 3 ml of degassed 1,4-dioxane, (S ) -4,6-dichloro-N- [1- (4-fluorophenyl) ethyl] pyrimidin-2-amine 100 mg (Reference Example 1), 2-pyrrolidone 33 mg, 4,5-bis (diphenylphosphino) -9 , 9′-dimethylxanthene 20 mg, tripotassium phosphate 149 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 19 mg were sequentially added, and the mixture was added at 100 ° C. under an argon atmosphere. Stir for hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (106 mg) as a yellow oil.

Step 2 (S) -1- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} pyrrolidin-2-one Degassed 1,4 -In 3 ml of dioxane, (S) -1- {6-chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl} pyrrolidin-2-one 104 mg, 2-aminopyrazine 33 mg, 4 , 5-bis (diphenylphosphino) -9,9′-dimethylxanthene, 132 mg of tripotassium phosphate and 17 mg of tris (dibenzylideneacetone) (chloroform) dipalladium were added successively, and the mixture was added at 100 ° C. under an argon atmosphere. Stir for hours. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 74 mg of the title compound as a light brown powder.
MS (ESI) m / z 394 (M + H) ⁺
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 (S) -4,6-dichloro 182 mg of N- [1- (4-fluorophenyl) ethyl] pyrimidin-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. , N-diisopropylethylamine 122 μl was added and stirred at 80 ° C. for 32 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, 136 mg of the title compound was obtained as a white powder.

Step 2 (S) -4- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} piperazine-2,6-dione Degassed 1 , 4-dioxane in 2.5 ml, (S) -4- {6-chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl} piperazine-2,6-dione, 119 mg, 2 -Aminopyrazine 34 mg, 4,5-bis (diphenylphosphino) -9,9'-dimethylxanthene 19 mg, tripotassium phosphate 139 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 17 mg were sequentially added, and an argon atmosphere The mixture was stirred at 100 ° C. for 2 hours. The reaction solution was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 26 mg of the title compound as a pale yellow powder.
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 In the same manner as in Example 16, tetrahydro-2-pyrimidinone was used instead of 2-pyrrolidone to obtain the title compound as a pale yellow powder.
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 [ In the same manner as in Example 1, pyrrolidine was used instead of piperazin-2-one to give the title compound as a pale yellow amorphous.
MS (ESI) m / z 380 (M + H) ⁺

Example ^{20 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -6-morpholino -N ⁴ - (pyrazin-2-yl) same manner as pyrimidine-2,4-diamine Example 1 Used morpholine instead of piperazin-2-one to give the title compound as a pale yellow amorphous.
MS (ESI) m / z 396 (M + H) ⁺
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 degassed to 1,4-dioxane 5 ml, (S)-6-chloro ^-N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4-diamine ( Example 9) 150 mg, 2-imidazolidinone 224 mg, 4,5-bis (diphenylphosphino) -9,9'-dimethylxanthene 26 mg, tripotassium phosphate 185 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 23 mg was sequentially added, and the mixture was stirred at 100 ° C. for 2 hours under an argon atmosphere. The reaction solution was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain (S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazine-2). 80 mg of -ylamino) pyrimidin-4-yl} imidazolidin-2-one were obtained as a white powder. Further, the hydrochloride was obtained according to a conventional method to obtain 56 mg of the title compound as a pale yellow powder.
MS (ESI) m / z 395 (M + H) ⁺
Elemental analysis (as _{C 19 H 19 FN 8 O ·} HCl + 0.5H 2 O + 0.1C 2 H 5 OH)
Calculated value (%) C: 51.88 H: 4.90 N: 25.21
Actual 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 salts <br/> step ^{1 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) -6- [2- (triisopropylsilyl) oxazole -5 - yl] pyrimidine-2,4-diamine degassed dimethylformamide 5ml, (S) -6- chloro ^-N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl ) Pyrimidine-2,4-diamine 150 mg (Example 9), 5- (tributylstannyl) -2- (triisopropylsilyl) oxazole 246 mg (synthesized according to WO2007 / 17096), tetrakis (Triphenylphosphine) palladium (25 mg) was sequentially added, and the mixture was stirred at 100 ° C. for 2.5 hours under an argon atmosphere. An additional 246 mg of 5- (tributylstannyl) -2- (triisopropylsilyl) oxazole was added and the mixture was further stirred for 4 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column ^{chromatography, (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2 Yl) -6- [2- (triisopropylsilyl) oxazol-5-yl] pyrimidine-2,4-diamine (153 mg) was obtained as a 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 ^{(S) -N 2 - [1-} (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) -6- [2- (triisopropylsilyl) oxazol-5-yl] pyrimidin-2, 122 mg of 4-diamine was dissolved in 1.2 ml of tetrahydrofuran, and 1M tetrabutylammonium fluoride. 0.5 ml of tetrahydrofuran solution was added. After stirring at room temperature for 20 minutes, the reaction solution was diluted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (S) -N ^2- [1- (4-fluorophenyl) ethyl] -6- (oxazol-5-yl) was obtained. ) -N ⁴ - (pyrazine-2-yl) pyrimidine-2,4-diamine 60mg as a white powder. This was converted into a hydrochloride according to a conventional method to obtain 45 mg of the title compound as a pale orange powder.
MS (ESI) m / z 378 (M + H) ⁺
Elemental analysis value (as C ₁₉ H ₁₆ FN ₇ O · HCl)
Calculated value (%) C: 55.14 H: 4.14 N: 23.69
Actual 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
In the same manner as in Example 10, 4- (methyl sulfonyl) phenylboronic acid, using 2-methoxy-5-pyridineboronic ^{acid, (S) -N 2 - [} 1- (4- fluorophenyl ) ethyl] -6- (6-methoxypyridin-3-yl) -N ⁴ - (pyrazine-2-yl) pyrimidine-2,4-diamine. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 418 (M + H) ⁺
Elemental analysis value (as C ₂₂ H ₂₀ FN ₇ O · HCl)
Calculated value (%) C: 58.21 H: 4.66 N: 21.60
Actual value (%) C: 57.80 H: 4.48 N: 21.54
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
By a method similar to that in Example 10, using 1H-pyrazole-3-boronic acid instead of 4- (methylsulfonyl) phenylboronic acid, (S) -N ^2- [1- (4-fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl)-6-(1H-pyrazol-3-yl) pyrimidine-2,4-diamine. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 377 (M + H) ⁺
Elemental analysis value (as C ₁₉ H ₁₇ FN ₈ · HCl + 0.8H ₂ O)
Calculated value (%) C: 53.41 H: 4.62 N: 26.23
Actual value (%) C: 53.21 H: 4.31 N: 26.25
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 ^{1 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -6- (2-fluoropyridin-4-yl) -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4-diamine In the same manner as in Example 10, the title compound was obtained 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 (S) -N ² - [1- (4-fluorophenyl) ethyl] -6- (2-fluoropyridin-4-yl) -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4-diamine 80mg in 1,2-dimethoxyethane Ethane (1 ml) and 10% aqueous hydrochloric acid solution (1 ml) were added, and the mixture was stirred at 85 ° C. for 2 hours. 0.5 ml of 10% aqueous hydrochloric acid solution was added, and the mixture was further stirred for 2 hours. Dilute with ethyl acetate and make alkaline with saturated aqueous sodium bicarbonate. After liquid separation, it was dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained solid was washed with diethyl ether, filtered and dried under reduced pressure to obtain 54 mg of the title compound as a white powder.
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 Same as Example 7 (S) —N ^{2 ′} -[1- (4-fluorophenyl) ethyl] -6-methoxy-N ^{6 ′} -(pyrazin-2-yl) -3,4′-bipyridine-2 ′, instead of ^{6'-diamine, (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -6- (6-methoxypyridin-3-yl) -N ⁴ - (pyrazin-2-yl) Using pyrimidine-2,4-diamine (Example 23), the title compound was obtained as a light brown powder.
MS (ESI) m / z 404 (M + H) ⁺
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} pyrrolidine-3 -Yl) acetamide hydrochloride In the same manner as in Example 1, (R) -N- (pyrrolidin-3-yl) acetamide was used instead of piperazin-2-one, and N-((R) -1- {2-[(S) -1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} pyrrolidin-3-yl) acetamide was prepared. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a white powder.
MS (ESI) m / z 437 (M + H) ⁺
Elemental analysis value (as C ₂₂ H ₂₅ FN ₈ O · HCl)
Calculated value (%) C: 55.87 H: 5.54 N: 23.69
Actual value (%) C: 55.49 H: 5.21 N: 23.59
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 To a mixed solution of 3 ml of degassed 1,4-dioxane and 1 ml of water, 2,6-dichloro-4- 188 mg iodopyridine, 201 mg 4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) -1H-pyrazole-1-carbamate, 284 mg potassium carbonate and 1, 56 mg of 1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex was sequentially added, and the mixture was stirred at 90 ° C. for 5 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 90 mg of the title compound.

Step 2 2,6-dichloro-4- (1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol-4-yl) pyridine 2,6-dichloro-4- (1H-pyrazole) under an argon atmosphere 90 mg of -4-yl) pyridine was dissolved in 2 ml of tetrahydrofuran, 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) ethyltrimethylsilane was added, and the mixture was warmed to room temperature and stirred for 2 hours. Water was added, extraction was performed with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 106 mg of the title compound.

Step 3 (S) -6-Chloro-N- [1- (4-fluorophenyl) ethyl] -4- (1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol-4-yl) pyridine 2-Amine 100 ml of 2,6-dichloro-4- (1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol-4-yl) pyridine obtained in Step 2 was added to 3 ml of degassed toluene. , 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 successively added, and an argon atmosphere was added. The mixture was stirred at 85 ° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 70 mg of the title compound as a 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 (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -4 obtained in step 3 was added to 2 ml of degassed toluene. -(1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol-4-yl) pyridin-2-amine 68 mg, 2-aminopyrazine 17 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6 '-Triisopropylbiphenyl 15 mg, sodium t-butoxide 21 mg, and tris (dibenzylideneacetone) (chloroform) dipalladium 8 mg were sequentially added, and argon atmosphere was added. Below, and the mixture was stirred for 1 hour at 100 ℃. The reaction solution was purified by silica gel column chromatography to obtain 70 mg of the title compound as a 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 obtained in step ^{4 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ⁶ - (pyrazin-2-yl) -4- (1 - {[2- (trimethylsilyl) ethoxy] A mixed solution of 1 ml of trifluoroacetic acid and 0.1 ml of water was added to 53 mg of methyl} -1H-pyrazol-4-yl) pyridine-2,6-diamine, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, diluted with water, and made alkaline with a saturated aqueous sodium hydrogen carbonate solution. Extraction operation was performed with ethyl acetate, and the organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain 15 mg of the title compound as a pale yellow amorphous.
MS (ESI) m / z 376 (M + H) ⁺
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
586 mg of 2,6-dichloroisonicotinic acid is dissolved in 10 ml of dimethylformamide, 690 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 490 mg of 1-hydroxybenzotriazole, N, O-dimethylhydroxyamine hydrochloride 440 mg of salt and 1.67 ml of triethylamine were added, and the mixture was stirred at room temperature for 17 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, diluted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 500 mg of the title compound.

Step 2 1- (2,6-Dichloropyridin-4-yl) ethanone
490 mg of 2,6-dichloro-N-methoxy-N-methylisonicotinamide was dissolved in tetrahydrofuran and 3 M methylmagnesium bromide at 0 ° C. A tetrahydrofuran solution (2.1 ml) was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour. Aqueous ammonium chloride solution was added to the reaction mixture, diluted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 325 mg of the title compound.

Step 3 2,6-Dichloro-4- (1H-pyrazol-3-yl) pyridine 5 ml of N, N-dimethylformamide diethyl acetal was added to 325 mg of 1- (2,6-dichloropyridin-4-yl) ethanone, and 30 Heated to reflux for minutes. Under reduced pressure, N, N-dimethylformamide diethyl acetal was distilled off, and 5 ml of ethanol and 91 μl of hydrazine monohydrate were added to the resulting residue, followed by heating under reflux for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 320 mg of the title compound.

Step 4 2,6-dichloro-4- (1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol-3-yl) pyridine 2,6-dichloro-4- (1H-pyrazole) under an argon atmosphere -3-yl) pyridine (250 mg) was dissolved in tetrahydrofuran (6 ml), 60% sodium hydride (56 mg) was added little by little at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. Subsequently, 0.25 ml of (2-chloromethoxy) ethyltrimethylsilane was added, and the mixture was warmed to room temperature and stirred for 2 hours. Water was added, extraction was performed with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 440 mg of the title compound.

Step 5 (S) -6-Chloro-N- [1- (4-fluorophenyl) ethyl] -6- (1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol-3-yl) pyridine 2-Amine 100 ml of 2,6-dichloro-4- (1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol-3-yl) pyridine obtained in Step 4 was added to 3 ml of degassed toluene. , (S)-(−)-1- (4-fluorophenyl) ethylamine 45 mg, 2- (di-t-butylphosphino) biphenyl 17 mg, sodium t-butoxide 70 mg and palladium acetate 7 mg were sequentially added, and an argon atmosphere was added. The mixture was stirred at 85 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 130 mg of the title compound as a 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 (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -6 obtained in Step 5 was added to 3 ml of degassed toluene. -(1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol-3-yl) pyridin-2-amine 130 mg, 2-aminopyrazine 35 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6 30 mg of '-triisopropylbiphenyl, 42 mg of sodium t-butoxide and 18 mg of tris (dibenzylideneacetone) (chloroform) dipalladium were sequentially added, and argon was added. Under 囲気, and the mixture was stirred for 1 hour at 100 ℃. The reaction solution was purified by silica gel column chromatography to obtain 95 mg of the title compound as a 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 obtained in step ^{6 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ⁶ - (pyrazin-2-yl) -4- (1 - {[2- (trimethylsilyl) ethoxy] A mixed solution of 3 ml of trifluoroacetic acid and 0.3 ml of water was added to 95 mg of (methyl} -1H-pyrazol-3-yl) pyridine-2,6-diamine, and the mixture was stirred at 60 ° C. for 1 hour. The solvent was distilled off under reduced pressure, diluted with water, and made alkaline with a saturated aqueous sodium hydrogen carbonate solution. Extraction operation was performed with ethyl acetate, and the organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off to obtain 20 mg of the title compound as a pale yellow powder.
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 - (S) -6-Chloro-N- [1- (4-fluorophenyl) ethyl] synthesized in the same manner as in Example 4, Steps 1 and 2 in 13 ml of 2,6-diamine maleate degassed toluene -4- (1-Methyl-1H-pyrazol-4-yl) pyridin-2-amine 1.34 g, 2-aminopyrazine 423 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 154 mg , 544 mg of sodium t-butoxide and 74 mg of tris (dibenzylideneacetone) dipalladium were sequentially added, and the mixture was stirred at 100 ° C. for 1 hour in an argon atmosphere. The reaction solution was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (S) -N ^2- [1- (4-fluorophenyl) ethyl] -4- (1-methyl-1H) was purified. -Pyrazol-4-yl) -N ^6- (pyrazin-2-yl) pyridine-2,6-diamine 1.26 g was obtained as a pale yellow powder. Subsequently, the obtained ^{(S) -N 2 - [1-} (4- fluorophenyl) ethyl] -4- (1-methyl -1H- pyrazol-4-yl) -N ⁶ - (pyrazin-2-yl ) 1.0 g of pyridine-2,6-diamine was dissolved in 1 ml of methanol, and 300 mg of maleic acid was added. 6 ml of ethyl acetate was added and stirred at room temperature for 2 hours. The precipitated solid was filtered to obtain 1.1 g of the title compound as a white powder.
MS (ESI) m / z 390 (M + H) ⁺
Elemental analysis (as _{C 25 H 24 FN 7 O 4} )
Calculated Value (%) C: 59.40 H: 4.79 N: 19.40
Actual value (%) C: 59.19 H: 4.58 N: 19.36
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 Example 20 It was synthesized by the method ^{(S) -N 2 - [1-} (4- fluorophenyl) ethyl] -6-morpholino -N ⁴ - a (pyrazin-2-yl) pyrimidine-2,4-diamine, example 30 A maleate was obtained by the same method.
MS (ESI) m / z 396 (M + H) ⁺
Elemental analysis (as _{C 24 H 26 FN 7 O 5} )
Calculated value (%) C: 56.35 H: 5.12 N: 19.17
Actual value (%) C: 56.42 H: 5.07 N: 19.41
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-diamine 1 / 2 was synthesized by the method of maleate example ^{13 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) -6- (pyridin-3 Yl) pyrimidine-2,4-diamine was converted to the maleate salt in the same manner as in Example 30.
MS (ESI) m / z 388 (M + H) ⁺
Elemental analysis (as _{C 23 H 20 FN 7 O 2} )
Calculated value (%) C: 62.02 H: 4.53 N: 22.01
Actual value (%) C: 61.79 H: 4.50 N: 22.14
Specific rotation [α] _D ²⁰ = −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] pyrrolidine -3-yl} acetamide maleate N-{(S) -1- [2-{[(S) -1- (4-fluorophenyl) ethyl] amino} -6-6 synthesized by the method of Example 2 (Pyrazin-2-ylamino) pyrimidin-4-yl] pyrrolidin-3-yl} acetamide was converted to the maleate salt in the same manner as in Example 30.
MS (ESI) m / z 437 (M + H) ⁺
Elemental analysis value (as C ₂₆ H ₂₉ FN ₈ O ₅ )
Calculated value (%) C: 56.52 H: 5.29 N: 20.28
Actual value (%) C: 56.49 H: 5.24 N: 20.45
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 was synthesized by the method of the diamine maleate example ^{11 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl)-6-(1H-pyrazol -4 -Yl) Pyrimidine-2,4-diamine was converted to the maleate salt in the same manner as in Example 30.
MS (ESI) m / z 377 (M + H) ⁺
Elemental analysis (as _{C 23 H 21 FN 8 O 4} + 0.2H 2 O)
Calculated value (%) C: 55.69 H: 4.35 N: 22.59
Actual value (%) C: 55.32 H: 4.33 N: 22.61
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 in the same manner as diamine hydrochloride example 10, 4- (methyl sulfonyl) phenylboronic acid, 3- with (methylsulfonyl) phenylboronic ^{acid, (S) -N 2 - [} 1- (4 - (pyrazin-2-yl) pyrimidine-2,4-diamine - fluorophenyl) ethyl] -6- [3- (methylsulfonyl) phenyl] -N ^4. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a white powder.
MS (ESI) m / z 465 (M + H) ⁺
Elemental analysis (as _{C 23 H 21 FN 6 O 2} S · HCl + 0.5H 2 O)
Calculated value (%) C: 54.17 H: 4.55 N: 16.48
Actual value (%) C: 54.04 H: 4.35 N: 16.10
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 In the same manner as in Example 4, instead of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole, using 4- (methylsulfonyl) phenyl boronic ^{acid, (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -4- [4- (methylsulfonyl) phenyl] -N ⁶ - (pyrazin-2 -Yl) Pyridine-2,6-diamine was prepared. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a yellow powder.
MS (ESI) m / z 464 (M + H) ⁺
Elemental analysis (as _{C 24 H 22 FN 5 O 2} S · HCl + 0.2H 2 O)
Calculated value (%) C: 57.24 H: 4.68 N: 13.91
Actual value (%) C: 56.97 H: 4.35 N: 13.71
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 Under argon atmosphere, 96 mg of 60% sodium hydride was suspended in 6 ml of N, N-dimethylformamide and brought to 0 ° C. 4-iodo-1H-pyrazole (388 mg) was added, and the mixture was stirred at 0 ° C. for 30 min. Subsequently, 0.21 ml of 2-bromopropane was added and stirred at 100 ° C. for 2 hours. Water was added, extraction was performed with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 328 mg of the title compound.

Step 2 2,6-Dichloro-4- (1-isopropyl-1H-pyrazol-4-yl) pyridine To a mixed solution of 6 ml of degassed 1,4-dioxane and 2 ml of water, 2,6-dichloro-4- ( 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) pyridine (synthesized according to the method described in J. Am. Chem. Soc., 2003, 125, 7792-7793 ) 251 mg, 4-iodo-1-isopropyl-1H-pyrazole 325 mg, potassium carbonate 381 mg, and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex 22 mg were sequentially added under an argon atmosphere. , And stirred at 90 ° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 145 mg of the title compound.

Step 3 (S) -6-Chloro-N- [1- (4-fluorophenyl) ethyl] -4- (1-isopropyl-1H-pyrazol-4-yl) pyridin-2-amine To 6 ml of degassed toluene , 145 mg of 2,6-dichloro-4- (1-isopropyl-1H-pyrazol-4-yl) pyridine obtained in 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 sequentially added, followed by stirring at 85 ° C. for 2 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 59 mg of the title compound as a pale yellow powder.

Step ^{4 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -4- (1-isopropyl -1H- pyrazol-4-yl) -N ⁶ - (pyrazin-2-yl) pyridin-2 , 6-diamine hydrochloride To 5 ml of degassed toluene, (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -4- (1-isopropyl-1H-pyrazol-4-yl) 59 mg pyridin-2-amine, 19 mg 2-aminopyrazine, 16 mg 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 22 mg sodium t-butoxide and tris (dibenzylideneacetone) (chloroform) dipalladium 9 mg was sequentially added, and the mixture was stirred at 85 ° C. for 1.5 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (S) -N ^2- [1- (4-fluorophenyl) ethyl] -4- (1-isopropyl-1H) was purified. - pyrazol-4-yl) -N ⁶ - (pyrazine-2-yl) pyridine-2,6-diamine 40mg as a pale yellow powder. This was converted into a hydrochloride according to a conventional method to obtain 30 mg of the title compound as a brown powder.
MS (ESI) m / z 418 (M + H) ⁺
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] pyrrolidine -3-yl} acetamide hydrochloride To 6 ml of degassed toluene, (S) -4-chloro-N ^2- [1- (4-fluorophenyl) ethyl] -N ^6- (pyrazin-2-yl) pyridine- 2,6-diamine (Reference Example 2) 100 mg, (S) -N- (pyrrolidin-3-yl) acetamide 112 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 69 mg, sodium t -Butoxide 92 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 30 mg were sequentially added, and the mixture was stirred at 100 ° C. for 2 hours in an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and N-{(S) -1- [2-{[(S) -1- (4-fluorophenyl) ethyl ] 115 mg of amino} -6- (pyrazin-2-ylamino) pyridin-4-yl] pyrrolidin-3-yl} acetamide was obtained as a light brown powder. This was converted into a hydrochloride according to a conventional method to obtain 67 mg of the title compound as a brown powder.
MS (ESI) m / z 436 (M + H) ⁺
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) pyridin-2,6-diamine Similar to Example 38 Gave the title compound as a brown powder using morpholine instead of (S) -N- (pyrrolidin-3-yl) acetamide.
MS (ESI) m / z 395 (M + H) ⁺
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-similar to the thiomorpholino pyridine-2,6-diamine Example 38 The method gave the title compound as a brown powder using thiomorpholine instead of (S) -N- (pyrrolidin-3-yl) acetamide.
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 Example 12 In the same manner as described above, 1,3-propanediol was used in place of ethylene glycol to obtain the title compound as a yellow powder.
MS (ESI) m / z 384 (M + H) ⁺

Example 42 (S) -N- (1- { 2- [1- (4- fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) Pirimi Jin-4-yl} azetidin-3-yl)
100 mg of t-butyl acetamidoazetidin -3-ylcarbamate was dissolved in 5 ml of methylene chloride, and 225 mg of N, N-diisopropylethylamine was added. Under ice cooling, 68 mg of acetyl chloride was added and stirred at room temperature for 2 days. The mixture was diluted with ethyl acetate, washed successively with 5% aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 146 mg of a brown oil. This was dissolved in 2.5 ml of methylene chloride, 1 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. After evaporating the solvent under reduced pressure, 66 mg of N- (azetidin-3-yl) acetamide trifluoroacetate was obtained. Subsequently, to 3 ml of degassed 1,4-dioxane, 33 mg of the obtained N- (azetidin-3-yl) acetamide trifluoroacetate salt, 148 mg of triethylamine, (S) -6-chloro-N ^2- [1- (4-fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4-diamine 100 mg, 2-dicyclohexyl phosphino-2 ', 4', 6'-triisopropyl biphenyl 28 mg, sodium t -56 mg of butoxide and 30 mg of tris (dibenzylideneacetone) (chloroform) dipalladium were sequentially added, followed by stirring at 90 ° C. for 2 hours in an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 17 mg of the title compound as a bright yellow powder.
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 [ In the same manner as in Example 1, azetidine hydrochloride was used in place of piperazin-2-one to obtain the title compound as a white amorphous.
MS (ESI) m / z 366 (M + H) ⁺

Example 44 (S) -6- (3- ^fluoro-1-yl) -N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidin-2, 4-Diamine By a method similar to that in Example 1, 3-fluoroazetidine hydrochloride was used in place of piperazin-2-one to give the title compound as a pale yellow amorphous.
MS (ESI) m / z 384 (M + H) ⁺
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 degassed 1, 4-dioxane 3ml, (S) -6- chloro ^-N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4-diamine 100 mg (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 successively. The mixture was stirred at 90 ° C. for 5 hours under an argon atmosphere. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 58 mg of the title compound as a white powder.
MS (ESI) m / z 380 (M + H) ⁺
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 By a method similar to that in Example 37, iodoethane was used in place of 2-bromopropane, and the title compound was obtained as a pale yellow powder.
MS (ESI) m / z 404 (M + H) ⁺
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 In the same manner as in Example 4, instead of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole was used to obtain the title compound as a white powder.
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 In the same manner as in Example 37, (bromomethyl) cyclopropane was used instead of 2-bromopropane to give the title compound as an ocher powder.
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) pyrimidin-2-amine To degassed dimethylformamide, (S ) -4,6-dichloro-N- [1- (4-fluorophenyl) ethyl] pyrimidin-2-amine 286 mg (Reference Example 1), 5- (tributylstannyl) thiazole 411 mg and tetrakis (triphenylphosphine) palladium 115 mg was sequentially added, and the mixture was stirred at 100 ° C. for 5 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (S) -4-chloro-N- [1- (4-fluorophenyl) ethyl] -6- (thiazole- 175 mg of 5-yl) pyrimidin-2-amine was obtained 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 (S ) -4-chloro-N- [1- (4-fluorophenyl) ethyl] -6- (thiazol-5-yl) pyrimidin-2-amine 155 mg, 2-aminopyrazine 53 mg, 4,5-bis (diphenylphos) Fino) -9,9′-dimethylxanthene 72 mg, tripotassium phosphate 196 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 4 ml were added with 4 ml of 1,4-dioxane, deaerated and purged with argon, 100 ° C. For 5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 105 mg of the title compound as a pale yellow powder.
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 By the same method as in Example 1, step 1, piperazine-2- DL-3-pyrrolidinol was used in place of ON to give the title compound as a white powder.

Step 2 1- {2-[(S) -1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} pyrrolidin-3-ol hydrochloride Degassed 1 , 4-dioxane 3 ml, 1- {6-chloro-2-[(S) -1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl} pyrrolidin-3-ol 119 mg, 2-aminopyrazine 40 mg , 4,5-bis (diphenylphosphino) -9,9'-dimethylxanthene, 150 mg of tripotassium phosphate and 19 mg of tris (dibenzylideneacetone) dipalladium were added in that order, and 2. at 100 ° C. under an argon atmosphere. Stir for 5 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1- {2-[(S) -1- (4-fluorophenyl) ethylamino]. 47 mg of -6- (pyrazin-2-ylamino) pyrimidin-4-yl} pyrrolidin-3-ol was obtained. Further, the hydrochloride was converted according to a conventional method to obtain 32 mg of the title compound as a pale yellow powder.
MS (ESI) m / z 396 (M + H) ⁺
Elemental analysis (as _{C 20 H 22 FN 7 O ·} HCl + 0.25H 2 O)
Calculated value (%) C: 55.04 H: 5.43 N: 22.47
Actual 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) pyrimidin-2, 4,6-Triamine In the same manner as in Example 16, 2-amino-5-methylthiazole was used in place of 2-pyrrolidone to obtain the title compound as a pale yellow powder.
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 <br/> step 1 (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -4,5′-bipyrimidin-2-amine To 3 ml of degassed 1,4-dioxane and 1 ml of water, (S) -4,6-dichloro-N- [1- (4-fluorophenyl) ethyl] pyrimidin-2-amine (Reference Example 1) 210 mg, pyrimidine-5-boronic acid 91 mg, potassium carbonate 304 mg and 1,1′-bis 60 mg of (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex was sequentially added, and the mixture was stirred at 90 ° C. for 6 hours in an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -4,5′- 73 mg of bipyrimidin-2-amine was obtained as a white amorphous.

Step ^{2 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ⁶ - (pyrazin-2-yl) 4,5'-bipyrimidine-2,6-diamine (S)-6- Chloro-N- [1- (4-fluorophenyl) ethyl] -4,5′-bipyrimidin-2-amine 90 mg, 2-aminopyrazine 31 mg, 4,5-bis (diphenylphosphino) -9,9′- To 4 mg of dimethylxanthene, 116 mg of tripotassium phosphate and 28 mg of tris (dibenzylideneacetone) (chloroform) dipalladium, 2 ml of 1,4-dioxane was added, deaerated, purged with argon, and stirred at 100 ° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 30 mg of the title compound as a pale yellow powder.
MS (ESI) m / z 389 (M + H) ⁺

Example ^{53 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -6- (2-methoxy-5-yl) -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4 - in the same manner as diamine example 49, 5- (tributylstannyl) thiazole, using 2-methoxy-5- (tributylstannyl) thiazole, the title compound was obtained as a pale orange powder.
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 ((S) -4,6-Dichloropyrimidin-2-yl) [1- (4-fluorophenyl) ethyl] carbamate t-butyl (S) -4,6-dichloro-N- [ 300 mg of 1- (4-fluorophenyl) ethyl] pyrimidin-2-amine was dissolved in 7 ml of tetrahydrofuran, 0.70 ml of di-t-butyl dicarbonate and 58 mg of 4-dimethylaminopyridine were added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 285 mg of the title compound as a colorless oil.

Step 2 (S) -4-Chloro-6- (thiazol-2-yl) pyrimidin-2-yl [1- (4-fluorophenyl) ethyl] carbamate t-butyl Degassed toluene (5% ) -4,6-dichloropyrimidin-2-yl) [1- (4-fluorophenyl) ethyl] carbamate 270 mg, 2- (tributylstannyl) thiazole 314 mg and tetrakis (triphenylphosphine) palladium 81 mg. The mixture was added sequentially and stirred at 100 ° C. for 3 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 150 mg of the title compound as a 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
To 4 ml of degassed 1,4-dioxane, 130 mg of t-butyl (S) -4-chloro-6- (thiazol-2-yl) pyrimidin-2-yl [1- (4-fluorophenyl) ethyl] carbamate 2-aminopyrazine 34 mg, 4,5-bis (diphenylphosphino) -9,9′-dimethylxanthene 35 mg, tripotassium phosphate 127 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 31 mg were sequentially added, The mixture was stirred at 100 ° C. for 3 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 90 mg of a pale yellow oil. To this, 2 ml of trifluoroacetic acid was added and stirred at room temperature for 2 hours. Under reduced pressure, trifluoroacetic acid was distilled off, diluted with water, and made alkaline with saturated aqueous sodium hydrogen carbonate solution. Extraction operation was performed with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and then dried over magnesium sulfate. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography to obtain 25 mg of the title compound as a white powder.
MS (ESI) m / z 394 (M + H) ⁺

Example 55 (S) -5- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} picolinonitrile Similar method to Example 52 Used 2-cyanopyridine-5-boronic acid pinacol ester instead of pyrimidine-5-boronic acid to give the title compound as a pale yellow powder.
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
Hydrochloric acid salt In the same manner as in Example 1, (S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazine) was used instead of piperazin-2-one using isonicopetamide. -2-ylamino) pyrimidin-4-yl} piperidine-4-carboxamide was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a white powder.
MS (ESI) m / z 437 (M + H) ⁺

Example 57 (S) -5- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} picolinamide (S) -5- {2 -[1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} picolinonitrile was added to 38 mg of t-butanol, followed by 60 mg of potassium fluoride supported on alumina. , And stirred at 90 ° C. for 4 hours. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 25 mg of the title compound as amorphous.
MS (ESI) m / z 431 (M + H) ⁺

Example 58 4- {2-[(S) -1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} piperazine-2-carboxamide As in Example 1. According to the method, piperazine-2-carboxamide was used instead of piperazin-2-one to obtain the title compound as a pale yellow amorphous.
MS (ESI) m / z 438 (M + H) ⁺

Example 59 6- ^{(3-Amino-l-yl) -N 2 - [(S)} -1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4 -Diamine 1- {2-[(S) -1- (4-Fluorophenyl) in the same manner as in Example 1 except that 3- (t-butoxycarbonylamino) pyrrolidine was used instead of piperazin-2-one. ) Ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} pyrrolidin-3-ylcarbamate t-butyl was obtained. To this, 2 ml of trifluoroacetic acid was added and stirred at room temperature for 1 hour. Trifluoroacetic acid was distilled off, diluted with water, and made alkaline with a saturated aqueous sodium hydrogen carbonate solution. Extraction operation was performed with ethyl acetate, and the organic layer was washed with water and dried over magnesium sulfate. After distilling off the solvent, the title compound was obtained as a pale yellow powder.
MS (ESI) m / z 395 (M + H) ⁺

Example 60 N- (1- {2-[(S) -1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} pyrrolidin-3-yl) methane sulfonamide hydrochloride 6- ^{(3-amino-l-yl) -N 2 - [(S)} -1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidin-2, 110 mg of 4-diamine (Example 59) was dissolved in 3 ml of tetrahydrofuran, 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. After adding water, the reaction solution was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and N- (1- {2-[(S) -1- (4-fluorophenyl) ethylamino] -6- 92 mg of (pyrazin-2-ylamino) pyrimidin-4-yl} pyrrolidin-3-yl) methanesulfonamide was obtained as a pale yellow amorphous. The hydrochloride was obtained by a conventional method to obtain 70 mg of the title compound as a pale yellow powder.
MS (ESI) m / z 473 (M + H) ⁺
Elemental analysis (as _{C 21 H 25 FN 8 O 2} S · HCl + 0.5H 2 O + 0.2CH 3 CO 2 C 2 H 5)
Calculated value (%) C: 48.88 H: 5.38 N: 20.92
Actual 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) ethane -1-ol hydrochloride In the same manner as in Example 1, instead of piperazin-2-one, diethanolamine was used, and (S) -2-({2- [1- (4-fluorophenyl) ethylamino] -6- (Pyrazin-2-ylamino) pyrimidin-4-yl} (2-hydroxyethyl) amino) ethane-1-ol was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a white powder.

MS (ESI) m / z 414 (M + H) ⁺
Elemental analysis value (as C ₂₀ H ₂₄ FN ₇ O ₂ .HCl + H ₂ O)
Calculated value (%) C: 52.97 H: 5.65 N: 21.62
Actual 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 in the same manner as 6-triamine dihydrochloride example 1, instead of piperazin-2-one, N, using N- ^{dimethylethylenediamine, (S) -N 4 - [} 2- ( dimethylamino) ethyl] -N ² - [1- (4- fluorophenyl) ethyl] -N ⁶ - (pyrazin-2-yl) pyrimidine-2,4,6-triamine. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a light brown powder.
MS (ESI) m / z 397 (M + H) ⁺
Elemental analysis (as _{C 20 H 25 FN 8 · 2HCl} + 1.5H 2 O)
Calculated value (%) C: 48.39 H: 6.09 N: 22.57
Actual 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} piperidine-3-carboxamide hydrochloride Example 1 1- {2-[(S) -1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) using nipecotamide instead of piperazin-2-one Pyrimidin-4-yl} piperidine-3-carboxamide was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a white powder.
MS (ESI) m / z 437 (M + H) ⁺

Example 64 (S) -1- {2-[(S) -1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} pyrrolidine-2-carboxamide Hydrochloric acid In the same manner as in Example 1, substituting L-prolinamide for piperazin-2-one, (S) -1- {2-[(S) -1- (4-fluorophenyl) ethylamino was used. ] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} pyrrolidine-2-carboxamide was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a yellow powder.
MS (ESI) m / z 423 (M + H) ⁺
Elemental analysis value (as C ₂₁ H ₂₃ FN ₈ O.HCl + 1.5H ₂ O)
Calculated value (%) C: 51.90 H: 5.60 N: 23.06
Actual 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 In the same manner as in Example 1, 1-methanesulfonylpiperazine was used instead of piperazin-2-one, and (S) —N ^2- [1- (4-fluorophenyl) ethyl was used. ] -6- [4- (methylsulfonyl) piperazin-1-yl] -N ⁴ - was obtained a (pyrazin-2-yl) pyrimidine-2,4-diamine. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a white powder.
MS (ESI) m / z 473 (M + H) ⁺
Elemental analysis value (as C ₂₁ H ₂₅ FN ₈ O ₂ S · HCl + 1.6H ₂ O)
Calculated value (%) C: 46.90 H: 5.47 N: 20.83
Actual 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 <br/> step ^{1 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) -6- [1- (triisopropylsilyl)-1H- [Pyrrole-3-yl] pyrimidine-2,4-diamine In the same manner as in Example 52, 1- (triisopropylsilyl) -1H-pyrrole-3-boronic acid was used instead of pyrimidine-5-boronic acid. To give the title compound.
Step ^{2 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl)-6-(1H-pyrrol-3-yl) pyrimidine-2,4-diamine ^(S) -N 2 - [1- (4-fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) -6- [1- (triisopropylsilyl)-1H-pyrrol-3-yl] pyrimidine 305 mg of 2,4-diamine was dissolved in 3 ml of tetrahydrofuran, 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. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 199 mg of the title compound as a light brown powder.
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-hydroxypyrrolidine- 2-one By the same method as in Example 16, (R)-(+)-4-hydroxy-2-pyrrolidinone was used instead of 2-pyrrolidone to obtain the title compound as a pale yellow amorphous.
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] pyrimidin-2, 4,6- Triamine In the same manner as in Example 1, tetrahydrofurfurylamine was used in place of piperazin-2-one to obtain the title compound as an amorphous substance.
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 In the same manner as in Example 1, using L-prolinol instead of piperazin-2-one, ((S) -1- {2-[(S) -1- (4-fluoro Phenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} pyrrolidin-2-yl) methanol was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a brown powder.
MS (ESI) m / z 410 (M + H) ⁺
Elemental analysis (as _{C 21 H 24 FN 7 O ·} HCl + 0.4H 2 O + 0.5CH 3 OH)
Calculated value (%) C: 55.04 H: 5.97 N: 20.90
Actual 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 In the same manner as in Example 1, D-prolinol was used instead of piperazin-2-one, and ((R) -1- {2-[(S) -1- (4-fluoro Phenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} pyrrolidin-2-yl) methanol was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a brown powder.
MS (ESI) m / z 410 (M + H) ⁺
Elemental analysis (as _{C 21 H 24 FN 7 O ·} HCl + 0.4H 2 O + 0.5CH 3 OH)
Calculated value (%) C: 55.04 H: 5.97 N: 20.90
Actual 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 Example 1 In the same manner as above, 4-hydroxypiperidine was used instead of piperazin-2-one, and (S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2 -Iylamino) pyrimidin-4-yl} piperidin-4-ol was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 410 (M + H) ⁺
Elemental analysis _{(C 21 H 24 FN 7 O} · HCl)
Calculated value (%) C: 56.56 H: 5.65 N: 21.99
Actual 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 Example 1 In the same manner as above, 3-hydroxyazetidine hydrochloride is used instead of piperazin-2-one, and (S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- ( Pyrazin-2-ylamino) pyrimidin-4-yl} azetidin-3-ol was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 382 (M + H) ⁺
Elemental analysis (as _{C 19 H 20 FN 7 O ·} HCl + 1.2H 2 O + 0.2CH 3 OH)
Calculated value (%) C: 51.72 H: 5.47 N: 21.99
Actual value (%) C: 51.45 H: 5.14 N: 22.29

Example 73 1- {2-[(S) -1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} piperidin-3-ol hydrochloride Example 1 1- {2-[(S) -1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2) using 3-hydroxypiperidine instead of piperazin-2-one -Iylamino) pyrimidin-4-yl} piperidin-3-ol was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 410 (M + H) ⁺
Elemental analysis (as _{C 21 H 24 FN 7 O ·} HCl + 0.9H 2 O + 0.4CH 3 OH)
Calculated value (%) C: 54.12 H: 6.03 N: 20.64
Actual 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 15 -(Trimethylstannyl) nicotinonitrile Into 5 ml of degassed 1,4-dioxane, 300 mg of 5-bromo-3-cyanopyridine, 750 mg of hexamethylditine and 185 mg of tetrakis (triphenylphosphine) palladium were sequentially added, and argon was added. The mixture was stirred at 100 ° C. for 3 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 178 mg of the title compound as a colorless oil.

Step 2 (S) -5- {6-Chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl} nicotinonitrile To 3 ml of degassed toluene, (S) -4,6 -Dichloro-N- [1- (4-fluorophenyl) ethyl] pyrimidin-2-amine 187 mg (Reference Example 1), 5- (trimethylstannyl) nicotinonitrile 175 mg, copper iodide 25 mg and tetrakis (triphenylphosphine) ) 75 mg of palladium was sequentially added, and the mixture was stirred at 110 ° C. for 17 hours under an argon atmosphere. The reaction solution was purified by silica gel column chromatography, and 58 mg of (S) -5- {6-chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl} nicotinonitrile was obtained as a colorless oil. Got as.

Step 3 ((S) -5- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} nicotinonitrile To 2 ml of degassed toluene, (S) -5- {6-Chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl} nicotinonitrile 55 mg, 2-aminopyrazine 16 mg, 2-dicyclohexylphosphino-2 ′ , 4 ′, 6′-triisopropylbiphenyl 15 mg, sodium t-butoxide 21 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 8 mg were sequentially added, and the mixture was stirred for 1 hour at 100 ° C. in an argon atmosphere. Purification by silica gel column chromatography gave 21 mg of the title compound as a white powder.
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 In the same manner as in Example 74, instead of 5- (trimethylstannyl) nicotinonitrile, 2- (benzyloxymethyl) -5- (tributylstannyl) -2H- Using tetrazole (synthesized according to Tetrahedron Lett., 2000, 41, 2805-2809), (S) -6- [2- (benzyloxymethyl) -2H-tetrazole- - ^yl] -N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4-diamine.

Step ^{2 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl)-6-(2H-tetrazol-5-yl) pyrimidine-2,4-diamine (S) -6- [2- (benzyloxymethyl) -2H- ^{tetrazol-5-yl]} N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidine - 50 mg of 2,4-diamine was dissolved in 1.5 ml of methanol, 1.5 ml of 10% aqueous hydrochloric acid solution was added, and the mixture was stirred at 80 ° C. for 20 hours. After cooling, the reaction mixture was diluted with ethyl acetate and adjusted to pH 4 with saturated aqueous sodium hydrogen carbonate solution. The organic layer was extracted, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was washed with methanol, filtered and dried under reduced pressure to obtain 15 mg of the title compound as a white powder.
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 In the same manner as in Example 59, instead of 3- (t-butoxycarbonylamino) pyrrolidine, t-butyl N- (2-aminoethyl) carbamate was used, and (S) —N ⁴ — ^{(2-aminoethyl)} -N 2 - [1- (4- fluorophenyl) ethyl] -N ⁶ - (pyrazin-2-yl) pyrimidine-2,4,6-triamine. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 369 (M + H) ⁺
Elemental analysis (as _{C 18 H 21 FN 8 · 2HCl} + 0.5H 2 O)
Calculated value (%) C: 48.01 H: 5.37 N: 24.88
Actual value (%) C: 47.72 H: 5.51 N: 24.70

Example 77 (S) -N- (2- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-ylamino} ethyl) methanesulfonamide hydrochloride in the same manner as in example 60, 6- ^{(3-amino-l-yl) -N 2 - [(S)} -1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl ) instead of ^{pyrimidine-2,4-diamine, (S) -N 4 - (} 2- ^aminoethyl) -N 2 - [1- (4- fluorophenyl) ethyl] -N ⁶ - (pyrazin-2-yl ) Pyrimidine-2,4,6-triamine and (S) -N- (2- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidine-4 -Ilamino} ethyl) To obtain a down sulfonamide. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 447 (M + H) ⁺
Elemental analysis (as _{C 19 H 23 FN 8 O 2} S · HCl + H 2 O)
Calculated value (%) C: 45.55 H: 5.23 N: 22.37
Actual value (%) C: 45.61 H: 5.07 N: 22.24

Example 78 (S) -N- (2- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-ylamino} ethyl) acetamide hydrochloride (S ) ^-N 4 - ^{(2-aminoethyl)} -N 2 - [1- (4- fluorophenyl) ethyl] -N ⁶ - (pyrazin-2-yl) pyrimidine-2,4,6-triamine dihydrochloride ( Example 76) To 141 mg, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added and separated. The organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in 3 ml of tetrahydrofuran, 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. Water was added to the reaction solution, and extraction with ethyl acetate was performed. The organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (S) -N- (2- {2- [1- (4-fluorophenyl) ethylamino] -6- 95 mg of (pyrazin-2-ylamino) pyrimidin-4-ylamino} ethyl) acetamide was obtained as a white powder. This was converted into a hydrochloride according to a conventional method to obtain 74 mg of the title compound as a pale yellow powder.
MS (ESI) m / z 411 (M + H) ⁺
Elemental analysis (as _{C 20 H 23 FN 8 O ·} HCl)
Calculated value (%) C: 53.75 H: 5.41 N: 25.07
Actual 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 Similar method to that of Example 1 By using 2-aminoacetamide instead of piperazin-2-one and (S) -2- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidine- 4-ylamino} acetamide was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a light brown powder.
MS (ESI) m / z 383 (M + H) ⁺
Elemental analysis (as _{C 18 H 19 FN 8 O ·} HCl + 1.2H 2 O)
Calculated value (%) C: 49.08 H: 5.13 N: 25.44
Actual 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 Method similar to that in Example 10 By using 4-carbamoylphenylboronic acid instead of 4- (methylsulfonyl) phenylboronic acid, (S) -4- {2- [1- (4-fluorophenyl) ethylamino] -6- ( Pyrazin-2-ylamino) pyrimidin-4-yl} benzamide was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a white powder.
MS (ESI) m / z 430 (M + H) ⁺
Elemental analysis (as _{C 23 H 20 FN 7 O ·} HCl + H 2 O)
Calculated value (%) C: 57.09 H: 4.79 N: 20.26
Actual 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 By a method similar to that in Example 10. Using 3-cyanophenylboronic acid instead of 4- (methylsulfonyl) phenylboronic acid, the title compound was obtained as a pale yellow amorphous.
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 in the same manner as salt example 10, 4- (methyl sulfonyl) phenylboronic acid, using 3-furylboronic ^{acid, (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] - 6- (furan-3-yl) -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4-diamine. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a white powder.
MS (ESI) m / z 377 (M + H) ⁺
Elemental analysis (as _{C 20 H 17 FN 6 O ·} HCl)
Calculated value (%) C: 58.18 H: 4.39 N: 20.36
Actual value (%) C: 57.88 H: 4.58 N: 20.24

Example 83 (S)-1- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} piperidine-4-carboxylate Example 1 In the same manner as above, ethyl isonipecotate was used in place of piperazin-2-one to give the title compound as a pale yellow amorphous product.
MS (ESI) m / z 466 (M + H) ⁺

Example 84 (S) -5- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} nicotinamide By a method similar to that in Example 57. Instead of (S) -5- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} picolinonitrile, (S) -5 The title compound was obtained as amorphous using-{2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} nicotinonitrile.
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 (S)- 128 mg (Example 83) of ethyl 1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} piperidine-4-carboxylate in 3 ml of ethanol After dissolution, 0.28 ml of 12% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 6 hours. Ethanol was distilled off, diluted with water and washed with diethyl ether. The aqueous layer was adjusted to pH 7 with 10% aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was washed with diethyl ether, filtered and dried under reduced pressure to obtain 58 mg of the title compound as a white powder.
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 In the same manner as in Example 1, (S)-(+)-2-phenylglycinol was used instead of piperazin-2-one, and the reaction was conducted at 135 ° C. using ethoxyethanol as the reaction solvent in Step 1. To give the title compound as a brown powder.
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-phenylpropane- 1-ol In the same manner as in Example 1, L-phenylalaninol was used instead of piperazin-2-one, and the reaction was conducted at 135 ° C. using ethoxyethanol as the reaction solvent in Step 1. Was obtained as a brown powder.
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-methylpentane- 1-ol In the same manner as in Example 1, D-leucinol was used in place of piperazin-2-one, and reaction was performed at 135 ° C. using ethoxyethanol as a reaction solvent in Step 1. Obtained as a powder.
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 (S)-6-chloro ^-N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4-diamine 172 mg, tripotassium phosphate To 212 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 95 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 4 ml, 2-dimethylaminoethanol 4 ml was added, degassed, and purged with argon And stirred at 100 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography, (S) -6- [2- (dimethylamino) ^ethoxy] -N 2 - [1- (4- fluorophenyl ) ethyl] -N ⁴ - (pyrazine-2-yl) pyrimidine-2,4-diamine 118 mg. Further, the hydrochloride was obtained according to a conventional method to obtain 101 mg of the title compound as a pale yellow powder.
MS (ESI) m / z 398 (M + H) ⁺
Elemental analysis (as _{C 20 H 24 FN 7 O ·} 2HCl + 1.2H 2 O)
Calculated value (%) C: 48.83 H: 5.82 N: 19.93
Actual 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 (S) -1- {6-Chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl} -1H-pyrazole-4-carboxylate ethyl degassed 1 , 4-dioxane (10 ml), (S) -4,6-dichloro-N- [1- (4-fluorophenyl) ethyl] pyrimidin-2-amine 150 mg (Reference Example 1) 500 mg, ethyl 4-pyrazolecarboxylate 270 mg , Trans-N, N′-dimethylcyclohexane-1,2-diamine (0.20 ml), tripotassium phosphate (780 mg) and copper iodide (100 mg) were sequentially added. Stir at 100 ° C. for 6 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 51 mg of the title compound as a white powder.
MS (ESI) m / z 390 (M + H) ⁺

Step 2 (S) -1- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} -1H-pyrazole-4-carboxylate To 2 ml of toluene, 50 mg of ethyl (S) -1- {6-chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl} -1H-pyrazole-4-carboxylate, -15 mg of 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 sequentially added, and an argon atmosphere The mixture was stirred at 100 ° C. for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain 45 mg of the title compound as a white powder.
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 (S ) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} -1H-pyrazole-4-carboxylate 35 mg and ethanol 2 ml, Tetrahydrofuran (1 ml) and 12% aqueous sodium hydroxide (80 μl) were added, and the mixture was stirred at room temperature for 18 hours. 160 μl of 12% aqueous sodium hydroxide solution was added, and the mixture was further stirred for 3 hours. Ethanol was distilled off, diluted with water, and adjusted to pH 7 with 10% aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, 14 mg of the title compound was obtained as a white powder.
MS (ESI) m / z 421 (M + H) ⁺

Example 91 (S) -3- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} benzamide (S) -3- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} benzonitrile (192 mg, Example 81) was added to t-butanol (5 ml), and alumina-supported potassium fluoride (384 mg). And stirred at 80 ° C. for 2 hours. 384 mg of potassium fluoride supported on alumina was added, and the mixture was further stirred for 15 hours. Insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 158 mg of the title compound as a white powder.
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 In the same manner as in Example 10, but using 3,4- (methylenedioxy) phenylboronic acid instead of 4- (methylsulfonyl) phenylboronic acid, (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. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a white powder.
MS (ESI) m / z 431 (M + H) ⁺
Elemental analysis value (as C ₂₃ H ₁₉ FN ₆ O ₂ .HCl + H ₂ O)
Calculated value (%) C: 56.97 H: 4.57 N: 17.33
Actual 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 By the same method as in Example 10, 2-fluoropyridine-4-boronic acid was used in place of 4- (methylsulfonyl) phenylboronic acid to give the title compound as a white powder.
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 (S)-6-chloro ^-N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4-diamine 200mg, tripotassium phosphate 246 mg, To 111 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl and 60 mg of tris (dibenzylideneacetone) (chloroform) dipalladium 4 ml of tetrahydrofurfuryl alcohol and 2 ml of 1,4-dioxane were added to remove The atmosphere was replaced with argon, and the mixture was stirred at 100 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 77 mg of the title compound as a pale yellow powder.
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 Method similar to that in Example 94 By using ethylene glycol instead of tetrahydrofurfuryl alcohol, (S) -2- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidine-4- Iroxy} ethanol was obtained. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 371 (M + H) ⁺
Elemental analysis value (as C ₁₈ H ₁₉ FN ₆ O ₂ .HCl)
Calculated value (%) C: 53.14 H: 4.95 N: 20.66
Actual 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 In the same manner as in Example 1, 1- (2-aminoethyl) pyrrolidine was used instead of piperazin-2-one to give the title compound as a brown powder.
MS (ESI) m / z 423 (M + H) ⁺

Example 97 (S) -3- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} isonicotinamide degassed 1,4- dioxane 3.5ml and water 1.5ml, (S) -6- chloro ^-N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4 150 mg of 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 sequentially added, and the mixture was stirred at 100 ° C. for 5 hours in an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained powder was washed with ethyl acetate, filtered, and dried under reduced pressure to give (S) -3- {2- [1- (4-fluorophenyl) ethylamino]- 31 mg of 6- (pyrazin-2-ylamino) pyrimidin-4-yl} isonicotinamide was obtained as a white powder.
MS (ESI) m / z 431 (M + H) ⁺

Example 98 (S) -3- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} isonicotinonitrile Obtained in Example 97 The filtrate was concentrated under reduced pressure, purified by silica gel column chromatography, and (S) -3- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidine-4. -Il} isonicotinonitrile 15 mg was obtained as a white powder.
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-methylbutane-1 -Ol Hydrochloride In the same manner as in Example 1, L-valinol was used instead of piperazin-2-one to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 412 (M + H) ⁺
Elemental analysis value (as C ₂₁ H ₂₆ FN ₇ O.HCl + H ₂ O)
Calculated value (%) C: 54.13 H: 6.27 N: 21.04
Actual 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) pyrimidin-2 , 4-diamine hydrochloride step 1 (S) -6-chloro-N- [1- (4-chlorophenyl) ethyl] -4- [4- (methylsulfonyl) piperazin-1-yl] pyrimidin-2-amine ( S) -4,6-dichloro-N- [1- (4-chlorophenyl) ethyl] pyrimidin-2-amine (200 mg) and 1-methanesulfonylpiperazine (119 mg) were dissolved in 1-butanol (3 ml), and N, N-diisopropylethylamine 0 .23 ml was added and stirred at 60 ° C. for 20 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 196 mg of the title compound as a white powder.
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) pyrimidin-2, 4-diamine hydrochloride To 6 ml of degassed toluene, (S) -6-chloro-N- [1- (4-chlorophenyl) ethyl] -4- [4- (methylsulfonyl) piperazin-1-yl] pyrimidine- 2-amine 210 mg, 2-aminopyrazine 56 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 47 mg, sodium t-butoxide 66 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 25 mg Sequentially added and stirred at 100 ° C. for 4 hours under an argon atmosphere. The reaction solution was purified by silica gel column ^{chromatography, (S) -N 2 - [} 1- (4- chlorophenyl) ethyl] -6- [4- (methylsulfonyl) piperazin-1-yl] -N ⁴ - (pyrazine 2-Iyl) pyrimidine-2,4-diamine (120 mg) was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 489 (M + H) ⁺
Elemental analysis value (as C ₂₁ H ₂₅ ClFN ₈ O ₂ S · HCl + 0.4H ₂ O)
Calculated value (%) C: 47.35 H: 5.07 N: 21.04
Actual 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 In the same manner as in Example 94, (1S, 2S) -trans-1,2-cyclohexanediol was used instead of tetrahydrofurfuryl alcohol, and (1S, 2S) -2- {2-[(S)- 1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yloxy} cyclohexanol was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 425 (M + H) ⁺
Elemental analysis value (as C ₂₂ H ₂₅ FN ₆ O ₂ .HCl + 0.2H ₂ O)
Calculated value (%) C: 56.88 H: 5.73 N: 18.09
Actual value (%) C: 56.94 H: 5.53 N: 18.14

Example ^{102 (S) -N 2 - [} 1- (4- fluorophenyl) ^ethyl] -N 4 - [(5- methyl-2-yl) methyl] -N ⁶ - (pyrazin-2-yl) pyrimidine by the same method as 2,4,6-triamine hydrochloride example 1, instead of piperazin-2-one, using 2- (aminomethyl) -5-methylpyrazine, (S) ^-N 2 - [ 1- (4-Fluorophenyl) ethyl] -N ⁴ -[(5-methylpyrazin-2-yl) methyl] -N ^6- (pyrazin-2-yl) pyrimidin-2,4,6-triamine was obtained. . Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 432 (M + H) ⁺
Elemental analysis (as _{C 22 H 22 FN 9 · HCl} + H 2 O + 0.5CH 3 OH)
Calculated value (%) C: 53.84 H: 5.42 N: 25.11
Actual 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 - in the same manner as triamine hydrochloride example 1, instead of piperazin-2-one, using furfuryl ^{amine, (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] ^-N 4 - ( furan-2-ylmethyl) -N ⁶ - (was obtained pyrazin-2-yl) pyrimidine-2,4,6-triamine. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 406 (M + H) ⁺
Elemental analysis value (as C ₂₁ H ₂₀ FN ₇ O.HCl + 1.5H ₂ O)
Calculated value (%) C: 53.79 H: 5.16 N: 20.91
Actual 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 In the same manner as in Example 1, 1- (3-pyridyl) ethylamine was used in place of piperazin-2-one, and ethoxyethanol was used as the reaction solvent in Step 1 at 135 ° C. To give the title compound as a brown powder.
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) piperidine-4 -. All <br/> step 1 4- (hydroxymethyl) piperidin-4-ol hydrochloride 1-benzyl-4- (hydroxymethyl) piperidin-4-ol 500mg (J.Med.Chem, 1988,486-491 Was synthesized in 10 ml of ethanol, 300 mg of 10% palladium carbon and 0.38 ml of concentrated hydrochloric acid were added, and hydrogenated at room temperature overnight. The insoluble material was filtered off, washed with ethanol and water, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue to form a powder, and 374 mg of the desired product was obtained as a white powder.

Step 2 (S) -1- {6-Chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl} -4- (hydroxymethyl) piperidin-4-ol (S) -4 , 6-dichloro-N- [1- (4-fluorophenyl) ethyl] pyrimidin-2-amine 150 mg and 4- (hydroxymethyl) piperidin-4-ol hydrochloride 97 mg are dissolved in 3 ml of 2-ethoxyethanol, , N-diisopropylethylamine (274 μl) was added, and the mixture was stirred at 135 ° C. for 20 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, 194 mg of the title compound was obtained as a brown oil.

Step 3 (S) -1- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} -4- (hydroxymethyl) piperidine-4- To a mixed solution of 3 ml of degassed toluene and 2 ml of 1,4-dioxane, (S) -1- {6-chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl}- 4- (hydroxymethyl) piperidin-4-ol 100 mg, 2-aminopyrazine 32 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 45 mg, sodium t-butoxide 38 mg and tris (dibenzylideneacetone) ) (Chloroform) dipalladium (27 mg) was sequentially added, and the mixture was stirred at 100 ° C. for 1 hour under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 80 mg of the title compound as a brown powder.
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 In the same manner as in Example 1, reaction was performed at 135 ° C using 2- (aminomethyl) pyridine in place of piperazin-2-one and using ethoxyethanol as the reaction solvent in Step 1. The compound was obtained as a brown powder.
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 In the same manner as in Example 1, the reaction was conducted at 135 ° C using 3- (aminomethyl) pyridine in place of piperazin-2-one and using ethoxyethanol as the reaction solvent in Step 1. The compound was obtained as a brown powder.
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 In the same manner as in Example 1, except that 4- (aminomethyl) pyridine was used in place of piperazin-2-one and ethoxyethanol was used as the reaction solvent in Step 1, the reaction was carried out at 135 ° C. The compound was obtained as a brown powder.
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 In the same manner as in Example 1, L-serine amide was used instead of piperazin-2-one, and reaction was performed at 135 ° C. using ethoxyethanol as a reaction solvent in Step 1 to obtain the title compound as a white powder. It was.
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} pyrrolidine-3, 4-Diol In the same manner as in Example 1, (3S, 4S) -3,4-pyrrolidinol was used in place of piperazin-2-one to obtain the title compound as a yellow powder.
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) pyrimidin-2,4-diamine In the same manner as in Example 1, 1,4-dioxa-8-azaspiro [4.5] decane was used instead of piperazin-2-one, and In Step 1, the reaction was carried out at 135 ° C. using ethoxyethanol as a reaction solvent to obtain the title compound as a brown powder.
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 (S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} -4- 50 mg of (hydroxymethyl) piperidin-4-ol (Example 105) and 24 mg of N, N′-carbonyldiimidazole were dissolved in 2 ml of methylene chloride and stirred at room temperature for 15 minutes. The reaction solution was purified by silica gel column chromatography to obtain 52 mg of the title compound as a light brown powder.
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 In the same manner as in Example 4, instead of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole And 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole was used to obtain the title compound as a pale yellow powder.
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 In the same manner as in Example 50, instead of DL-3-pyrodinol, 1-phenylsulfonylpiperazine was used, and (S) —N ^2- [1- (4-fluorophenyl) ethyl was used. ] -6- [4- (phenylsulfonyl) piperazin-1-yl] -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4-diamine. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a white powder.
MS (ESI) m / z 535 (M + H) ⁺
Elemental analysis value (as C ₂₆ H ₂₇ FN ₈ O ₂ S · HCl + 1.3H ₂ O)
Calculated value (%) C: 52.53 H: 5.19 N: 18.85
Actual 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
To a mixed solution of 3 ml of degassed 1,4-dioxane and 0.6 ml of water, (S) -4-chloro-N ^2- [1- (4-fluorophenyl) ethyl] -N ^6- (pyrazine-2- Yl) pyridine-2,6-diamine (Reference Example 2) 150 mg, 4-carbamoylphenylboronic acid 108 mg, cesium carbonate 567 mg, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl 21 mg and tris (dibenzylideneacetone) 13 mg of dipalladium was sequentially added, and the mixture was stirred at 100 ° C. for 17 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (S) -4- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazine- 39 mg of 2-ylamino) pyridin-4-yl} benzamide were obtained. Furthermore, the hydrochloride was obtained according to a conventional method to obtain 31 mg of the title compound as an orange powder.
MS (ESI) m / z 429 (M + H) ⁺
Elemental analysis (as _{C 24 H 21 FN 6 O ·} 2HCl + H 2 O)
Calculated value (%) C: 55.50 H: 4.85 N: 16.18
Actual 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 In the same manner as in Example 115, but using 1- (triisopropylsilyl) -1H-pyrrole-3-boronic acid instead of 4-carbamoylphenylboronic acid, (S) —N ² — [1- (4-Fluorophenyl) ethyl] -N ^6- (pyrazin-2-yl) -4- (1H-pyrrol-3-yl) pyridine-2,6-diamine was obtained. This was converted into a hydrochloride according to a conventional method to obtain the title compound as an orange powder.
MS (ESI) m / z 375 (M + H) ⁺
Elemental analysis (as _{C 21 H 19 FN 6 · 2HCl} + 0.4H 2 O)
Calculated value (%) C: 55.49 H: 4.83 N: 18.49
Actual 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 <br/> Step 1 (S ) -6-Chloro-N- [1- (4-fluorophenyl) ethyl] pyridin-2-amine To 6 ml of degassed toluene, 300 mg of 2,6-dichloropyridine, (S)-(−)-1- ( 296 mg of 4-fluorophenyl) ethylamine, 119 mg of 2- (di-t-butylphosphino) biphenyl, 487 mg of sodium t-butoxide and 45 mg of palladium acetate were sequentially added, followed by stirring at 85 ° C. for 2 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 210 mg of the title compound as a pale yellow oil.

Step 2 (S) -N ^2- [1- (4-Fluorophenyl) ethyl] -N ^6- (pyrazin-2-yl) pyridine-2,6-diamine dihydrochloride To 4 ml of degassed toluene, (S ) -6-chloro-N- [1- (4-fluorophenyl) ethyl] pyridin-2-amine 207 mg, 2-aminopyrazine 86 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 79 mg, sodium t-butoxide 111 mg, and tris (dibenzylideneacetone) (chloroform) dipalladium 43 mg were sequentially added, and the mixture was stirred at 100 ° C. for 1 hour in an argon atmosphere. The reaction solution was purified by silica gel column chromatography, and (S) -N ^2- [1- (4-fluorophenyl) ethyl] -N ^6- (pyrazin-2-yl) pyridine-2,6-diamine (202 mg) was pale. Obtained as a yellow powder. Furthermore, it was converted into a hydrochloride according to a conventional method to obtain 128 mg of the title compound as a pale orange powder.
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) Pyrimidin-2-amine (S) -4,6-dichloro-N- [1- (4-fluorophenyl) ethyl] pyrimidin-2-amine (200 mg) and 4-methylimidazole (63 mg) were dissolved in dimethylformamide (2 ml) to obtain potassium carbonate. 193 mg was added and stirred at 100 ° C. for 17 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 62 mg of the title 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) pyrimidin-2 , 4-diamine hydrochloride To 2 ml of degassed toluene, (S) -4-chloro-N- [1- (4-fluorophenyl) ethyl] -6- (4-methyl-1H-imidazoyl-1-yl) Pyrimidin-2-amine 60 mg, 2-aminopyrazine 19 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 17 mg, sodium t-butoxide 35 mg and tris (dibenzylideneacetone) dipalladium 9 mg successively The mixture was added and stirred at 100 ° C. for 2 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column ^{chromatography, (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -6- (4-methyl -1H - (pyrazin-2-yl) pyrimidine-2,4-diamine 69 mg - imidazol-1-yl) -N ^4. Further, the hydrochloride was obtained according to a conventional method to obtain 48 mg of the title compound as a pale yellow powder.
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 In the same manner as in Example 37, instead of 4-iodo-1-isopropyl-1H-pyrazole, 4-bromoanisole was used, and (S) —N ^2- [1- (4-fluorophenyl) ethyl]- 4- (4-Methoxyphenyl) -N ^6- (pyrazin-2-yl) pyridine-2,6-diamine was obtained. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a brown powder.
MS (ESI) m / z 416 (M + H) ⁺
Elemental analysis (as _{C 24 H 22 FN 5 O ·} HCl + 1.5H 2 O)
Calculated value (%) C: 60.19 H: 5.47 N: 14.62
Actual 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 In the same manner as in Example 37, instead of 4-iodo-1-isopropyl-1H-pyrazole, 4-bromofluorobenzene was used, and (S) -4- (4-fluorophenyl) -N ^2- [1 - (pyrazin-2-yl) pyridine-2,6-diamine - (4-fluorophenyl) ethyl] -N ^6. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a brown powder.
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 <br/> step 1 (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -4-methylpyridin-2-amine To 6 ml of degassed dimethylformamide, 500 mg of 2,6-dichloro-4-iodopyridine Then, 0.51 ml of trimethylboroxine, 1.0 g of potassium carbonate and 208 mg of tetrakis (triphenylphosphine) palladium were sequentially added, followed by stirring at 110 ° C. for 3 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 330 mg of a pale yellow solid. This 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 was sequentially added, and the mixture was stirred at 80 ° C. for 1 hour under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 100 mg of the title compound as a colorless oil.

Step 2 ^(S) -N 2 - in (pyrazin-2-yl) pyridine-2,6-diamine hydrochloride degassed toluene 6ml - [1- (4- fluorophenyl) ethyl] -4-methyl -N ⁶ , (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -4-methylpyridin-2-amine 95 mg, 2-aminopyrazine 40 mg, 2-dicyclohexylphosphino-2 ′, 4 ′ , 6′-triisopropylbiphenyl 34 mg, sodium t-butoxide 48 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 19 mg were sequentially added, and the mixture was stirred at 100 ° C. for 1 hour in an argon atmosphere. The reaction solution was purified by silica gel column ^{chromatography, (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -4-methyl -N ⁶ - (pyrazin-2-yl) pyridine-2,6 85 mg of diamine was obtained. Furthermore, the hydrochloride was obtained according to a conventional method to obtain 38 mg of the title compound as a yellow powder.
MS (ESI) m / z 324 (M + H) ⁺
Elemental analysis (as _{C 18 H 18 FN 5 · HCl} + 0.5H 2 O)
Calculated value (%) C: 58.62 H: 5.47 N: 18.99
Actual 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 - (S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} piperidine-4-carboxylic acid ( - ) under a carboxamide argon atmosphere Example 85) 92 mg was dissolved in 2 ml of tetrahydrofuran, 41 mg of N, N′-carbonyldiimidazole was added, and the mixture was stirred at 70 ° C. for 1 hour. After cooling to room temperature, 80 mg of methanesulfonamide and 63 μl of 1,8-diazabicyclo [5,4,0] -7-undecene were added, and the mixture was stirred at room temperature for 4 hours. After dilution with water, acetic acid was added to pH 4. The mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, 42 mg of the title compound was obtained as a white powder.
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 [ In the same manner as in Example 37, 3-bromofuran was used instead of 4-iodo-1-isopropyl-1H-pyrazole to give the title compound as a pale yellow powder.
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 In the same manner as in Example 38, 1-methanesulfonylpiperazine was used instead of (S) -N- (pyrrolidin-3-yl) acetamide and 1,4 as the reaction solvent. - with ^{dioxane, (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -4- [4- (methylsulfonyl) piperazin-1-yl] -N ⁶ - (pyrazin-2-yl) Pyridine-2,6-diamine was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a brown powder.
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) piperidine-4 - in a similar manner to that ol example 38, (S) -N- (pyrrolidin-3-yl) instead of acetamide, 2,2-dimethyl-1,3-dioxa-8-azaspiro [4.5] decane And 1,4-dioxane as a reaction solvent, and (S) -4- (2,2-dimethyl-1,3-dioxa-8-azaspiro [4.5] decan-8-yl)- N ² - (pyrazin-2-yl) pyridine-2,6-diamine - [1- (4-fluorophenyl) ethyl] -N ^6. 46 mg of this was dissolved in 1 ml of chloroform, and 0.5 ml of 50% aqueous trifluoroacetic acid solution was added at 0 ° C. and stirred. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 21 mg of the title compound as a brown powder.
MS (ESI) m / z 439 (M + H) ⁺

Example 126 (S) -4- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} benzenesulfonamide Similar method to Example 37 Used 4-bromobenzenesulfonamide instead of 4-iodo-1-isopropyl-1H-pyrazole to give the title compound as a brown powder.
MS (ESI) m / z 465 (M + H) ⁺

Example 127 (S) -N ^2- [1- (4-Fluorophenyl) ethyl] -4-methoxy-N ^6- (pyrazin-2-yl) pyridin-2,6-diamine Similar to Example 4 By using 2,6-dichloro-4-methoxypyridine (synthesized according to WO2007 / 21710A1) instead of 2,6-dichloro-4- (1-methyl-1H-pyrazol-4-yl) pyridine, The title compound was obtained as a white powder.
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-thiomorpholine-1 , 1-dione In the same manner as in Example 38, using thiomorpholine-1,1-dioxide instead of (S) -N- (pyrrolidin-3-yl) acetamide and 1,4 as the reaction solvent. Using dioxane, the title compound was obtained as a brown powder.
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 Same as Example 38 By using 4-hydroxypiperidine instead of (S) -N- (pyrrolidin-3-yl) acetamide and 1,4-dioxane as a reaction solvent, the title compound was obtained as a brown powder. .
MS (ESI) m / z 409 (M + H) ⁺

Example 130 (S) -1- (4- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} -1,4-diazepane- 1-yl) ethanone In the same manner as in Example 38, N-acetylhomopiperazine was used instead of (S) -N- (pyrrolidin-3-yl) acetamide to give the title compound as a brown powder.
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 In the same manner as in Example 38, using 2-aminopyrimidine instead of (S) -N- (pyrrolidin-3-yl) acetamide and 1,4-dioxane as the reaction solvent, The compound was obtained as a brown powder.
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 In the same manner as in Example 38, 2-aminopyridine was used instead of (S) -N- (pyrrolidin-3-yl) acetamide, and 1,4-dioxane was used as the reaction solvent. The compound was obtained as a brown powder.
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 In the same manner as in Example 38, instead of (S) -N- (pyrrolidin-3-yl) acetamide, 1,4-dioxa-8-azaspiro [ 4.5] Using decane and 1,4-dioxane as the reaction solvent, the title compound was obtained as a brown powder.
MS (ESI) m / z 451 (M + H) ⁺

Example 134 (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinic acid methyl ester Step 1 (S) -2-Chloro- 6- [1- (4-Fluorophenyl) ethylamino] isonicotinic acid methyl ester To 100 ml of degassed 1,4-dioxane, 8.3 g of 2,6-dichloroisonicotinic acid methyl ester, (S)-(- )-(4-Fluoro-1-phenyl) ethylamine 6.1 ml, cesium carbonate 20.5 g, (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl 2.1 g and palladium acetate 505 mg was sequentially added, and the mixture was stirred at 70 ° C. for 7 hours under an argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 4.4 g of the title compound as a pale yellow powder.

Step 2 (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinic acid methyl ester To 100 ml of degassed toluene, (S) -2-chloro- 6- [1- (4-Fluorophenyl) ethylamino] isonicotinic acid methyl ester 4.4 g, 2-aminopyrazine 1.3 g, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 2 .67 g, tripotassium phosphate 5.0 g and tris (dibenzylideneacetone) dipalladium 1.28 g were sequentially added, and the mixture was stirred at 100 ° C. for 24 hours in an argon atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 4.9 g of the title compound as a white powder.
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 In the same manner as in Example 10, instead of 4- (methylsulfonyl) phenylboronic acid, 4- (N-methylsulfamoyl) phenylboronic acid pinacol ester was used, and (S) -4- {2- [ 1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} -N-methylbenzenesulfonamide was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a white powder.
MS (ESI) m / z 480 (M + H) ⁺
Elemental analysis (as _{C 23 H 22 FN 7 O 2} S · HCl + 0.2H 2 O)
Calculated value (%) C: 53.17 H: 4.54 N: 18.87
Actual 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 2,6-dichloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) pyridine 1.10 g, 4-methylimidazole 164 mg, 0.56 ml of triethylamine and 0.32 ml of pyridine were dissolved in 4 ml of methylene chloride, 545 mg of copper acetate was added, and the mixture was stirred at room temperature for 24 hours. After diluting the reaction solution with water, chloroform and concentrated aqueous ammonia were added to separate the solution. The aqueous layer was further extracted with chloroform, and the organic layers were combined and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, 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, 2,6-dichloro-4- (1-methyl-1H-pyrazol-4-yl) pyridine instead of 2,6-dichloro-4- (1-methyl-1H-pyrazol-4-yl) pyridine was prepared in the same manner as in Example 2, Steps 2 and 3. Using (4-methyl-1H-imidazol-1-yl) pyridine, (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. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a yellow powder.
MS (ESI) m / z 390 (M + H) ⁺

Example 137 ^(S) -N 2 - same as di (pyrazin-2-yl) pyridine-2,4,6-triamine Example 38 - [1- (4-fluorophenyl) ^ethyl] -N 4, ^{N 6} By using 2-aminopyrazine instead of (S) -N- (pyrrolidin-3-yl) acetamide, the title compound was obtained as a brown powder.
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 <br / > Step 1 109 mg of 2,6-dichloro-4- (cyclopropylmethoxy) pyridine cyclopropylcarbinol was dissolved in 2 ml of dimethylformamide, 60 mg of 60% sodium hydride was added under ice water cooling, and the mixture was stirred at room temperature for 20 minutes. 2,4,6-Trichloropyridine (400 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and extraction with ethyl acetate was performed. The organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 133 mg of the title compound as a colorless oil.

Step 2 (S) -6-Chloro-4- (cyclopropylmethoxy) -N- [1- (4-fluorophenyl) ethyl] pyridin-2-amine To 2 ml of degassed toluene, 2,6-dichloro-4 -(Cyclopropylmethoxy) pyridine 130 mg, (S)-(-)-1- (4-fluorophenyl) ethylamine 92 mg, 2- (di-t-butylphosphino) biphenyl 36 mg, sodium t-butoxide 144 mg and palladium acetate 14 mg was sequentially added, and the mixture was stirred at 80 ° C. for 15 minutes under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 122 mg of the title compound as a colorless oil.

Step 3 (S) -4- ^{(cyclopropylmethoxy)} -N 2 - [1- (4- fluorophenyl) ethyl] -N ⁶ - (pyrazin-2-yl) pyridine-2,6-diamine degassed 1 , 4-dioxane in 2 ml, (S) -6-chloro-4- (cyclopropylmethoxy) -N- [1- (4-fluorophenyl) ethyl] pyridin-2-amine 112 mg, 2-aminopyrazine 43 mg, -67 mg of dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, 51 mg of sodium tert-butoxide and 36 mg of tris (dibenzylideneacetone) (chloroform) were added sequentially, and the mixture was added at 100 ° C under an argon atmosphere. Stir for 5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 103 mg of the title compound as a brown powder.
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) pyridin-2-amine (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -4- (1-methyl-1H-pyrazol-4-yl) ) 92 mg of pyridin-2-amine was dissolved in 1.5 ml of tetrahydrofuran, 17 mg of 60% sodium hydride was added, and the mixture was stirred at room temperature for 10 minutes. 26 μl of methyl iodide was added, and the mixture was reacted at 100 ° C. for 5 minutes in a microwave. 60 mg sodium hydride 8 mg and methyl iodide 26 μl were added, and the mixture was stirred at 130 ° C. for 10 minutes. Further, 60% sodium hydride 17 mg and methyl iodide 26 μl was added, and the mixture was stirred at 130 ° C. for 10 minutes. Water was added to the reaction solution, and extraction with ethyl acetate was performed. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 62 mg of the title compound as a 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 To 2 ml of degassed toluene, (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -N-methyl-4- (1-methyl) -1H-pyrazol-4-yl) pyridin-2-amine 60 mg, 2-aminopyrazine 18 mg, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl 16 mg, sodium t-butoxide 24 mg and tris ( Dibenzylideneacetone) (chloroform) dipalladium (9 mg) was sequentially added, and the mixture was stirred at 100 ° C. for 1 hour in an argon atmosphere. The reaction solution was purified by silica gel column ^{chromatography, (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ² - methyl-4- (1-methyl -1H- pyrazol-4-yl) 60 mg of —N ^6- (pyrazin-2-yl) pyridine-2,6-diamine was obtained as a pale yellow oil. Furthermore, the hydrochloride was obtained according to a conventional method to obtain 29 mg of the title compound as a pale yellow powder.
MS (ESI) m / z 404 (M + H) ⁺
Elemental analysis (as _{C 22 H 22 FN 7 · HCl} + 2.2H 2 O)
Calculated value (%) C: 55.10 H: 5.76 N: 20.45
Actual 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 (S) -2- [1- (4 -Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinic acid methyl ester (100 mg) was dissolved in tetrahydrofuran (1 ml), lithium aluminum hydride (20 mg) was added little by little, and the mixture was stirred at room temperature for 6 hours. After diluting with tetrahydrofuran, the mixture was cooled to 0 ° C., 25 μl of water, 25 μl of 2N aqueous sodium hydroxide solution, and 75 μl of water were further added, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 60 mg of the title compound as a pale yellow powder.
MS (ESI) m / z 340 (M + H) ⁺

Example 141 (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinic acid (S) -2- [1- (4-fluorophenyl) ethyl 5 ml of methanol was added to 500 mg of amino] -6- (pyrazin-2-ylamino) isonicotinic acid methyl ester (Example 134), followed by 2.7 ml of 2N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 6 hours. After diluting with ethyl acetate and water and extracting the aqueous layer, 2N hydrochloric acid was added. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 160 mg of the title compound as a white powder.
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 in the same manner as in example 12, in place of the ethylene glycol, with ^{2-methoxyethanol, (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -4- (2-methoxyethoxy) -N ^6- (pyrazin-2-yl) pyridine-2,6-diamine was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a brown powder.
MS (ESI) m / z 384 (M + H) ⁺

Example 143 (S) -2- [1- ( 4- fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidine-4-carbonitrile (S) -6-chloro ^-N 2 - [1 - (4-fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4-diamine (example 9) 500 mg, zinc cyanide 197 mg, 2-dicyclohexyl phosphino-2 ', 6' -A mixed solution of dimethylformamide / water (99/1) was added to 66 mg of dimethoxybiphenyl and 66 mg of tris (dibenzylideneacetone) dipalladium, and argon was bubbled for 3 minutes, followed by stirring at 150 ° C. for 15 minutes in a microwave. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 323 mg of the title compound as a pale yellow powder.
MS (ESI) m / z 336 (M + H) ⁺

Example 144 (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinonitrile In the same manner as in Example 143, (S) -6- chloro ^-N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - instead of (pyrazin-2-yl) pyrimidine-2,4-diamine (example 9), (S)-4-chloro Using -N ^2- [1- (4-fluorophenyl) ethyl] -N ^6- (pyrazin-2-yl) pyridine-2,6-diamine, the title compound was obtained as a pale yellow powder.
MS (ESI) m / z 335 (M + H) ⁺

Example 145 (S) -2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinamidomethyl (S) -2- [1- (4-fluorophenyl) Ethylamino] -6- (pyrazin-2-ylamino) isonicotinic acid (Example 134) was added with 15 ml of a 7N ammonia / methanol solution and sealed, and then stirred at 100 ° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 310 mg of the title compound as a pale yellow powder.
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) 150 mg of pyrimidine-2,4-diamine hydrochloride (S) -2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidine-4-carbonitrile (Example 143) It melt | dissolved in 5 ml of absolute ethanol, 156 mg of hydroxyamine hydrochloride and 309 microliters of triethylamine were added, and it heated and refluxed for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 140 mg of brown amorphous. To this, 5 ml of triethyl orthoformate and 7 mg of p-tosylic acid were added and stirred at 60 ° C. for 4 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (S) -N ^2- [1- (4-fluorophenyl) ethyl] -6- (1,2,4) was obtained. - (pyrazin-2-yl) pyrimidine-2,4-diamine 141 mg - oxadiazol-3-yl) -N ^4. This was converted into a hydrochloride according to a conventional method to obtain 67 mg of the title compound as a yellow powder.
MS (ESI) m / z 379 (M + H) ⁺
Elemental analysis value (as C ₁₈ H ₁₅ FN ₈ O · HCl)
Calculated value (%) C: 52.12 H: 3.89 N: 27.01
Actual 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 In the same manner as in Example 146, (S) -2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidine-4- Instead of carbonitrile, (S) -2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinonitrile was used, and (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. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a white powder.
MS (ESI) m / z 378 (M + H) ⁺

Example 148 (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) methyl nicotinate Step 1 (S) -6-Chloro-2- [1- (4-Fluorophenyl) ethylamino] methyl nicotinate 5.0 g of 2,6-dichloronicotinic acid methyl ester is dissolved in 50 ml of dimethylformamide, and (S)-(−)-1- (4-fluorophenyl) is dissolved. ) 4.39 g of ethylamine, 6.27 g of diisopropylethylamine and 150 mg of 4-dimethylaminopyridine were added and stirred at 60 ° C. for 24 hours. The reaction mixture was cooled, diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 2.83 g of the title compound as a white powder.

Step 2 (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) methyl nicotinate To 15 ml of degassed 1,4-dioxane, (S) -6- 2.83 g of methyl chloro-2- [1- (4-fluorophenyl) ethylamino] nicotinate, 870 mg of 2-aminopyrazine, 1.06 g of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl Then, 4.09 g of tripotassium phosphate and 475 mg of tris (dibenzylideneacetone) (chloroform) dipalladium were sequentially added, and the mixture was stirred at 100 ° C. for 1 hour in an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 3.14 g of the title compound as an orange powder.
MS (ESI) m / z 368 (M + H) ⁺

Example 149 (S) -2- [1- (4-fluorophenyl) ethylamino] -N, N-dimethyl-6- (pyrazin-2-ylamino) isonicotinamide (S) -2- [1- ( 4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinic acid (Example 141) 70 mg was dissolved in dimethylformamide 0.5 ml, dimethylamine hydrochloride 81 mg, 1-ethyl-3- ( 3-Dimethylaminopropyl) carbodiimide hydrochloride 37 mg, 1-hydroxy-7-azabenzotriazole 32 mg and diisopropylethylamine 0.18 ml were added and stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over magnesium sulfate. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography to obtain 45 mg of the title compound as a pale yellow powder.
MS (ESI) m / z 381 (M + H) ⁺

Example 150 (S) -N- [2- (Dimethylamino) ethyl] -2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinamide Example 149 and By the same method, N, N-dimethylethylenediamine was used in place of dimethylamine hydrochloride to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 424 (M + H) ⁺

Example 151 (S) -Nt-butyl-2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinamide In a manner similar to Example 149, dimethyl T-Butylamine was used in place of amine hydrochloride to give the title compound as a white powder.
MS (ESI) m / z 409 (M + H) ⁺

Example 152 (S) -N-ethyl-2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinamide (S) -2- [1- (4- Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinic acid (Example 141) 450 mg of N, N-diisopropylethylamine in dimethylformamide solution in 2.2 ml of 1H-benzotriazol-1-yloxy 1.32 g of tripyrrolidinophosphonium hexafluorophosphate was added and stirred for 15 minutes. 520 mg of ethylamine hydrochloride was added and stirred for 2 days. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over magnesium sulfate. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography to obtain 390 mg of the title compound as a pale yellow powder.
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 By the same method as in Example 152, 1-methanesulfonylpiperazine was used instead of ethylamine hydrochloride to give the title compound as a pale yellow powder.
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 of Example 153 As a by-product, (S)-{2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} (pyrrolidin-1-yl) methanone is pale. Obtained as a yellow powder.
MS (ESI) m / z 407 (M + H) ⁺

Example 155 (S) -2- [1- (4-Fluorophenyl) ethylamino] -N-isopropyl-6- (pyrazin-2-ylamino) isonicotinamide In the same manner as in Example 149, dimethylamine hydrochloride Isopropylamine was used in place of the salt to give the title compound as a pale yellow powder.
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 Implementation In the same manner as in Example 1, instead of piperazin-2-one, (S) -azetidine-2-carboxamide (synthesized according to Chem. Phram. Bull., 1998, 787-796) was used. In 1,4-dioxane was used as a reaction solvent to give the title compound as a brown powder.
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) pyridin-2, 6-diamine hydrochloride In the same manner as in Example 138, instead of cyclopropylcarbinol, tetrahydro-2H-pyran-4-ol was used and (S) -N ^2- [1- (4-fluorophenyl) Ethyl] -N ^6- (pyrazin-2-yl) -4- (tetrahydro-2H-pyran-4-yloxy) pyridine-2,6-diamine was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a pale yellow powder.
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 As in Example 1. According to the above method, 3-azetidinecarboxamide was used in place of piperazin-2-one, and 1,4-dioxane was used as a reaction solvent in Step 2 to obtain the title compound as a brown powder.
MS (ESI) m / z 409 (M + H) ⁺

Example 159 (S) -2- [1- (4-Fluorophenyl) ethylamino] -N- (2-hydroxyethyl) -6- (pyrazin-2-ylamino) isonicotinamide Similar method to Example 149 Used 2-hydroxyethylamine in place of dimethylamine hydrochloride to give the title compound as a reddish brown powder.
MS (ESI) m / z 397 (M + H) ⁺

Example 160 (S) -2- [1- (4-Fluorophenyl) ethylamino] -N-methyl-6- (pyrazin-2-ylamino) isonicotinamide Dimethylamine hydrochloride by a method similar to that in Example 149 Instead of the salt, methylamine hydrochloride was used to give the title compound as a pale yellow powder.
MS (ESI) m / z 367 (M + H) ⁺

Example 161 (S)-{2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} (morpholino) methanone By a method similar to that in Example 149 Instead of dimethylamine hydrochloride, morpholine was used to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 423 (M + H) ⁺

Example 162 (S) -N-benzyl-2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinamide hydrochloride In the same manner as in Example 152, ethylamine Instead of hydrochloride, benzylamine was used to obtain (S) -N-benzyl-2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinamide. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a yellow powder.
MS (ESI) m / z 443 (M + H) ⁺

Example 163 (S) —N-cyclopropyl-2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinamide In the same manner as in Example 149, dimethylamine Cyclopropylamine was used in place of the hydrochloride to give the title compound as a pale yellow powder.
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 In the same manner as in Example 152, instead of ethylamine hydrochloride, 1-methylpiperazine was used and (S)-{2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazine- 2-ylamino) pyridin-4-yl}) (4-methylpiperazin-1-yl) methanone was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a yellow powder.
MS (ESI) m / z 436 (M + H) ⁺

Example 165 (S) -2- [1- (4-Fluorophenyl) ethylamino] -N- (2-methoxyethyl) -6- (pyrazin-2-ylamino) isonicotinamide Similar method to Example 152 Used methoxyethylamine in place of ethylamine hydrochloride to give the title compound as a yellow powder.
MS (ESI) m / z 411 (M + H) ⁺

Example 166 (S) -2- [1- (4-Fluorophenyl) ethylamino] -N-propyl-6- (pyrazin-2-ylamino) isonicotinamide In the same manner as in Example 152, ethylamine hydrochloride Instead of 1, 1-propylamine was used to give the title compound as a pink powder.
MS (ESI) m / z 395 (M + H) ⁺

Example 167 (S) -N-cyclopropylmethyl-2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinamide In the same manner as in Example 152, ethylamine Cyclopropylmethylamine was used in place of the hydrochloride to give the title compound as a pale yellow powder.
MS (ESI) m / z 407 (M + H) ⁺

Example 168 (S) -N-cyclobutyl-2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinamide In the same manner as in Example 152, ethylamine hydrochloride Instead of, cyclobutylamine was used to give the title compound as a reddish brown powder.
MS (ESI) m / z 407 (M + H) ⁺

Example 169 (S) -N-butyl-2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinamide In the same manner as in Example 152, ethylamine hydrochloride N-Butylamine was used instead of to give the title compound as a yellow powder.
MS (ESI) m / z 409 (M + H) ⁺

Example 170 (S) -2- [1- (4-Fluorophenyl) ethylamino] -N-isobutyl-6- (pyrazin-2-ylamino) isonicotinamide In the same manner as in Example 152, ethylamine hydrochloride Instead of, isobutylamine was used to give the title compound as a pale yellow powder.
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 In the same manner as in Example 152, 2,2,2, -trifluoroethylamine was used instead of ethylamine hydrochloride to give the title compound as a pale yellow powder.
MS (ESI) m / z 435 (M + H) ⁺

Example 172 (S) -2- [1- (4-Fluorophenyl) ethylamino] -N- (3-hydroxypropyl) -6- (pyrazin-2-ylamino) isonicotinamide Similar method to Example 152 Used 3-hydroxypropylamine instead of ethylamine hydrochloride to give the title compound as a yellow powder.
MS (ESI) m / z 411 (M + H) ⁺

Example 173 (S) -N- (2-Ethoxyethyl) -2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinamide Similar method to Example 152 Used 2-ethoxyethylamine in place of ethylamine hydrochloride to give the title compound as a yellow powder.
MS (ESI) m / z 425 (M + H) ⁺

Example 174 (S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} -N-methylazetidine-3-carboxamide Step 1 1-Benzhydryl-N-methylazetidine-3-carboxamide 400 mg of 1-benzhydrylazetidine-3-carboxylic acid (synthesized according to WO2005 / 49602) was dissolved in 4 ml of dimethylformamide, and triethylamine was dissolved. 683 mg, methylamine hydrochloride 122 mg, 1-hydroxybenzotriazole 304 mg and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 431 mg were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 158 mg of the title compound.

Step 2 (S) -1- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} -N-methylazetidine-3-carboxamide 1 -150 mg of benzhydryl-N-methylazetidine-3-carboxamide was dissolved in 6 ml of methanol, 535 μl of 4N hydrochloric acid / ethyl acetate solution and 150 mg of 20% palladium hydroxide were added, and hydrogenated at room temperature and 4 atm overnight. Palladium hydroxide was filtered off and the solvent was distilled off under reduced pressure to obtain 150 mg of a pale yellow oil. Of this 81 mg, was dissolved in degassed 1,4-dioxane 5 ml, triethylamine 81mg, (S) -6- chloro ^-N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin - 2-yl) pyrimidine-2,4-diamine 184 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 51 mg, sodium t-butoxide 103 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 55 mg was sequentially added, and the mixture was stirred at 90 ° C. for 3.5 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography, and (S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazine- 24 mg of 2-ylamino) pyrimidin-4-yl} -N-methylazetidine-3-carboxamide were obtained as a yellow powder.
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 (S) - 20 mg of {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} methanol (Example 140) was dissolved in methylene chloride. Carbon bromide 59 mg and triphenylphosphine 47 mg were added and stirred for 30 minutes. Subsequently, 90 μl of a 9.8M sodium methoxide / methanol solution was added, and the mixture was further stirred overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 7 mg of the title compound as a yellow powder.
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-dimethylazetidine-3 Carboxamide In the same manner as in Example 174, but using dimethylamine hydrochloride instead of methylamine hydrochloride, the title compound was obtained as a white powder.
MS (ESI) m / z 437 (M + H) ⁺

Example 177 (S) -N- (1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} azetidin-3-yl) methane Sulfonamide 1- (t-butoxycarbonyl) -3-aminoazetidine (100 mg) was dissolved in 5 ml of methylene chloride, and 225 mg of diisopropylethylamine was added. Subsequently, 100 mg of methanesulfonyl chloride was added under ice-water cooling, the temperature was raised to room temperature, and the mixture was stirred overnight. The mixture was diluted with ethyl acetate, washed successively with 5% aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, 199 mg of a colorless oil was obtained. This was dissolved in 2.5 ml of methylene chloride, 1 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure to obtain a yellow oil. This was dissolved in degassed 1,4-dioxane 6ml, (S) -6- chloro ^-N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidine - 200 mg 2,4-diamine, 55 mg 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 111 mg sodium t-butoxide, 294 mg triethylamine and 60 mg tris (dibenzylideneacetone) (chloroform) dipalladium in order The mixture was added and stirred at 90 ° C. for 3 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 12 mg of the title compound as a pale yellow powder.
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 1- (t -Butoxycarbonyl) -3-cyanoazetidine (216 mg) was dissolved in methylene chloride (2.5 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure to give a light brown oil. This was dissolved in degassed 1,4-dioxane 4 ml, triethylamine 302mg, (S) -6- chloro ^-N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl ) Pyrimidine-2,4-diamine 205 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 57 mg, sodium t-butoxide 229 mg and tris (dibenzylideneacetone) (chloroform) dipalladium 62 mg The mixture was added and stirred at 90 ° C. for 3 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 58 mg of the title compound as a pale yellow powder.
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) oxazolidine-2-one 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 130 ° C. The mixture was stirred for 2.5 hours, and further stirred at 100 ° C. for 2.5 hours to remove the generated ethanol. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, 610 mg of the title compound was obtained as a pale yellow oil.

Step 2 3- [6-Chloro-4- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl] -4- (4-fluorophenyl) oxazolidine-2-one Degassed 1,4 -To 10 ml of dioxane, 379 mg of 2,6-dichloro-4- (1-methyl-1H-pyrazol-4-yl) pyridine, 300 mg of 4- (4-fluorophenyl) oxazolidine-2-one, 4,5-bis ( Diphenylphosphino) -9,9′-dimethylxanthene (192 mg), tripotassium phosphate (705 mg) and tris (dibenzylideneacetone) (chloroform) dipalladium (172 mg) were sequentially added, followed by stirring at 90 ° C. for 5 hours in an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 212 mg of the title compound as a yellow powder.

Step 3 2- (4-Fluorophenyl) -2- [4- (1-methyl-1H-pyrazol-4-yl) -6- (pyrazin-2-ylamino) pyridin-2-ylamino] ethanol Degassed 1 , 4-dioxane in 2.5 ml, 3- [6-chloro-4- (1-methyl-1H-pyrazol-4-yl) pyridin-2-yl] -4- (4-fluorophenyl) oxazolidine-2- ON 80mg, 2-aminopyrazine 20mg, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl 20mg, sodium t-butoxide 41mg and tris (dibenzylideneacetone) (chloroform) dipalladium 22mg And stirred at 90 ° C. for 1 hour under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 34 mg of the title compound as a white powder.
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 Implementation In the same manner as in Example 174, ethylamine hydrochloride was used in place of methylamine hydrochloride to give the title compound as a pale yellow powder.
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 In the same manner as in Example 174, but using diethylamine instead of methylamine hydrochloride, the title compound was obtained as a white powder.
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
To 10 ml of deaerated toluene, 535 mg of 1- (2,6-dichloropyridin-4-yl) ethanone (Example 29, Steps 1 and 2), (S)-(−)-1- (4-fluorophenyl) ethylamine 391 mg, (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (262 mg), cesium carbonate (1.28 g) and palladium acetate (63 mg) were sequentially added, and the mixture was stirred at 100 ° C. for 3 hours in an argon atmosphere. did. The reaction solution was purified by silica gel column chromatography to obtain 132 mg of the title compound as a pale yellow powder.
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 To 6 ml of degassed toluene, ( S) -1- {2-Chloro-6- [1- (4-fluorophenyl) ethylamino] pyridin-4-yl} ethanone 150 mg, 2-aminopyrazine 51 mg, 2-dicyclohexylphosphino-2 ′, 4 ′ , 6′-triisopropylbiphenyl 49 mg, sodium t-butoxide 59 mg and tris (dibenzylideneacetone) dipalladium 23 mg were sequentially added, and the mixture was stirred at 100 ° C. for 20 minutes under an argon atmosphere. The reaction solution was purified by silica gel column chromatography, and (S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} ethanone 77 mg Got. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a yellow powder.
MS (ESI) m / z 352 (M + H) ⁺
Elemental analysis (as _{C 19 H 18 FN 5 O ·} HCl + 0.8H 2 O)
Calculated value (%) C: 56.73 H: 5.16 N: 17.41
Actual value (%) C: 57.06 H: 5.20 N: 17.02

Example ^{183 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -6- (3-methoxy-1-yl) -N ⁴ - (pyrazin-2-yl) pyrimidin-2, 4-diamine hydrochloride In the same manner as in Example 1, 3-methoxyazetidine hydrochloride was used instead of piperazin-2-one, and (S) -N ^2- [1- (4-fluorophenyl) ethyl was used. ] -6- (3-methoxy-1-yl) -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4-diamine. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 396 (M + H) ⁺
Elemental analysis (as _{C 20 H 22 FN 7 O ·} HCl + 0.3H 2 O)
Calculated value (%) C: 54.93 H: 5.44 N: 22.42
Actual 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 In the same manner as in Example 1, instead of piperazin-2-one, 3-methylazetidin-3-ol hydrochloride was used and (S) -1- {2- [1- (4-fluoro Phenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} -3-methylazetidin-3-ol was obtained. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a white powder.
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 (S) -2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) ) 1.0 g of methyl nicotinate was dissolved in 60 ml of methanol, 20 ml of 10% aqueous sodium hydroxide solution was added, and the mixture was heated to reflux for 4 hours. The reaction solution was concentrated under reduced pressure to remove methanol. The obtained aqueous layer was washed with diethyl ether, adjusted to pH 3 with 10% hydrochloric acid, and the precipitated solid was collected by filtration and washed with water. Drying under reduced pressure gave 880 mg of the title compound as a pale yellow powder.

Step 2 (S) -2- [1- (4-Fluorophenyl) ethylamino] -N-methyl-6- (pyrazin-2-ylamino) nicotinamide (S) -2- [1- (4-fluorophenyl) ) Ethylamino] -6- (pyrazin-2-ylamino) nicotinic acid was dissolved in 1 ml of tetrahydrofuran, and O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexa 86 mg of fluorophosphate (HBTU) and 59 mg of triethylamine were added. After stirring for 30 minutes at room temperature, 119 μl of 2M methylamine / tetrahydrofuran solution was added and stirred for 5 hours. The reaction solution was purified by silica gel column chromatography to obtain 45 mg of the title compound as a white powder.
MS (ESI) m / z 367 (M + H) ⁺

Example 186 (S) -2- [1- (4-Fluorophenyl) ethylamino] -N, N-dimethyl-6- (pyrazin-2-ylamino) nicotinamide 2M methyl by a method similar to that in Example 185 Dimethylamine hydrochloride was used in place of the amine / tetrahydrofuran solution to give the title compound as a white powder.
MS (ESI) m / z 381 (M + H) ⁺

Example 187 (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) nicotinamide (S) -2- [1- (4-fluorophenyl) ethylamino ] 6- (Pyrazin-2-ylamino) nicotinic acid (Example 185, Step 1) 2 ml of oxalyl chloride was added to 82 mg, and the mixture was heated to reflux for 30 minutes. The reaction solution was concentrated under reduced pressure, 5 ml of concentrated aqueous ammonia was added, and the mixture was stirred at 100 ° C. for 30 minutes. After allowing to cool, the reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 13 mg of the title compound as a brown powder.
MS (ESI) m / z 353 (M + H) ⁺

Example 188 (S)-{2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-3-yl} (morpholino) methanone as in dihydrochloride example 185 (S)-{2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridine-, using morpholine instead of 2M methylamine / tetrahydrofuran solution 3-yl} (morpholino) methanone was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a white powder.
MS (ESI) m / z 423 (M + H) ⁺
Elemental analysis value (as C ₂₂ H ₂₃ FN ₆ O ₂ · 2HCl)
Calculated value (%) C: 53.34 H: 5.09 N: 16.96
Actual 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 In a manner similar to Example 185, Cyclopropylmethylamine was used in place of the 2M methylamine / tetrahydrofuran solution to give the title compound as a white powder.
MS (ESI) m / z 407 (M + H) ⁺

Example 190 (S) -N- (1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} azetidin-3-yl) ethane Sulfonamide By the same method as in Example 177, ethanesulfonyl chloride was used in place of methanesulfonyl chloride, and the title compound was obtained as a pale orange powder.
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 In the same manner as in Example 174, using isopropylamine instead of methylamine hydrochloride, the title compound was obtained as a pale yellow powder.
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) azetidine- 3-ol hydrochloride In the same manner as in Example 1, instead of piperazin-2-one, 3- (trifluoromethyl) azetidin-3-ol hydrochloride (synthesized according to US2007 / 275930) was used ( S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} -3- (trifluoromethyl) azetidin-3-ol Obtained. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a pale yellow powder.
MS (ESI) m / z 450 (M + H) ⁺
Elemental analysis (as _{C 20 H 19 F 4 N 7} O · HCl + H 2 O)
Calculated value (%) C: 47.67 H: 4.40 N: 19.46
Actual 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) (pyrrolidine- 1-yl) methanone In the same manner as in Example 174, but using pyrrolidine instead of methylamine hydrochloride, the title compound was obtained as a white powder.
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 In the same manner as in Example 174, using 2-methoxyethylamine instead of methylamine hydrochloride, the title compound was obtained as a white powder.
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) (piperidine- 1-yl) methanone In the same manner as in Example 174, but using piperidine instead of methylamine hydrochloride, the title compound was obtained as a white powder.
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) In the same manner as in Methanone Example 174, morpholine was used instead of methylamine hydrochloride to give the title compound as a white powder.
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 In the same manner as in Example 174, but using cyclopropylamine instead of methylamine hydrochloride, the title compound was obtained as a white powder.
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 In the same manner as in Example 174, cyclopropylmethylamine was used instead of methylamine hydrochloride to give the title compound as a white powder.
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 In the same manner as in Example 174, using 2-hydroxyethylamine instead of methylamine hydrochloride, the title compound was obtained as a pale yellow powder.
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 In the same manner as in Example 1, instead of piperazin-2-one, 3-cyclopropylazetidin-3-ol hydrochloride (synthesized according to US2007 / 275930) was used, and (S) -3- Cyclopropyl-1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} azetidin-3-ol was obtained. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a brown powder.
MS (ESI) m / z 422 (M + H) ⁺
Elemental analysis (as _{C 22 H 24 FN 7 O ·} HCl + 0.5H 2 O)
Calculated value (%) C: 56.59 H: 5.61 N: 21.00
Actual 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 In the same manner as in Example 1, using 3-isopropylazetidin-3-ol hydrochloride (synthesized according to US2007 / 275930) instead of piperazin-2-one, (S) -1- { 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} -3-isopropylazetidin-3-ol was obtained. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a brown powder.
MS (ESI) m / z 424 (M + H) ⁺
Elemental analysis (as _{C 22 H 26 FN 7 O ·} HCl + 0.4H 2 O)
Calculated value (%) C: 56.56 H: 6.00 N: 20.99
Actual 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 in 2 ml of methanol 100 mg of 3-hydroxyazetidine hydrochloride was dissolved, 43 mg of sodium t-butoxide was added, and the solvent was distilled off under reduced pressure. To this residue was added 4 ml of degassed 1,4-dioxane followed by (S) -4-chloro-N ^2- [1- (4-fluorophenyl) ethyl] -N ^6- (pyrazin-2-yl). ) Pyridine-2,6-diamine (Reference Example 2) 105 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 57 mg, sodium t-butoxide 96 mg and tris (dibenzylideneacetone) (chloroform) 32 mg of dipalladium was sequentially added, and the mixture was stirred at 100 ° C. for 1 hour under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazine-2). 78 mg of -ylamino) pyridin-4-yl} azetidin-3-ol were obtained. Furthermore, the hydrochloride was obtained according to a conventional method to obtain 60 mg of the title compound as a brown powder.
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-ol In the same manner as in Example 202, but using 3-cyclopropylazetidin-3-ol hydrochloride instead of 3-hydroxyazetidine hydrochloride, (S) -3-cyclopropyl-1- { 2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} azetidin-3-ol was obtained. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a brown powder.
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 In the same manner as in Example 202, 3-isopropylazetidin-3-ol hydrochloride was used instead of 3-hydroxyazetidine hydrochloride, and toluene was used instead of 1,4-dioxane as the solvent. (S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} -3-isopropylazetidin-3-ol Obtained. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a brown powder.
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 In the same manner as in Example 202, instead of 3-hydroxyazetidine hydrochloride, 3-methylazetidin-3-ol hydrochloride was used, and toluene was used instead of 1,4-dioxane as the solvent. (S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} -3-methylazetidin-3-ol Obtained. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a brown powder.
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) azetidine- 3-ol hydrochloride In the same manner as in Example 202, 3- (trifluoromethyl) azetidin-3-ol hydrochloride was used instead of 3-hydroxyazetidine hydrochloride, and 1,4-dioxane was used as the solvent. And (S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} -3- (tri Fluoromethyl) azetidin-3-ol was obtained. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a brown powder.
MS (ESI) m / z 449 (M + H) ⁺

Example 207 (S) -4- (3,3- ^{difluoro-1-yl)} -N 2 - [1- (4- fluorophenyl) ethyl] -N ⁶ - (pyrazin-2-yl) pyridine - 2,6-diamine hydrochloride In the same manner as in Example 202, 3,3-difluoroazetidine hydrochloride was used in place of 3-hydroxyazetidine hydrochloride, and 1,4-dioxane was used as the solvent. Using toluene, (S) -4- (3,3-difluoroazetidin-1-yl) -N ^2- [1- (4-fluorophenyl) ethyl] -N ^6- (pyrazin-2-yl) Pyridine-2,6-diamine was obtained. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a brown powder.
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 2,6 -Dichloropyridin-4-ylcarbamate t-butyl 2,6-dichloroisonicotinic acid 1.0 g was dissolved in t-butyl alcohol 20 ml, triethylamine 0.87 ml and diphenylphosphoryl azide 1.2 ml were added, and the mixture was heated to reflux overnight. did. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 969 mg of the title compound as a white powder.

Step 2 (S) -2-Chloro-6- [1- (4-fluorophenyl) ethylamino] pyridin-4-ylcarbamate t-butyl 2,6-Dichloro 390 mg of t-butyl pyridin-4-ylcarbamate, 220 μl of (S)-(−)-1- (4-fluorophenyl) ethylamine, 243 mg of bis [2- (diphenylphosphino) phenyl] ether, 199 mg of sodium t-butoxide And 67 mg of palladium acetate were sequentially added, followed by stirring at 100 ° C. for 10 hours under an argon atmosphere. After adding 118 μl of acetic acid to the reaction solution, it was diluted with ethyl acetate. Insoluble matters were removed by Celite filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 210 mg of the title compound as a white amorphous substance.

Step 3 (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-ylcarbamate t-butyl Degassed toluene (10 ml) 2-chloro-6- [1- (4-fluorophenyl) ethylamino] pyridin-4-ylcarbamate t-butyl 195 mg, 2-aminopyrazine 61 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6 152 mg of '-triisopropylbiphenyl, 71 mg of sodium t-butoxide and 73 mg of tris (dibenzylideneacetone) (chloroform) dipalladium were sequentially added, and the mixture was stirred at 100 ° C. overnight under an argon atmosphere. After adding 43 μl of acetic acid to the reaction solution, it was diluted with ethyl acetate. Insolubles were removed by Celite filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 203 mg of the title compound as a pale yellow amorphous product.

Step ^{4 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -N ⁶ - (pyrazin-2-yl) pyridine-2,4,6-triamine (S) -2- [1- ( 4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-ylcarbamate 210 mg was dissolved in 3 ml of methylene chloride, 1 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 5 hours. did. The reaction solution was poured into an ice-cooled saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 151 mg of the title compound as a pale yellow amorphous.

Step 5 (S) —N- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} acetamide (S) —N ² — [1- 50 mg of (4-fluorophenyl) ethyl] -N ^6- (pyrazin-2-yl) pyridine-2,4,6-triamine is dissolved in 1 ml of methylene chloride, 43 μl of triethylamine, 22 μl of acetic anhydride and 1 mg of 4-dimethylaminopyridine. And stirred at room temperature overnight. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 32 mg of the title compound as a yellow powder.
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 Example 208, process In the same manner as in No. 5, methanesulfonic anhydride was used instead of acetic anhydride, and (S) -N- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazine-2- (Ilamino) pyridin-4-yl} methanesulfonamide was obtained. This was converted into a hydrochloride according to a conventional method to obtain the title compound as a yellow powder.
MS (ESI) m / z 403 (M + H) ⁺

Example 210 (S) -1- {2- [ 1- (4- fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} urea (S) ^-N 2 - [1 -(4-Fluorophenyl) ethyl] -N ^6- (pyrazin-2-yl) pyridine-2,4,6-triamine 50 mg was dissolved in 2 ml of methylene chloride, and 49 mg of N, N′-carbonyldiimidazole was added at room temperature. And stirred overnight. Saturated ammonia / methanol solution was added and further stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 23 mg of the title compound as a pale yellow powder.
MS (ESI) m / z 368 (M + H) ⁺

Example 211 (S) -4- (3- ^{cyclopropyl-3-methoxy-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 To 3.8 ml of 1M cyclopropylmagnesium bromide / tetrahydrofuran solution under ice-water cooling, 1-benz 2 ml of a tetrahydrofuran solution containing 300 mg of hydrylazetidin-3-one was added, and the mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was poured into saturated aqueous sodium carbonate, extracted with diethyl ether, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 334 mg of the title compound.

Step 2 1-Benzhydryl-3-cyclopropyl-3-methoxyazetidine 334 mg of 1-benzhydryl-3-cyclopropylazetidin-3-ol was dissolved in dimethylformamide, and 72 mg of 60% sodium hydride was added under ice water cooling. And stirred at room temperature for 30 minutes. 112 μl of methyl iodide was added, and the mixture was further stirred at room temperature for 2 hours. Water was added to the reaction solution, extraction operation was performed with diethyl ether, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 280 mg of the title compound.

Step 3 (S) -4- (3- ^{cyclopropyl-3-methoxy-1-yl)} -N 2 - [1- (4- fluorophenyl) ethyl] -N ⁶ - (pyrazin-2-yl) Pyridine-2,6-diamine hydrochloride 1-benzhydryl-3-cyclopropyl-3-methoxyazetidine (275 mg) was dissolved in 15 ml of methanol, 0.70 ml of 2N hydrochloric acid and 150 mg of 20% palladium hydroxide were added, and 3.5 kgf / cm 2. And stirred at room temperature overnight. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain 146 mg of white powder. Of this, 62 mg was dissolved in 2 ml of methanol, 41 mg of sodium t-butoxide was added, and the solvent was distilled off under reduced pressure. To this residue was added 4 ml of degassed toluene followed by (S) -4-chloro-N ^2- [1- (4-fluorophenyl) ethyl] -N ^6- (pyrazin-2-yl) pyridine-2. , 6-diamine (Reference Example 2) 100 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 55 mg, sodium t-butoxide 41 mg and tris (dibenzylideneacetone) dipalladium 27 mg were sequentially added. The mixture was stirred at 100 ° C. for 1 hour in an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (S) -4- (3-cyclopropyl-3-methoxyazetidin-1-yl) -N ^2- [1. - (4-fluorophenyl) ethyl] -N ⁶ - (pyrazin-2-yl) pyridine-2,6-diamine 47 mg. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a brown powder.
MS (ESI) m / z 435 (M + H) ⁺

Example ^{212 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -4- (3-isopropyl-3-methoxy-1-yl) -N ⁶ - (pyrazin-2-yl) Pyridine-2,6-diamine hydrochloride In the same manner as in Example 211, instead of 1M cyclopropyl magnesium bromide / tetrahydrofuran solution, 0.79M isopropyl magnesium bromide / tetrahydrofuran solution was used, and (S) -N ^2- [ 1- (4-Fluorophenyl) ethyl] -4- (3-isopropyl-3-methoxyazetidin-1-yl) -N ^6- (pyrazin-2-yl) pyridin-2,6-diamine was obtained. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a brown powder.
MS (ESI) m / z 437 (M + H) ⁺

Example ^{213 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -4- (3-methoxy-3-methyl-1-yl) -N ⁶ - (pyrazin-2-yl) in a similar manner to that pyridine-2,6-diamine hydrochloride example 211, instead of 1M cyclopropyl magnesium bromide / tetrahydrofuran solution, with 3M methyl magnesium bromide / tetrahydrofuran ^{solution, (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. Further, the hydrochloride was obtained according to a conventional method to obtain the title compound as a brown powder.
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-methyl-2-yl ) To 4 ml of dimethylformamide degassed pyridine-2,6-diamine, 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 sequentially added. The mixture was stirred at 110 ° C. overnight under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 100 mg of a pale yellow oil. This was dissolved in 6 ml of degassed toluene and (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -4- (1-methyl-1H-pyrazol-4-yl) pyridine- 100 mg of 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 sequentially added, and 100% in an argon atmosphere. Stir at 1 ° C. for 1 hour. The reaction solution was purified by silica gel column chromatography to obtain 90 mg of the title compound as a pale yellow powder.
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 4- (2,6-dichloropyridin-4-yl) -5,6-dihydropyridine-1 (2H) -carbamic acid t-butyl ester To 16 ml of degassed dimethylformamide , 2,6-dichloro-4- (4,4,5,5, -tetramethyl-1,3,2-dioxaboran-2-yl) pyridine 874 mg, 4- (trifluoromethylsulfonyloxy) -5,6 -Dihydropyridine-1 (2H) -carbamic acid t-butyl ester 1.06 g, potassium carbonate 1.33 g and 1,1′-bis (diphenylphosphino) ferrocene-palladium ( I) dichloride - dichloromethane was added complex 26mg successively under an argon atmosphere and stirred for 1.5 hours at 80 ° C.. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 631 mg of the title compound.

Step 2 2,6-Dichloro-4- [1- (methylsulfonyl) -1,2,3,6-tetrahydropyridin-4-yl] pyridine 4- (2,6-dichloropyridin-4-yl) -5 , 6-Dihydropyridine-1 (2H) -carbamic acid t-butyl ester (327 mg) was dissolved in 4 ml of methylene chloride, 2 ml of trifluoroacetic acid was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, 221 mg of a brown solid was obtained. This was dissolved in 10 ml of methylene chloride, 270 μl of triethylamine, 251 mg of methanesulfonic anhydride and 1 mg of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 236 mg of the title compound as a light 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 To 5 ml of degassed tetrahydrofuran, 225 mg of 2,6-dichloro-4- [1- (methylsulfonyl) -1,2,3,6-tetrahydropyridin-4-yl] pyridine (S)-( -)-1- (4-fluorophenyl) ethylamine 104 μl, (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl 68 mg, cesium carbonate 359 mg and palladium acetate 17 mg were sequentially added, The mixture was stirred at 60 ° C. for 10 hours under an argon atmosphere. After dilution with ethyl acetate, the insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 118 mg of the title compound as a 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 To 5 ml of degassed toluene, (S) -6-chloro-N- [1- (4-fluorophenyl) ethyl] -4- [1- (methyl) (Sulfonyl) -1,2,3,6-tetrahydropyridin-4-yl] pyridin-2-amine 115 mg, 2-aminopyrazine 40 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 53 mg , Sodium t-butoxide 40 mg and tris (dibenzylideneacetone) dipalladium 26 mg were sequentially added, and the mixture was stirred at 100 ° C. for 5 hours in an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 89 mg of the title compound as a light brown powder.

Step ^{5 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -4- [1- (methanesulfonyl) piperidin-4-yl] -N ⁶ - (pyrazin-2-yl) pyridin-2 , 6-diamine
^(S) -N 2 - [1- (4-fluorophenyl) ethyl] -4- [1- (methylsulfonyl) -1,2,3,6-tetrahydropyridin-4-yl] -N ⁶ - (pyrazin 2-yl) 88 mg of pyridine-2,6-diamine was dissolved in 5 ml of methanol, 599 mg of ammonium formate and 18 mg of 20% palladium hydroxide were added, and the mixture was refluxed for 3 hours. 599 mg of ammonium formate and 18 mg of 20% palladium hydroxide were added, and the mixture was further refluxed for 2 hours. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 34 mg of the title compound as a pale yellow powder.
MS (ESI) m / z 471 (M + H) ⁺

Example 216 (S) -N- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} propionamide Similar to Example 208, Step 5. By using propionic anhydride instead of acetic anhydride, the title compound was obtained as a yellow amorphous.
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 In the same manner as in Example 37, 2-bromoethyl methyl ether was used instead of 2-bromopropane to give the title compound as a pale yellow powder.
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
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 in which 267 mg of copper acetate and 230 mg of 2,2-bipyridine were suspended was dropped. For 4 hours. The mixture was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride solution, water and saturated brine, and dried over magnesium sulfate. After removing the solvent under reduced pressure, 148 mg was obtained as a yellow oil. This was dissolved in 3 ml of acetonitrile, 209 mg of iodine and 451 mg of diammonium cerium (IV) nitrate were added under ice water cooling, and the mixture was stirred at room temperature for 5 hours. To this was added 6 ml of 5% aqueous sodium hydrogen sulfite solution, and the mixture was stirred at room temperature for 10 minutes. The mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 167 mg of the title compound as a 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 In the same manner as in Example 37, instead of 4-iodo-1-isopropyl-1H-pyrazole, 1-cyclopropyl-4-iodo-1H-pyrazole was used, and the title compound was obtained as a pale yellow powder. Got as.

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 In the same manner as in Example 37, but using bromomethyl methyl ether instead of 2-bromopropane, the title compound was obtained as a brown powder.
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} azetidine- 3-one (S) -1- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} azetidin-3-ol 156 mg (Example 72) ) Was dissolved in 1 ml of dimethyl sulfoxide, 571 μl of triethylamine was added, and the mixture was cooled to 15 ° C. To this was added 388 mg of a pyridine-sulfur trioxide complex suspended in 0.5 ml of dimethyl sulfoxide, and the mixture was stirred overnight at room temperature. Ice and saturated aqueous ammonium chloride were added to the reaction mixture, stirred for about 15 minutes, diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride and water, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 50 mg of the title compound as a brown amorphous.
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) pyrimidin-2 , 4-diamine (S) -1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} azetidin-3-one, After dissolving in 5 ml of 2-dichloroethane, 12 ml of 2M-dimethylamine / tetrahydrofuran solution and 290 μl of acetic acid were added and stirred at room temperature for 30 minutes. To this, 340 mg of sodium triacetoxyhydroborate was added and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 187 mg of the title compound as a brown powder.
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 In the same manner as in Example 220, the 2M-methylamine / tetrahydrofuran solution was used in place of the 2M-dimethylamine / tetrahydrofuran solution to give the title compound as a white powder.
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 In the same manner as in Example 220, pyrrolidine was used in place of the 2M-dimethylamine / tetrahydrofuran solution to give the title compound as a white powder.
MS (ESI) m / z 435 (M + H) ⁺

Example ^{223 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -6- (3-morpholinopropoxy-1-yl) -N ⁴ - (pyrazin-2-yl) pyrimidin-2, 4-Diamine In the same manner as in Example 220, morpholine was used in place of the 2M-dimethylamine / tetrahydrofuran solution to give the title compound as a white powder.
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 In the same manner as in Example 220, N-methylpiperazine was used in place of the 2M-dimethylamine / tetrahydrofuran solution to give the title compound as a brown powder.
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) piperidine-4 - in a similar manner to that ol example 220, instead of 2M- dimethylamine / tetrahydrofuran solution, using 4-hydroxypiperidine to give the title compound as a white powder.
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-thiomorpholine-1 , 1-dione <br/> step 1 4- {6-chloro -2 - [(1S) -1- ( 4- fluorophenyl) ethylamino] pyrimidin-4-yl} llambda ^6, 4-thiomorpholine - 1,1-dione In the same manner as in Example 1, step 1, after reaction using thiomorpholine-1,1-dioxide instead of piperazin-2-one, the product was purified by silica gel column chromatography. Obtained as a colorless amorphous.
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-thiomorpholine-1, 1-dione In the same manner as in Example 1, step 2, 4- {6-chloro-2-[(1S) -1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl} -1λ ^{6 was used as a} starting material. , 4-thiomorpholine-1,1-dione was used, and the reaction solvent was a toluene / 1,4-dioxane mixed solvent instead of toluene to give the title compound as a brown amorphous substance.
MS (ESI) m / z 444 (M + H) ⁺

Example 227 (S) -1- (1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) 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 3- ( 105 mg of carbamoylamino) azetidine-1-carboxylate t-butyl was dissolved in 2 ml of methylene chloride, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in 3 ml of 1-butanol. (S) -4,6-dichloro-N- [1- (4-fluorophenyl) ethyl] pyrimidin-2-amine (108 mg) and N, N-diisopropylethylamine (331 μl) were added, and the mixture was stirred at 60 ° C. for 20 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, 89 mg of the title compound was obtained as a white powder.

Step 2 (S) -1- (1- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} azetidin-3-yl) urea (S) -1- (1- {6-chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidine- was added to 3 ml of a mixed solvent of toluene / 1,4-dioxane (1/1). 4-yl} azetidin-3-yl) urea 73 mg, 2-aminopyrazine 25 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 38 mg, sodium t-butoxide 29 mg and tris (dibenzylideneacetone) ) 18 mg of dipalladium was sequentially added and stirred at 90 ° C. for 1 hour under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 31 mg of the title compound as a brown powder.
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 Same as Example 1 Step 1 By using azetidin-3-yl-methanol hydrochloride instead of piperazin-2-one, the title compound was obtained as a white powder.
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 Example 1 In the same manner as in Step 2, (S)-(1- {6-chloro-2- [1- (4-fluorophenyl) ethylamino] pyrimidin-4-yl) azetidin-3-yl) methanol was used as a raw material. Using 1,4-dioxane instead of toluene as the reaction solvent, the title compound was obtained as a brown amorphous.
MS (ESI) m / z 396 (M + H) ⁺

Example 229 (S)-(1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} azetidin-3-yl) methylcarbamic acid t - in the same manner as butyl example 1, instead of piperazin-2-one, using azetidin-3-yl methylcarbamate t- butyl, to give the title compound as a brown amorphous.
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 (S)-(1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} azetidin-3-yl) methylcarbamine 80 mg of t-butyl acid was dissolved in 4 ml of dichloromethane, 0.8 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography to obtain 63 mg of the title compound as a brown amorphous.
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] ethanesulfonamide (S) -6- [3- (aminomethyl) ^{azetidin-1-yl]} -N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) 23 mg of pyrimidine-2,4-diamine was dissolved in 2 ml of 1,2-dichloroethane, 8.1 mg of ethanesulfonyl chloride and 22 μl of N, N-diisopropylethylamine were added, and the mixture was stirred overnight at room temperature. After the solvent was distilled off, the resulting residue was purified by silica gel column chromatography to obtain 15 mg of the title compound as a brown amorphous.
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 (S) -6- [3- (aminomethyl) ^{azetidin-1-yl]} -N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidine - 23 mg of 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 and stirred overnight at room temperature. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography to obtain 20 mg of the title compound as a brown amorphous.
MS (ESI) m / z 437 (M + H) ⁺

Example ^{233 (S) -N 2 - [} 1- (4- fluorophenyl) ethyl] -4- [3- morpholino-1-yl] -N ⁶ - (pyrazin-2-yl) pyridin-2, 6-diamine In a manner similar to Example 38, substituting 4- (azetidin-3-yl) morpholine dihydrochloride for (S) -N- (pyrrolidin-3-yl) acetamide, the title compound was prepared. Obtained as a brown powder.
MS (ESI) m / z 450 (M + H) ⁺

Example 234 (S) -1- (1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} azetidin-3-yl) piperidine 4-ol In the same manner as in Example 38, but using 1- (3-azetidinidyl) -4-piperidinol dihydrochloride instead of (S) -N- (pyrrolidin-3-yl) acetamide, the title The compound was obtained as a brown powder.
MS (ESI) m / z 464 (M + H) ⁺

The structural formulas of Examples 1 to 234 are shown in Tables 1 to 12.

Test Example 1 c-Src tyrosine kinase inhibitory activity test Preparation of test substance solution The test substance was dissolved in 10 mM with dimethyl sulfoxide (DMSO) and further 100 times the measured concentration (1000, 300, 100, 30, 10, 3, 1, 0.3, 0.1, 0.1, (0.03, 0.01 μM) was diluted with DMSO. Further, a solution diluted 20 times with assay buffer was used as a test substance solution. As a negative control, a solution obtained by diluting DMSO 20 times with assay buffer was used. As the assay buffer, 15 mM Tris-Cl (pH 7.5), 0.01 (v / v)% Tween-20, 1 mM dithiothreitol was used.

2. Measurement of c-Src tyrosine kinase activity The ELISA method was used to measure the activity. The test substance solution was added to Streptavidin coated 96 well plate (DELFIA Strip Plate 8 × 12 well, PerkinElmer) (10 μL each) (n = 2), and substrate solution (625 nM biotin-labeled peptide substrate, 25 μM ATP, 10 mM MgCl ₂ Cl (pH 7.5), 0.01 (v / v)% Tween-20, 1 mM dithiothreitol) was added in an amount of 20 μL and stirred. Finally, 20 μL of c-Src tyrosine kinase (human origin; Carna Biosciences) (diluted to 2.5 nM with assay buffer) was added and stirred, and reacted at 30 ° C. for 1 hour. The plate was washed 4 times with wash buffer (50 mM Tris-Cl, pH 7.5, 150 mM NaCl, 0.02 (v / v)% Tween-20), and then blocking buffer (0.1% Bovine Serum Albumin, 50 mM Tris, 50 mM Tris). -Cl, pH 7.5, 150 mM NaCl, 0.02 (v / v)% Tween-20) was added in an amount of 150 μL, and blocking was performed at 30 ° C. for 30 minutes. The blocking buffer was removed, and Horse Radish Peroxidase-labeled anti-phosphotyrosine antibody (BD Bioscience) (diluted 10,000 times with blocking buffer) was added in an amount of 100 μL, and incubated at 30 ° C. for 30 minutes. The plate was washed 4 times with a washing buffer, and 100 μL of 3,3 ′, 5,5′-tetramethylbenzidine solution (Sigma-Aldrich) was added and allowed to develop for 10 minutes. The reaction was stopped by adding 100 μL of 0.1 M sulfuric acid. Absorbance at 450 nm was measured with a microplate reader (Thermo Scientific Multiskan FC).

3. Analysis of Measurement Results The measured absorbance was subjected to nonlinear regression analysis with a SAS system (SAS Institute Inc.), and the concentration of the test substance that inhibits c-Src tyrosine kinase activity by 50% (IC ₅₀ ) was calculated. Tables 13 and 14 show the inhibitory activity (IC ₅₀ , nM) of the example compounds against c-Src tyrosine kinase.

Test Example 2 Src Family Tyrosine Kinase Inhibitory Activity Test The inhibitory activity against Fyn tyrosine kinase, Yes tyrosine kinase, Lyn tyrosine kinase, Fgr tyrosine kinase, and Lck tyrosine kinase was measured at Carna Biosciences (Kobe, Japan).

1. Preparation of test substance solution The test substance was dissolved in DMSO and further diluted with DMSO to prepare a solution having a concentration 100 times the test concentration. The solution was further diluted 25 times with assay buffer to obtain a test substance solution. As an assay buffer, 20 mM HEPES, 0.01 (v / v)% Triton X-100, 2 mM dithiothreitol, pH 7.5 was used.

2. Measurement of Src Family Tyrosine Kinase Activity A test substance solution (5 μL) prepared in 1 above, a substrate solution (4 μM peptide substrate, ATP ^* , 20 mM MgCl ₂ at a concentration set for each kinase) 5 μL, and 10 μL of a kinase solution 384 made of polypropylene are used. The mixture was mixed in the well of the well plate and reacted at room temperature for 1 or 5 hours. The reaction was stopped by adding 60 μL Termination Buffer (Quick Scout Screening Assist MSA; Carna Biosciences). The substrate peptide and phosphorylated peptide in the reaction solution were separated and quantified using LabChip 3000 System (Caliper Life Science). The kinase reaction was evaluated by the product ratio (P / (P + S)) calculated from the substrate peptide peak height (S) and the phosphorylated peptide peak height (P).
(*) The ATP concentration used for each kinase activity measurement was 200 mM for Fyn tyrosine kinase, 40 mM for Yes tyrosine kinase, 40 mM for Lyn tyrosine kinase, 200 mM for Fgr tyrosine kinase, and 40 mM for Lck tyrosine kinase.

3. Analysis of measurement results The average signal of control wells containing all reaction components is 0% Inhibition, the average signal of background wells (without enzyme addition) is 100% Inhibition, and the inhibition rate is calculated from the average signal of each test substance test well did.
As a result, it was revealed that the test compound used in this test example had a strong inhibitory activity against Src family tyrosine kinase.

Test Example 3 Src Family Tyrosine Kinase Inhibitory Activity Test The inhibitory activity on Fyn tyrosine kinase, Yes tyrosine kinase, Lyn tyrosine kinase, Fgr tyrosine kinase, and Lck tyrosine kinase was measured as follows.

1. Preparation of test substance solution The test substance was dissolved in DMSO to 10 mM, and further diluted with DMSO to a concentration 100 times the measured concentration (100 μM). Further, a solution diluted 20 times with assay buffer was used as a test substance solution. As a negative control, a solution obtained by diluting DMSO 20 times with assay buffer was used. As the assay buffer, 15 mM Tris-Cl (pH 7.5), 0.01 (v / v)% Tween-20, 1 mM dithiothreitol was used.

プレートを洗浄バッファー（５０ｍＭ Ｔｒｉｓ−Ｃｌ、ｐＨ７．５、１５０ｍＭ ＮａＣｌ、０．０２（ｖ／ｖ）％ Ｔｗｅｅｎ−２０）で４回洗浄した後、ブロッキングバッファー（０．１％Ｂｏｖｉｎｅ Ｓｅｒｕｍ Ａｌｂｕｍｉｎ、５０ｍＭ Ｔｒｉｓ−Ｃｌ、ｐＨ７．５、１５０ｍＭ ＮａＣｌ、０．０２（ｖ／ｖ）％ Ｔｗｅｅｎ−２０）を１５０μＬずつ添加して、３０℃で３０分間ブロッキングを行った。ブロッキングバッファーを取り除き、Ｈｏｒｓｅ Ｒａｄｉｓｈ Ｐｅｒｏｘｉｄａｓｅ標識抗リン酸化チロシン抗体（ＢＤ Ｂｉｏｓｃｉｅｎｃｅ社）（ブロッキングバッファーにて１００００倍に希釈）を１００μＬずつ添加し、３０℃で３０分間インキュベートした。プレートを洗浄バッファーで４回洗浄し、３，３’，５，５’−テトラメチルベンジジン溶液（Ｓｉｇｍａ−Ａｌｄｒｉｃｈ社）を１００μＬずつ添加して１０分間発色させた。０．１Ｍ硫酸を１００μＬずつ添加して反応を停止した。マイクロプレートリーダー（Ｔｈｅｒｍｏ Ｓｃｉｅｎｔｉｆｉｃ Ｍｕｌｔｉｓｋａｎ ＦＣ）にて４５０ｎｍの吸光度を測定した。2. Measurement of Src family tyrosine kinase inhibitory activity The ELISA method was used to measure the activity. A test substance solution was added to Streptavidin-coated 96 well plate (DELFIA Strip Plate 8 × 12 well, PerkinElmer) 10 μL at a time (n = 2), and substrate solution (625 nM biotin-labeled peptide substrate, ATP at a concentration set for each kinase ⁾ 10 μM MgCl ₂ , 15 mM Tris-Cl (pH 7.5), 0.01 (v / v)% Tween-20, 1 mM dithiothreitol) were added in an amount of 20 μL and stirred. Finally, 20 μL of a kinase solution ^* (human origin; Carna Biosciences) at a concentration set for each Src family tyrosine kinase was added and stirred, and reacted at 30 ° C. for 1 hour.

The plate was washed 4 times with wash buffer (50 mM Tris-Cl, pH 7.5, 150 mM NaCl, 0.02 (v / v)% Tween-20), and then blocking buffer (0.1% Bovine Serum Albumin, 50 mM Tris, 50 mM Tris). -Cl, pH 7.5, 150 mM NaCl, 0.02 (v / v)% Tween-20) was added in an amount of 150 μL, and blocking was performed at 30 ° C. for 30 minutes. The blocking buffer was removed, and Horse Radish Peroxidase-labeled anti-phosphotyrosine antibody (BD Bioscience) (diluted 10,000 times with blocking buffer) was added in an amount of 100 μL, and incubated at 30 ° C. for 30 minutes. The plate was washed 4 times with a washing buffer, and 100 μL of 3,3 ′, 5,5′-tetramethylbenzidine solution (Sigma-Aldrich) was added and allowed to develop for 10 minutes. The reaction was stopped by adding 100 μL of 0.1 M sulfuric acid. Absorbance at 450 nm was measured with a microplate reader (Thermo Scientific Multiskan FC).

3. Analysis of measurement results In the Fyn, Yes, Lyn, Fgr, and Lck tyrosine kinase inhibitory activity tests, the average absorbance of negative control wells was 0% Inhibition, and the average absorbance of background wells (no enzyme added) was 100% Inhibition. The activity inhibition rate (% inhibition) was calculated from the average absorbance of the substance test wells. Table 16 shows the inhibitory activity of the example compounds.

The compounds of the present invention and pharmaceutically acceptable salts thereof are useful as pharmaceuticals because they have high inhibitory activity against Src family tyrosine kinases.

Test Example 4 Cell Adhesion Inhibitory Activity Test Multiple myeloma-derived cell line RPMI-8226 cells were suspended in serum-free RPMI 1640 medium at 2 × 10 ⁴ cells / mL. Test substances of 10 nM, 100 nM, 1000 nM, and 10000 nM were added to the cell suspension at a final concentration and incubated for 30 minutes, and then 100 μL was seeded on a 96-well plate coated with Type I Collagen or VCAM-1. After allowing to stand for 30 minutes in a CO ₂ incubator, 10 μL of a fixing solution (37% formaldehyde) was added to the well, and the adherent cells were fixed by allowing to stand for 15 minutes. After washing twice with a phosphate buffer, a staining solution (0.05% crystal violet) was added to the fixed cells and allowed to stand for 1 hour for staining. After washing 3 times with phosphate buffer, 100 μL of Sorenson buffer was added. The dye was dissolved by shaking for 1 minute, and the absorbance at a wavelength of 595 nm was measured.
As a result, the test compound used in this test example inhibited cell adhesion via Type I Collagen or VCAM-1 in a concentration-dependent manner.

Test Example 5 Osteoclast Differentiation Inhibitory Activity Test Healthy osteoclast precursor cells (Human Osteoblast Precursors) were cultured in Osteoblast Precursor Growth Medium. Cells were seeded at a concentration of 1 × 10 ⁴ cells / well in 96 well plates. 66 ng / mL soluble RANKL, 33 ng / mL M-CSF, and test substances were added so that the final concentrations were 0, 10 nM, 100 nM, and 1000 nM. On the seventh day of culture, the medium was removed, a fixative (phosphate buffer containing 4% paraformaldehyde) was added, and the mixture was allowed to stand at room temperature for 15 minutes for fixation. After washing with a phosphate buffer, an ethanol: acetone = 1: 1 solution was added and the mixture was allowed to stand for 1 minute to solubilize cells. After washing with a phosphate buffer, TRAP / ALP stain kit (Wako Pure Chemical Industries) was added, and the mixture was allowed to stand at 37 ° C. for 15 minutes for staining. Observed under a microscope, cells stained in red and having three or more nuclei were counted as mature osteoclasts.
As a result, the test compound used in this test example inhibited osteoclast differentiation in a concentration-dependent manner.

Formulation Example 1
Tablet (internal tablet)
Prescription 1 tablet 80mg
The compound of the present invention of Example 1 5.0 mg
Corn starch 46.6mg
Crystalline cellulose 24.0mg
Methylcellulose 4.0mg
Magnesium stearate 0.4mg
This proportion of the mixed powder is formed into tablets by a conventional method.

Formulation Example 2
Tablet (internal tablet)
Prescription 1 tablet 80mg
The compound of the present invention of Example 2 5.0 mg
Corn starch 46.6mg
Crystalline cellulose 24.0mg
Methylcellulose 4.0mg
Magnesium stearate 0.4mg
This proportion of the mixed powder is formed into tablets by a conventional method.

  The application of the pharmaceutical composition containing the compound of the present invention and a pharmaceutically acceptable salt thereof as an active ingredient is not limited as long as it is a disease involving Src family tyrosine kinase. Specific indications include rectal cancer, colon cancer, colon cancer, melanoma, pancreatic cancer, ovarian cancer, bladder cancer, gastric cancer, head and neck cancer, esophageal cancer, lung cancer, neuroblastoma, retinoblastoma, flat Epithelial cancer, oral squamous cell carcinoma, mesothelioma, thymic tumor, skin cancer, oral cancer, retinoblastoma, cancer (eg prostate cancer, breast cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, testicular cancer, Bone metastasis of cervical cancer, stomach cancer, colon cancer, bladder cancer), bronchial asthma, diseases caused by allergic reactions (eg allergic rhinitis, atopic dermatitis, atopic asthma), autoimmune diseases (eg systemic) Lupus erythematosus, type I diabetes, psoriasis, glomerulonephritis), atherosclerosis, diseases caused by leukocyte accumulation during vascular injury (eg restenosis after percutaneous coronary intervention), organ transplantation (eg Rejection at heart transplant), acute Syndrome, AIDS, Alzheimer's disease, age-related macular degeneration.

Claims (7)

Rectal cancer, colon cancer, containing as an active ingredient a compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, which is either of the following (I) or (II): Colorectal cancer, melanoma, pancreatic cancer, ovarian cancer, bladder cancer, gastric cancer, head and neck cancer, esophageal cancer, lung cancer, neuroblastoma, retinoblastoma, squamous cell carcinoma, oral squamous cell carcinoma, mesothelioma, thymic tumor , Skin cancer, oral cancer, retinoblastoma, bone metastasis of cancer, bronchial asthma, allergic rhinitis, atopic dermatitis, atopic asthma, systemic lupus erythematosus, type I diabetes, psoriasis, glomerulonephritis, atheromatous Arteriosclerosis, diseases caused by leukocyte accumulation during vascular injury (eg, restenosis after percutaneous coronary intervention, rejection during organ transplantation, acute coronary syndrome, AIDS, Alzheimer's disease and age-related macular degeneration) Selected from the group Therapeutic or prophylactic agents.

(I)
X represents CH or N.
R ¹ represents halogen.
R ² is
(1) H,
(2) halogen,
(3) Cyano,
(4) a group represented by the following general formula [2],

(In the formula, * represents a bonding position. R ^C , R ^D and R ^E are the same or different and each represents (a) H or (b) alkyl optionally substituted with hydroxy or alkoxy. Or two of R ^C , R ^D and R ^E together with adjacent C represent a saturated heterocyclic group containing one N. The remaining one represents H. A saturated heterocyclic group may be substituted with an alkylsulfonyl),
(5) a group represented by the following general formula [3],

(In the formula, * is as defined above. R ^F and R ^G are the same or different, and (a) H, (b) hydroxy, amino, dialkylamino, saturated cyclic amino group, alkylcarbonylamino, alkyl (C) alkylcarbonyl, (c) alkyl optionally substituted with one or two groups selected from the group consisting of sulfonylamino, aryl, heteroaryl optionally substituted with alkyl, tetrahydrofuranyl, and carbamoyl d) represents alkylsulfonyl, (e) carbamoyl, or (f) heteroaryl optionally substituted with alkyl, or R ^F and R ^G together with adjacent N to form a saturated cyclic amino group Such saturated cyclic amino groups include (a) halogen, (b) cyano, (c) hydroxy, (d) hydroxy, alcohol Alkyl optionally substituted with one or two groups selected from the group consisting of cis, amino, alkoxycarbonylamino, alkylsulfonylamino, and alkylcarbonylamino, (e) cycloalkyl, (f) haloalkyl, ( g) alkoxy, (h) oxo, (i) a group represented by the following general formula [4],

(Wherein, * is as defined above, R ^H represents alkyl or aryl), (j) a group represented by the following general formula [5],

(Wherein * is as defined above. R ^I and R ^J are the same or different and represent H, alkyl, carbamoyl, alkylcarbonyl, or alkylsulfonyl), (k) the following general formula [ 6],

(Wherein * has the same meaning as defined above .R ^K is alkyl, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, (cycloalkyl) alkylamino, (hydroxyalkyl) amino, (alkoxyalkyl) (Represents an amino, alkoxy, alkylsulfonylamino, or saturated cyclic amino group), and (l) substituted with one or two groups selected from the group consisting of a saturated cyclic amino group optionally substituted with hydroxy Or a spiro bond to a group represented by the following general formula [7A] or [7B].

(Wherein * is as defined above)),
(6) a group represented by the following general formula [8],

(Wherein * is as defined above. R ^L is a saturated cyclic amino group optionally substituted with (a) alkyl, (b) hydroxy, (c) alkoxy, (d) alkyl or alkylsulfonyl. Or (e) optionally substituted with one or two groups selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, alkoxyalkyl, and hydroxyalkyl Represents amino).
(7) a group represented by the following general formula [9],

(In the formula, * is as defined above. R ^M , R ^N and R ^O are the same or different and represent H, halogen, cyano, alkoxy, carbamoyl, sulfamoyl, monoalkylaminosulfonyl, or alkylsulfonyl. Or two groups of R ^M , R ^N and R ^O together represent methylenedioxy, the other one represents H).
(8) —OR ^P (R ^P may be alkyl substituted with a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl, or may be substituted with hydroxy Or a saturated cyclic group which may contain one O.), or (9) cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl Represents heteroaryl optionally substituted with 1 or 2 groups selected from the group consisting of hydroxycarbonyl and alkoxyalkyl.
R ³ represents H or hydroxy.
R ⁴ represents H or alkyl.
R ⁵ represents H or alkyl.

(II)
X represents a -CR ^A.
R ^A represents a group represented by the following general formula [10].

(Wherein * is as defined above, R ^B is substituted with 1 or 2 groups selected from the group consisting of (a) alkyl, cycloalkyl, (cycloalkyl) alkyl, and alkoxyalkyl). Which may represent amino, (b) alkoxy, (c) hydroxy, or (d) a saturated cyclic amino group.)
R ¹ represents halogen.
R ² represents H.
R ³ represents H or hydroxy.
R ⁴ represents H or alkyl.
R ⁵ represents H or alkyl. The therapeutic or prophylactic agent according to claim 1, wherein the compound represented by the general formula [1] is a compound in the case of any of the following [i] or [ii].
[I]
X is CH or N,
R ² is
(1) a group represented by the following general formula [11],

(In the formula, * represents a bonding position. R ^F1 and R ^G1 are the same or different, and (a) H, (b) hydroxy, amino, dialkylamino, saturated cyclic amino group, alkylcarbonylamino, alkylsulfonyl Alkyl optionally substituted with 1 or 2 groups selected from the group consisting of heteroaryl optionally substituted with amino, aryl, alkyl, tetrahydrofuranyl, and carbamoyl, (c) alkylcarbonyl, (d ) Represents alkylsulfonyl, (e) carbamoyl, or (f) heteroaryl optionally substituted with alkyl, or R ^F1 and R ^G1 together with adjacent N form a saturated cyclic amino group Such saturated cyclic amino groups are (a) halogen, (b) cyano, (c) hydroxy, (d) hydroxy Alkyl optionally substituted with one or two groups selected from the group consisting of alkoxy, amino, alkoxycarbonylamino, alkylsulfonylamino, and alkylcarbonylamino, (e) cycloalkyl, (f) haloalkyl, ( g) alkoxy, (h) oxo, (i) a group represented by the following general formula [4],

(Wherein, * is as defined above, R ^H represents alkyl or aryl), (j) a group represented by the following general formula [5],

(Wherein * is as defined above. R ^I and R ^J are the same or different and represent H, alkyl, carbamoyl, alkylcarbonyl, or alkylsulfonyl), (k) the following general formula [ 6],

(Wherein * has the same meaning as defined above .R ^K is alkyl, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, (cycloalkyl) alkylamino, (hydroxyalkyl) amino, (alkoxyalkyl) (Represents an amino, alkoxy, alkylsulfonylamino, or saturated cyclic amino group), and (l) substituted with one or two groups selected from the group consisting of a saturated cyclic amino group optionally substituted with hydroxy May be. ),
(2) a group represented by the following general formula [8],

(Wherein * is as defined above. R ^L is a saturated cyclic amino group optionally substituted with (a) alkyl, (b) hydroxy, (c) alkoxy, (d) alkyl or alkylsulfonyl. Or (e) optionally substituted with one or two groups selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, alkoxyalkyl, and hydroxyalkyl Represents amino).
(3) a group represented by the following general formula [9],

(In the formula, * is as defined above. R ^M , R ^N and R ^O are the same or different and represent H, halogen, cyano, alkoxy, carbamoyl, sulfamoyl, monoalkylaminosulfonyl, or alkylsulfonyl. Or two groups of R ^M , R ^N and R ^O together represent methylenedioxy, the other one represents H).
(4) -OR ^P1 (wherein R ^P1 represents alkyl optionally substituted with a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl), or ( 5) substituted with 1 or 2 groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl Optionally heteroaryl.

[Ii]
X is -CR ^A ,
R ^A is a group represented by the following general formula [10]:

(Wherein * is as defined above, R ^B is substituted with 1 or 2 groups selected from the group consisting of (a) alkyl, cycloalkyl, (cycloalkyl) alkyl, and alkoxyalkyl). Which may be amino, (b) represents alkoxy, (c) hydroxy, or (d) a saturated cyclic amino group).
R ² is H. Of the compounds represented by the general formula [1],
X is CH,
R ² is
(1) a group represented by the following general formula [11],

(In the formula, * represents a bonding position. R ^F1 and R ^G1 are the same or different, and (a) H, (b) hydroxy, amino, dialkylamino, saturated cyclic amino group, alkylcarbonylamino, alkylsulfonyl Alkyl optionally substituted with 1 or 2 groups selected from the group consisting of heteroaryl optionally substituted with amino, aryl, alkyl, tetrahydrofuranyl, and carbamoyl, (c) alkylcarbonyl, (d ) Represents alkylsulfonyl, (e) carbamoyl, or (f) heteroaryl optionally substituted with alkyl, or R ^F1 and R ^G1 together with adjacent N form a saturated cyclic amino group Such saturated cyclic amino groups are (a) halogen, (b) cyano, (c) hydroxy, (d) hydroxy One or two groups selected from the group consisting of alkoxy, amino, alkoxycarbonylamino, alkylsulfonylamino, and alkylcarbonylamino, optionally substituted alkyl, (e) cycloalkyl, (f) haloalkyl, ( g) alkoxy, (h) oxo, (i) a group represented by the following general formula [4],

(Wherein, * is as defined above, R ^H represents alkyl or aryl), (j) a group represented by the following general formula [5],

(Wherein * is as defined above. R ^I and R ^J are the same or different and represent H, alkyl, carbamoyl, alkylcarbonyl, or alkylsulfonyl), (k) the following general formula [ 6],

(Wherein * has the same meaning as defined above .R ^K is alkyl, hydroxy, amino, alkylamino, dialkylamino, cycloalkylamino, (cycloalkyl) alkylamino, (hydroxyalkyl) amino, (alkoxyalkyl) (Represents an amino, alkoxy, alkylsulfonylamino, or saturated cyclic amino group), and (l) substituted with one or two groups selected from the group consisting of a saturated cyclic amino group optionally substituted with hydroxy May be. ),
(2) a group represented by the following general formula [8],

(Wherein * is as defined above. R ^L is a saturated cyclic amino group optionally substituted with (a) alkyl, (b) hydroxy, (c) alkoxy, (d) alkyl or alkylsulfonyl. Or (e) optionally substituted with one or two groups selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, alkoxyalkyl, and hydroxyalkyl Represents amino).
(3) a group represented by the following general formula [9],

(In the formula, * is as defined above. R ^M , R ^N and R ^O are the same or different and represent H, halogen, cyano, alkoxy, carbamoyl, sulfamoyl, monoalkylaminosulfonyl, or alkylsulfonyl. Or two groups of R ^M , R ^N and R ^O together represent methylenedioxy, and the other group represents hydrogen).
(4) -OR ^P1 (wherein R ^P1 represents alkyl optionally substituted with a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl), or ( 5) substituted with 1 or 2 groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl) alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl The therapeutic or prophylactic agent according to claim 1, which is a compound which may be a heteroaryl. The therapeutic or prophylactic agent according to claim 1, wherein the compound represented by the general formula [1] is a compound selected from the group consisting of the following compounds (1) to (229).
(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] pyrrolidine -3-yl} acetamide,
(3) (S) -6- ( 3,3- ^{difluoro-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) -N2 ^' -[1- (4-fluorophenyl) ethyl] -N6 ^' -(pyrazin-2-yl) -3,44'-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 A diamine,
^{(24) (S) -N 2} - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl)-6-(1H-pyrazol-3-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} pyrrolidine-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] pyrrolidine -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-thiomorpholino-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-ylamino) 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- ^fluoro-1-yl) -N 2 - [1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) pyrimidin-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- fluorophenyl) 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-methoxy-5-yl) -N ⁴ - (pyrazin-2-yl) pyrimidine-2,4 A 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-amino-pyrrolidin-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-ylamino) pyrimidin-4-yl} pyrrolidin-3-yl) methane Sulfonamide,
(56) (S) -2-({2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} (2-hydroxyethyl) amino) ethane -1-ol,
^{(57) (S) -N 4} - [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-hydroxypyrrolidine- 2-on,
^{(63) N 2 - [(} S) -1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) ^-N 6 - [(tetrahydrofuran-2-yl) methyl] pyrimidin-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-ylamino) pyrimidin-4-ylamino} ethyl) methanesulfonamide,
(73) (S) -N- (2- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) 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-phenylpropane- 1-ol,
(83) (R) -2- {2-[(S) -1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-ylamino} -4-methylpentane- 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 A diamine,
^{(89) N 2 - [(} S) -1- (4- fluorophenyl) ethyl] -N ⁴ - (pyrazin-2-yl) -6 - [(tetrahydrofuran-2-yl) methoxy] pyrimidine-2,4 A 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-methylbutane-1 -All,
^{(95) (S) -N 2} - [1- (4- chlorophenyl) ethyl] -6- [4- (methylsulfonyl) piperazin-1-yl] -N ⁴ - (pyrazin-2-yl) pyrimidin-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- methyl-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-ylmethyl) -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) piperidine-4 -All,
^{(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-fluorophenyl) 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) piperidine-4 -All,
(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-thiomorpholine-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-ylamino) pyridin-4-yl} -1,4-diazepane- 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) (S) -2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) isonicotinic acid methyl ester,
(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) -Nt-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) pyridin-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) methane Sulfonamide,
(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-1-yl) -N ⁴ - (pyrazin-2-yl) pyrimidin-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-ylamino) pyrimidin-4-yl} azetidin-3-yl) ethane Sulfonamide,
(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) azetidine- 3-ol,
(188) (S)-(1- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} azetidin-3-yl) (pyrrolidine- 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) (piperidine- 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) ethylamino] -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) azetidine- 3-ol,
(202) (S) -4- ( 3,3- ^{difluoro-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-methoxy-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-methoxy-1-yl) -N ⁶ - (pyrazin-2-yl) Pyridine-2,6-diamine,
^{(208) (S) -N 2} - [1- (4- fluorophenyl) ethyl] -4- (3-methoxy-3-methyl-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-methyl-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) -N 2} - [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-morpholinopropoxy-1-yl) -N ⁴ - (pyrazin-2-yl) pyrimidin-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) piperidine-4 -All,
(221) 4- {2-[(1S) -1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} -1λ ⁶ , 4-thiomorpholine-1 , 1-dione,
(222) (S) -1- (1- {2- [1- (4-fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) 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) (S)-(1- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyrimidin-4-yl} azetidin-3-yl) methylcarbamic acid t -Butyl,
(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- morpholino-1-yl] -N ⁶ - (pyrazin-2-yl) pyridin-2, 6-diamine,
(229) (S) -1- (1- {2- [1- (4-Fluorophenyl) ethylamino] -6- (pyrazin-2-ylamino) pyridin-4-yl} azetidin-3-yl) piperidine -4-ol. Bone metastasis of cancer is bone metastasis of cancer selected from the group consisting of prostate cancer, breast cancer, lung cancer, head and neck cancer, pancreatic cancer, kidney cancer, testicular cancer, cervical cancer, stomach cancer, colon cancer or bladder cancer The therapeutic agent or preventive agent of any one of Claims 1-4. The therapeutic or prophylactic agent according to any one of claims 1 to 4, wherein the disease caused by leukocyte accumulation at the time of vascular injury is restenosis after percutaneous coronary intervention. The therapeutic or prophylactic agent according to any one of claims 1 to 4, wherein the rejection at the time of organ transplantation is rejection at the time of heart transplantation.