JP2009007342A - Medicinal composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a CCR4 function control agent useful for preventing and treating diseases such as bronchial asthma and atopic dermatitis. <P>SOLUTION: The CCR4 function control agent comprises a compound represented by formula (wherein, the ring A is a heterocyclic ring; the ring B is a carbon ring, a heterocyclic ring, or the like; G<SP>1</SP>, G<SP>2</SP>, G<SP>3</SP>, G<SP>4</SP>, and G<SP>5</SP>are each CH or N; X is -NH-, -O-, -CH<SB>2</SB>-, or the like; Y is -CH<SB>2</SB>-, -CO-, -SO<SB>2</SB>-, or the like; Z is a single bond, -CO-, -SO<SB>2</SB>-, -NH-, -CONH-, -SO<SB>2</SB>NH-, or the like; R<SP>2</SP>is H, an alkyl, an alkoxy, a halogen or the like; R<SP>3</SP>is a carbon cyclic group, a heterocyclic group, an alkyl or the like) or its pharmaceutically acceptable salt. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a compound having a function-regulating action of CCR4 or TARC and / or MDC useful for the prevention or treatment of allergic diseases such as bronchial asthma and atopic dermatitis, inflammatory diseases and autoimmune diseases.

  Allergic diseases such as bronchial asthma and atopic dermatitis are chronic inflammatory diseases accompanied by infiltration and activation of inflammatory cells (Non-patent Documents 1 and 2). Bronchial asthma is a disease that exhibits reversible airway obstruction accompanied by airway inflammation and increased airway hyperresponsiveness. Symptoms include wheezing, shortness of breath, and cough. Histologically, there is evidence of chronic inflammation, such as infiltration of eosinophils, lymphocytes and mast cells into the respiratory tract, submucosal edema, eosinophil-derived tissue damage granule protein deposition, and airway epithelial damage. Observed. Atopic dermatitis is a chronic inflammatory disease of the skin that has strong pruritus and has eczema that repeats exacerbations and remissions as the main lesion. The pathological condition is considered to involve both destruction of the stratum corneum barrier function mainly composed of skin dryness and abnormal cytokine production of immune cells. Therefore, suppressing these chronic inflammations is considered an approach in the treatment of allergic diseases.

  In recent years, it has been clarified that helper T (Th) cells and cytokines produced by Th cells play an important role in the onset process of allergic inflammation (Non-patent Documents 1 and 3). Th cells, interferon γ (IFN-γ) and interleukin 2 (IL-2) producing Th1 cells, interleukin 4 (IL-4), and interleukin 5 (IL-5) due to differences in cytokine production patterns. ) Are produced into two subpopulations called Th2 cells (Non-patent Document 4). IFN-γ and IL-2 regulate cellular immunity such as infection defense by activating macrophages and natural killer (NK) cells. On the other hand, since IL-4 and IL-5 are involved in immunoglobulin (Ig) E production and eosinophil activation, respectively, Th2 cells play a major role in the pathogenesis of allergic inflammation. (Non-patent document 1, Non-patent document 5, Non-patent document 6, Non-patent document 7).

  Chemokines are classified as endogenous leukocyte chemotactic factors and play an important role in leukocyte tissue accumulation. Most chemokines are induced in the inflamed area by inflammatory stimuli, etc., and act on leukocytes to induce a migratory reaction. To date, more than 40 chemokines have been identified and classified into CXC, CC, C and CX3C subfamilies by their structural features. On the other hand, the chemokine receptor is a seven-transmembrane receptor to which G protein is coupled, and is composed of a CXC chemokine receptor, a CC chemokine receptor, a CX3C chemokine receptor, and a C chemokine receptor. Many chemokine receptors are known to bind to multiple chemokines, and many chemokines bind to multiple chemokine receptors.

  The CC chemokine receptor 4 (CCR4) gene was cloned from human basophil-like cell line KU-812 in 1995 (Non-patent Document 8). Thereafter, TARC (Thymus and activation-regulated chemokine) / CCL17 is used as a CC chemokine for specifically migrating T cells, and MDC (Macrophage-) as a CC chemokine that exhibits migration activity against monocytes, dendritic cells and NK cells. derived chemokine) / CCL22 (Non-Patent Document 9 and Non-Patent Document 10), and these chemokines were found to be CCR4 ligands (Non-Patent Document 11 and Non-Patent Document 12). CCR4 is strongly expressed in thymus and peripheral blood lymphocytes (Non-patent document 8), and in lymphocytes, expression is relatively restricted to Th cells (Non-patent document 11). As CCR4 is selectively expressed in Th2 cells and migration of Th2 cells is induced by stimulation with TARC / CCL17 or MDC / CCL22 (Non-Patent Documents 11 to 15), allergic diseases The role of CCR4 in the onset process has attracted attention.

  Regarding the relationship between allergic diseases and CCR4 and its ligands TARC / CCL17 and MDC / CCL22, (1) T cells expressing mRNA of CCR4 were detected in the bronchial mucosa of patients with chronic bronchial asthma, the number of which is the antigen Increased after exposure (Non-patent Document 16), (2) Increased expression of CCR4 mRNA is observed in peripheral blood T cells of patients with atopic dermatitis, the degree thereof, blood eosinophil count, serum IgE level or There is a correlation between the severity of dermatitis (Non-patent document 17, Non-patent document 18), (3) In patients with atopic dermatitis, TARC / CCL17 and MDC in serum compared to healthy individuals / CCL22 concentration increase is observed (Non-patent document 19, Non-patent document 20) (4) In an experimental asthma model, anti-TARC antibody or The inflammatory cell infiltration into the airways hyperreactivity and airways or lung interstitium is suppressed by treating the MDC antibody (Non-patent Document 21, Non-Patent Document 22) have been reported.

In addition, the following reports have shown the relationship between CCR4 and / or its ligand and allergic diseases, inflammatory diseases and autoimmune diseases.
Dermatitis (atopic dermatitis, contact dermatitis): Non-patent documents 23 to 25
Asthma: Non-patent documents 16, 26
・ Rhinitis: Non-patent document 27
・ Conjunctivitis: Non-patent document 28
・ Psoriasis: Non-patent document 29
・ Rheumatoid arthritis: Non-patent document 30
Systemic lupus erythematosus: Non-patent documents 31 to 33
Insulin dependent diabetes mellitus (IDDM): Non-patent document 34
・ Rejection during organ transplantation: Non-patent document 35
Inflammatory bowel disease (ulcerative colitis, Crohn's disease): Non-patent document 36
-Glomerulonephritis: Non-patent document 37
・ Sepsis: Non-patent document 38
・ Pain: Non-patent document 39
Adult T cell leukemia (ATL): Non-patent document 40
・ Pulmonary fibrosis: Non-patent documents 41 and 42
Eosinophilic pneumonia: Non-patent document 43
Lung eosinophilic granulation species: Non-patent document 44
Cutaneous T-cell lymphoma: Non-patent documents 20, 45
・ Ankylosing spondylitis: Non-patent document 46
Coronary artery disease: Non-patent document 47
・ Pemphigus: Non-patent document 48
Hodgkin's disease: Non-patent document 49

  These reports suggest that abnormal expression of CCR4 and its ligands TARC / CCL17 and MDC / CCL22 is greatly involved in the development of various pathologies including allergic diseases, and CCR4 and its ligands. This suggests the possibility that these conditions can be cured or ameliorated by controlling their functions.

As therapeutic agents for bronchial asthma currently used in clinical practice, there are β2 stimulants, xanthines, steroids, antiallergic drugs (particularly leukotriene antagonists) and the like. Of these, inhaled steroids are positioned as the first choice for the treatment of asthma and are currently widely used for treatment. However, the problem of side effects caused by long-term administration of steroids continues to be a concern, and the current situation is that high compliance cannot be maintained.
In addition, for the treatment of atopic dermatitis, tacrolimus having an immunosuppressive action is used as an external preparation in addition to steroids for the purpose of suppressing inflammation. Topical steroids have problems of side effects such as hirsutism and skin atrophy even in dermatological diseases. On the other hand, tacrolimus topical agents have no side effects like steroids, but have been pointed out to be related to the appearance of skin irritation and skin cancer.

  Therefore, development of a preventive or therapeutic agent for allergic diseases, inflammatory diseases and autoimmune diseases having a strong therapeutic effect equivalent to that of a steroid and having few side effects based on a novel mechanism of action is eagerly desired. In addition, unlike steroids and immunosuppressive drugs, compounds with CCR4 antagonistic action or CCR4 function-regulating action selectively suppress invasion and activation of Th2 cells in the local area of inflammation, and can be administered orally with few side effects. Can be expected to become a new drug.

As compounds having CCR4 antagonistic action or CCR4 function regulating action, 5-cyanopyrimidine derivatives (Patent Document 1), bicyclic pyrimidine derivatives (Patent Document 2), 5-arylpyrimidine derivatives (Patent Document 3), bicyclic compounds (Patent Literature 4), tricyclic compounds (Patent Literatures 5 and 6), condensed bicyclic pyrimidine derivatives (Patent Literature 7), substituted pyrimidine derivatives (Patent Literature 8), sulfonamide compounds (Patent Literatures 9 to 15), etc. It has been known.
WO03 / 082855 WO03 / 104230 WO2004 / 074260 WO2004 / 020584 WO2004 / 007472 WO2005 / 023771 WO2005 / 082865 WO2005 / 085212 WO2005 / 021513 WO2004 / 108692 WO2004 / 108717 WO2004 / 108690 WO03 / 059893 WO03 / 051870 WO02 / 30358

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Journal of Investigative Dermatology, 124, 1241, 2005 Clinical Experimental Immunology, 138, 342, 2004 Arthritis & Rheumatism, 46, 735, 2002 The Journal of Clinical Investigation, 110, 1675, 2002 European Journal of Immunology, 35, 128, 2005 Clinical & Experimental Immunology, 132, 332, 2003 American Journal of Pathology, 162, 1061, 2003 The Journal of Experimental Medicine, 191, 1755, 2000 The Journal of Neuroscience, 21, 5027, 2001 Cancer Res. 2005 Mar 15, 11 (6), 2427-35 American Journal of Respiratory and Critical Care Medicine, Vol. 173, pp. 310-317 (2006) The Journal of Immunology, 173, 4692, 2004 Clinical Immunology, 116, 83, 2005 American Journal of Pathology, 165, 1211, 2004 British Journal of Dermatology, 152, 746, 2005 Clinical Experimental Immunology, 138, 342, 2004 Journal of the American College of Cardiology, 41, 1460, 2003 British Journal of Dermatology, 148, 203, 2003 International Journal of Cancer, 98, 567, 2002

  The present invention provides an excellent CCR4 or TARC / CCL17 and / or MDC / CCL22 function-regulating action with few side effects, and a compound useful for the prevention or treatment of allergic diseases, inflammatory diseases and autoimmune diseases. There is to do.

  As a result of diligent research, the present inventors have found that the compound represented by the following formula has an excellent CCR4 or TARC / CCL17 and / or MDC / CCL22 function-regulating action as a result of intensive studies. Was completed.

（式中、環Ａは下式からなる群から選ばれる基を示す。

環Ｂは置換されていてもよい芳香族炭素環または置換されていてもよい複素環を示す。 That is, the present invention is as follows.
1. Formula (1)

(In the formula, ring A represents a group selected from the group consisting of the following formulas.

Ring B represents an aromatic carbocyclic ring which may be substituted or a heterocyclic ring which may be substituted.

G ¹ , G ² , G ³ , G ⁴ and G ⁵ are the same or different and each represents CH or N. However, two or more of G ¹ , G ² , G ³ , G ⁴ and G ⁵ represent CH.
Q represents an oxygen atom, a sulfur atom or —N (R ⁶ ) —.
m represents 1 or 2. n shows the integer of 1-3.
w represents 0, 1 or 2.
X represents —N (R ⁷ ) —, —O— or —C (R ⁸ ) (R ⁹ ) —.
Y represents —C (R ¹⁰ ) (R ¹¹ ) —, —CO— or —SO ₂ —.
Z is a single bond, —CO—, —SO ₂ —, —N (R ¹² ) —, —CON (R ¹³ ) —, —SO ₂ N (R ¹³ ) —, —N (R ¹³ ) CO—, — N (R ¹³ ) SO ₂ —, —N (R ¹⁴ ) CON (R ¹⁵ ) — or —N (R ¹⁴ ) SO ₂ N (R ¹⁵ ) — is shown.
R ¹ represents hydrogen, alkyl, alkoxy, halogen, carboxy, alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted amino, nitro, or optionally substituted ureido.

R ² represents hydrogen, alkyl, alkoxy, halogen, haloalkyl, carboxy, alkoxycarbonyl, an optionally substituted carbamoyl or an optionally substituted amino.
R ³ represents an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, or an optionally substituted alkyl.
R ⁴ represents hydrogen or alkyl.
R ⁵ represents hydrogen, alkyl or alkanoyl which may be substituted.
R ⁶ is hydrogen, alkyl or optionally alkanoyl optionally substituted.
R ⁷ represents hydrogen or alkyl.
R ⁸ and R ⁹ and R ¹⁰ and R ¹¹ are the same or different and each represents hydrogen or alkyl.
R ¹² represents hydrogen, alkyl, alkanoyl or carboxyalkyl.
R ¹³ represents hydrogen or alkyl.
R ¹⁴ and R ¹⁵ are the same or different and each represents hydrogen or alkyl. )
Or an pharmaceutically acceptable salt thereof.

（式中、各記号は前記と同義である。）
３．環Ａが下式からなる群から選ばれる基である前記１または２に記載の化合物またはその製薬上許容しうる塩。

（式中、各記号は前記と同義である。）
４．Ｚが単結合、−ＣＯＮＨ−、−ＮＨＣＯ−または−ＣＯ−である前記１〜３のいずれかに記載の化合物またはその製薬上許容しうる塩。 2. 2. The compound according to 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a group selected from the group consisting of the following formulas:

(In the formula, each symbol has the same meaning as described above.)
3. 3. The compound or a pharmaceutically acceptable salt thereof according to 1 or 2, wherein ring A is a group selected from the group consisting of the following formulae:

(In the formula, each symbol has the same meaning as described above.)
4). The compound or a pharmaceutically acceptable salt thereof according to any one of the above 1 to 3, wherein Z is a single bond, -CONH-, -NHCO- or -CO-.

5). R ³ is mono- or di-substituted with (1) (a) oxo, (b) hydroxymethyl, (c) alkyl, (d) amino which may be mono- or di-substituted with alkyl or (e) alkyl Pyrrolidine optionally substituted with carbamoyl, (2) alkyl, alkanoyl, cyano, piperidine optionally substituted with amino or oxo optionally mono- or disubstituted with alkyl, (3) alkyl substituted The compound according to any one of 1 to 4 above, which is an optionally substituted piperazine, (4) an alkyl-substituted morpholine, or (5) an alkyl-substituted tetrahydropyridine, or a pharmaceutical thereof Acceptable salt.
6). 1 or X in which X is —NH—, Y is —CH ₂ —, —CH (CH ₃ ) — or —C (CH ₃ ) ₂ —, and ring B is selected from the group consisting of halogen, alkyl and haloalkyl. 6. The compound or a pharmaceutically acceptable salt thereof according to any one of 1 to 5 above, which is benzene substituted with two groups.

（式中、環Ａは下式からなる群から選ばれる基

を示し、
環Ｂはハロゲンおよびシアノからなる群から選ばれる同一または異なる１〜３個の基で置換されていてもよい芳香族炭素環を示し、
環

は、ベンゼン、ピリジンまたはピリミジンを示し、
ｍは１または２を示し、ｎは１〜３の整数を示し、
Ｘ−Ｙは、−ＮＨ−ＣＨ₂−または−ＮＨ−ＣＨ（ＣＨ₃）−を示し、
Ｚは、単結合、−ＣＯ−または−Ｎ（Ｒ¹²）−を示し、
Ｒ¹は水素、アルキル、アルコキシ、ハロゲン、カルボキシ、アルコキシカルボニル、置換されていてもよいカルバモイル、置換されていてもよいアミノ、ニトロまたは置換されていてもよいウレイドを示し、
Ｒ²は水素、アルキル、アルコキシ、ハロゲン、ハロアルキル、カルボキシ、アルコキシカルボニル、置換されていてもよいカルバモイルまたは置換されていてもよいアミノを示し、
Ｒ³は置換されていてもよい複素環式基を示し、
Ｒ⁴は水素またはアルキルを示す。）
により表される芳香族化合物またはその製薬上許容しうる塩。 Moreover, as another preferable embodiment among the compound (I) of this invention, the following compounds are mention | raise | lifted, for example.
7). Formula (1)

Wherein ring A is a group selected from the group consisting of

Indicate
Ring B represents an aromatic carbocyclic ring optionally substituted with 1 to 3 identical or different groups selected from the group consisting of halogen and cyano,
ring

Represents benzene, pyridine or pyrimidine;
m represents 1 or 2, n represents an integer of 1 to 3,
X—Y represents —NH—CH ₂ — or —NH—CH (CH ₃ ) —,
Z represents a single bond, —CO— or —N (R ¹² ) —,
R ¹ represents hydrogen, alkyl, alkoxy, halogen, carboxy, alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted amino, nitro, or optionally substituted ureido;
R ² represents hydrogen, alkyl, alkoxy, halogen, haloalkyl, carboxy, alkoxycarbonyl, optionally substituted carbamoyl or optionally substituted amino;
R ³ represents an optionally substituted heterocyclic group,
R ⁴ represents hydrogen or alkyl. )
Or an pharmaceutically acceptable salt thereof.

がベンゼンである前記７〜１３のいずれかに記載の化合物またはその製薬上許容しうる塩。
１５．環Ａが下式からなる群から選ばれる基

である前記７〜１４のいずれかに記載の化合物またはその製薬上許容しうる塩。
更には以下の態様も本発明の対象である。
１６．前記１〜１５のいずれかに記載の化合物またはその製薬上許容しうる塩からなる医薬。
１７．前記１〜１５のいずれかに記載の化合物またはその製薬上許容しうる塩を有効成分として含有するＣＣＲ４あるいはＴＡＲＣ／ＣＣＬ１７および／またはＭＤＣ／ＣＣＬ２２の機能調節剤、あるいはそれを患者に投与することによる該機能調節方法。
１８．前記１〜１５のいずれかに記載の化合物またはその製薬上許容しうる塩を有効成分として含有するアレルギー性疾患、炎症性疾患、自己免疫疾患もしくは癌疾患の予防または治療剤、あるいはそれを患者に投与することによる該疾患の治療方法。
１９．前記１〜１５のいずれかに記載の化合物またはその製薬上許容しうる塩を有効成分として含有する喘息もしくは皮膚炎の予防または治療剤、あるいはそれを患者に投与することによる該疾患の治療方法。 8). 8. The compound or a pharmaceutically acceptable salt thereof as described in 7 above, wherein R ¹ is hydrogen.
9. 9. The compound or a pharmaceutically acceptable salt thereof as described in 7 or 8 above, wherein R ² is hydrogen, alkyl, or optionally substituted amino.
10. 9. The compound according to 7 or 8 or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen.
11. R ⁷ is an optionally substituted pyrrolidine, an optionally substituted piperidine, an optionally substituted piperazine, an optionally substituted morpholine or an optionally substituted tetrahydropyridine. A compound according to any one or a pharmaceutically acceptable salt thereof.
12 R ³ is (1) (a) oxo, optionally mono- or disubstituted with (b) hydroxymethyl, (c) alkyl, (d) alkyl which may be mono- or di-substituted amino or (e) alkyl Pyrrolidine optionally substituted with carbamoyl, (2) Alkyl, alkanoyl, cyano, Piperidine optionally substituted with amino or oxo optionally mono- or disubstituted with alkyl, (3) Alkyl substituted The compound according to any one of 7 to 11 above, which is optionally piperazine, (4) morpholine optionally substituted with alkyl, or (5) tetrahydropyridine optionally substituted with alkyl, or a pharmaceutically acceptable salt thereof Possible salt.
13. The compound or a pharmaceutically acceptable salt thereof according to any one of the above 7 to 12, wherein Ring B is benzene optionally substituted with the same or different 1 to 3 groups selected from the group consisting of halogen and cyano .
14 ring

14. The compound or a pharmaceutically acceptable salt thereof according to any one of 7 to 13, wherein is benzene.
15. A group wherein ring A is selected from the group consisting of

The compound according to any one of the above 7 to 14, or a pharmaceutically acceptable salt thereof.
Furthermore, the following aspects are also objects of the present invention.
16. A medicament comprising the compound according to any one of 1 to 15 above or a pharmaceutically acceptable salt thereof.
17. CCR4 or TARC / CCL17 and / or MDC / CCL22 function-regulating agent containing the compound according to any one of 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient, or by administering it to a patient The function adjusting method.
18. A prophylactic or therapeutic agent for allergic disease, inflammatory disease, autoimmune disease or cancer disease comprising the compound according to any one of 1 to 15 above or a pharmaceutically acceptable salt thereof as an active ingredient, or a method for providing the same to a patient A method for treating the disease by administration.
19. A prophylactic or therapeutic agent for asthma or dermatitis containing the compound according to any one of 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient, or a method for treating the disease by administering it to a patient.

Hereinafter, groups represented by symbols in this specification will be described. In addition, the symbol used in this specification represents the following meaning, respectively.
THF: Tetrahydrofuran DMF: N, N-dimethylformamide DMSO: Dimethyl sulfoxide DMA: Dimethylacetamide DME: 1,2-dimethoxyethane LDA: Lithium diisopropylamide DBU: 1,8-diazabicyclo [5.4.0] -7 -Undecene DBN: 1,5-diazabicyclo [4.3.0] non-5-ene Ac: acetyl Me: methyl Et: ethyl Pr: n-propyl iPr: isopropyl t-Bu: tert-butyl Boc: tert-butoxy Carbonyl Bn: benzyl Ph: phenyl Cy: cycloalkyl

Examples of the “aromatic carbocycle” include 6- to 14-membered monocyclic, bicyclic or tricyclic unsaturated carbocycles, and specific examples include benzene, naphthalene, phenanthrene, anthracene and the like. Is given.
Examples of the “heterocycle” include, for example, a 3 to 15-membered monocyclic or bicyclic unsaturated heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and Heterocycles, all or part of which are saturated. Specific examples of the unsaturated heterocyclic ring and a heterocyclic ring saturated in whole or in part include, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, Pyran, oxepin, thiophene, thiapyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, Benzothiophene, indazole, quinoline, isoquinoline, quinoxaline, quinazoline, benzoxazole, benzothiazole, benzimi Sol, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydroazepine, tetrahydroazepine, dihydrodiazepine, tetrahydrodiazepine, dihydrofuran, tetrahydrofuran , Dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiapyran, tetrahydrothiapyran, piperidine, piperazine, morpholine, thiamorpholine, homopiperidine and the like.

Examples of the “alicyclic heterocycle” include a 5- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Specifically, piperidine, piperazine, morpholine, thiamorpholine, homopiperidine, tetrahydrooxazine and the like can be mentioned.
Examples of the “alkyl” include linear or branched C1-C6 alkyl, and specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like. Can be given.

Examples of the “alkoxy” include linear or branched C1-C6 alkoxy, and specifically include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, And hexyloxy.
“Halogen” includes fluorine, chlorine, bromine and iodine.
Examples of the “haloalkyl” include those in which 1 to 6 halogens are substituted on linear or branched C1-C6 alkyl, and specifically include fluoromethyl, chloromethyl, trifluoromethyl, and the like. 2,2,2-trifluoroethyl and the like.

  Examples of the “alkoxycarbonyl” include linear or branched C2-C7 alkoxycarbonyl, etc., and specifically include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxy. Examples thereof include carbonyl and tert-butoxycarbonyl.

Examples of “alkanoyl” include linear or branched C1-C6 alkanoyl, and specific examples include formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl and the like.
Examples of the “carboxyalkyl” include linear or branched C1-C6 alkyl substituted with 1 to 2 carboxy, specifically, carboxymethyl, carboxyethyl, carboxypentyl and the like. Etc.
“Aralkyl” includes, for example, a linear or branched C1-C6 alkyl substituted with an aromatic carbocycle (preferably benzene), and specifically includes benzyl, 2-phenylethyl, Examples thereof include 1-phenylethyl and 3-phenylpropyl.
Examples of “cycloalkyl” include C3-C6 cycloalkyl, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

Examples of the “alkylsulfonyl” include linear or branched C1-C6 alkylsulfonyl, and specific examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl and the like. .
Examples of the “carbocyclic group” include a 3 to 15-membered monocyclic, bicyclic or tricyclic unsaturated carbocyclic group, and a carbocyclic ring in which all or a part thereof is saturated. can give. Specific examples of these carbocycles include, for example, phenyl, naphthyl, phenanthryl, anthryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexyl. Examples include sadienyl, cycloheptadienyl, cyclooctadienyl, indenyl, indanyl, dihydronaphthyl, tetrahydronaphthyl and the like.

  Examples of the “heterocyclic group” include a 3 to 15-membered monocyclic or bicyclic unsaturated heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. And a heterocyclic group in which all or part of the group is saturated.

  Specific examples of the unsaturated heterocyclic group and a heterocyclic group saturated in whole or in part include, for example, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, azepinyl, Diazepinyl, furyl, pyranyl, oxepinyl, thienyl, thiapyranyl, thiepinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, oxazinyl, oxadiazinyl, oxazepinyl, oxadiazepinyl, thiadiazolyl, thiazinyl, thiazinyl, thiazinyl , Benzofuranyl, benzothiophenyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolin Benzoxazolyl, benzothiazolyl, benzimidazolyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, dihydropyridyl, tetrahydropyridyl, dihydropyrazinyl, tetrahydropyrazinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydroazepinyl, Tetrahydroazepinyl, dihydrodiazepinyl, tetrahydrodiazepinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, dihydrothiapyranyl, tetrahydrothiapyranyl, piperidyl, piperazinyl, morpholinyl , Thiamorpholinyl, homopiperidyl and the like.

Examples of the “alicyclic heterocyclic group” include a 5- to 7-membered monocyclic saturated heterocyclic group containing 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Specific examples include piperidyl, piperazinyl, morpholinyl, thiamorpholinyl, homopiperidyl, tetrahydrooxazinyl and the like.
Examples of the substituent of “optionally substituted aromatic carbocycle” and “optionally substituted heterocycle” in ring B include, for example, halogen, alkyl, haloalkyl, hydroxyl group, alkoxy, cyano, carboxy, alkoxycarbonyl , Nitro and the like, and may have 1 to 3 of these substituents. Preferred substituents include halogen, alkyl and haloalkyl, with halogen being particularly preferred.
Examples of the substituent of "carbamoyl which may be substituted" in R ¹ and R ^2, for example, hydroxyl, alkoxy or alkylsulphonyl alkyl optionally substituted with, including aralkyl, and these identical or different substituents 1 or 2 may be included. Further, R ¹ and R ² may form a heterocyclic ring with the adjacent nitrogen atom, and examples thereof include pyrrolidine, piperidine, morpholine, thiamorpholine, homopiperidine and the like, and may have a substituent such as oxo. Good.

Examples of the substituent of “optionally substituted amino” in R ¹ and R ² include alkyl, optionally substituted alkanoyl, alkylsulfonyl, optionally substituted alkoxycarbonyl, cycloalkylcarbonyl, hydroxyl group And may have one or two of these same or different substituents. Here, examples of the substituent of the optionally substituted alkanoyl and the optionally substituted alkoxycarbonyl include alkoxy, a hydroxyl group and the like.
Examples of the substituent of “optionally substituted ureido” in R ¹ include alkyl and the like, and may have one or two of the same or different substituents. Two substituents may be combined to form a 5- to 7-membered alicyclic heterocycle with an adjacent nitrogen atom.

Examples of the substituent of the “optionally substituted carbocyclic group” in R ³ include an alicyclic heterocyclic group optionally substituted with oxo, an optionally substituted alkyl, cyano, and substituted. Examples thereof include amino and alkylenedioxy which may be used. Here, examples of the optionally substituted alkyl substituent include cyano and the like. Examples of the optionally substituted amino substituent include alkylsulfonyl.
Examples of the substituent of the “optionally substituted heterocyclic group” in R ³ include (a) oxo, (b) carboxy, (c) alkoxycarbonyl, (d) optionally substituted with alkyl. Heterocyclic group substituted amino or (e) oxo, alkyl, alkylsulfonyl, or alkanoyl optionally substituted mono- or di-substituted with sulfonyl or alkyl, (f) substituted with phenyl Optionally substituted alkyl, (g) carbamoyl optionally mono- or disubstituted with alkyl, (h) alkylsulfonyl, (i) alkanoyl, (j) phenyl optionally substituted with alkoxy, (k) Halogen, (l) cyano, (m) hydroxyl group, (n) alkoxy and the like.

Examples of the substituent of “optionally substituted alkyl” in R ³ include, for example, halogen, hydroxyl group, alkoxy, amino optionally mono- or disubstituted with alkyl, optionally substituted heterocyclic group, etc. And may have one or two of these same or different substituents. Here, the substituent of the heterocyclic group which may be substituted is synonymous with the substituent of the heterocyclic group which may be substituted in R ³ .
Examples of the substituent of “optionally substituted alkanoyl” in R ⁵ and R ⁶ include cycloalkyl and the like.

により表される基の好ましい具体例としては、以下の基があげられる。

The following formula

Preferable specific examples of the group represented by the following include the following groups.

  Examples of the pharmaceutically acceptable salt of the compound of the present invention include inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide, acetate, fumarate, oxalate, citrate, Examples thereof include organic acid salts such as methanesulfonate, benzenesulfonate, tosylate and maleate. In addition, when it has an acidic group such as carboxy, a salt with a base (for example, an alkali metal salt such as sodium salt or potassium salt, an alkaline earth metal salt such as calcium salt, an organic base salt such as triethylamine salt, a lysine salt, etc. And amino acid salts thereof.

The compound of the present invention or a pharmaceutically acceptable salt thereof includes any solvate such as an inner salt or hydrate thereof.
The compound (I) of the present invention may have optical isomers based on asymmetric carbon, but the compound (I) of the present invention includes any of these isomers and mixtures thereof. Further, when the compound (I) of the present invention has a double bond or cycloalkanediyl, there exist cis and trans isomers, and the compound (I) of the present invention has tautomers based on unsaturated bonds such as carbonyl. However, the compound (I) of the present invention includes any isomers and mixtures thereof. Further, when the compound of the present invention has an amino group, a quaternary ammonium salt is also included.

（式中、Ｐ¹はハロゲンまたはアルキルスルホニルオキシなどの脱離基を示し、Ｐ²は−Ｂ（ＯＨ）₂、−Ｂ（ＯＲ^A）₂または−Ｓｎ（Ｒ^A）₃を示し、Ｒ^Aはアルキルを示し、他の記号は前記と同義である。） Compound (1) of the present invention can be produced by the following method.
Method 1: Compound (1) is prepared by the following method.

(Wherein, P ¹ represents a leaving group such as halogen or alkylsulfonyloxy, P ² is -B (OH) _2, -B (indicates OR ^A) ₂ or _{^{-Sn (R A) 3, R}} A Represents alkyl, and other symbols are as defined above.

Compound (2) is compounded with Compound (3) and a solvent (DME, THF, dioxane, DMF, DMA, toluene, benzene, water or a mixture thereof) in a palladium catalyst [tetrakis (triphenylphosphine) palladium (0), bis The compound (1-A) is obtained by reacting in the presence of (triphenylphosphine) palladium (II) chloride, palladium (II) acetate or other zero-valent or divalent palladium catalyst].
When using the compound (3) in which P ² is —B (OH) ₂ or —B (OR ^A ) _2, it is preferable to add a base. As the base, for example, an inorganic base such as alkali metal carbonate, alkali metal hydroxide, alkali metal phosphate, or alkali metal fluoride, or an organic base such as triethylamine can be used.
The reaction temperature of this reaction is usually from room temperature to 150 ° C., and the reaction time is usually from 1 to 24 hours.

（式中、環Ｃは置換されていてもよいピペラジン、置換されていてもよいピペリジン、置換されていてもよいピロリジンなどの全部または一部が飽和された５〜７員の含窒素複素環式基を示し、他の記号は前記と同義である。） Method 2: Compound (1) wherein R ³ is a nitrogen-containing heterocyclic group and Z is —CO— or Z is —N (R ¹³ ) CO— is prepared by the following method. Is done.

(In the formula, ring C is a 5- to 7-membered nitrogen-containing heterocyclic group in which all or part of saturated piperazine, optionally substituted piperidine, optionally substituted pyrrolidine, etc. is saturated. The other symbols are as defined above.

This reaction is carried out by any of the following methods.
(1) After compound (4) is treated with a halogenating agent (thionyl chloride, oxalyl chloride (DMF may be added if necessary), etc.) and converted to an acid halide, compound (5-a) or By reacting compound (5-b) with a base (sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, triethylamine, pyridine, etc.) at -20 to 100 ° C. for 30 minutes to 24 hours, compound (1 -B) or compound (1-C) is obtained.

  (2) Condensing agent (1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, compound (4) in a solvent (DMF, THF, dioxane, dichloromethane, etc.) as necessary. By condensation with compound (5-a) or compound (5-b) in the presence of carbonyldiimidazole, diethyl cyanophosphate, PyBOP [(benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate], etc.) , Compound (1-B) or compound (1-C) is obtained. This reaction usually proceeds at 0 ° C. to 100 ° C., usually 30 minutes to 24 hours. In addition, reaction using a condensing agent can also be performed in presence of 1-hydroxy benztriazole, N-hydroxysuccinimide, etc. as needed.

  (3) Compound (4) is converted into a mixed acid anhydride (a carbonate ester with methyl chlorocarbonate, ethyl chlorocarbonate, or a sulfonate ester with mesyl chloride, tosyl chloride, etc.) In a suitable solvent (such as THF, toluene, nitrobenzene or a mixed solvent thereof), in the presence of a base (such as triethylamine, pyridine, 4-dimethylaminopyridine, diethylaniline, collidine, Hunig (diisopropylethylamine)) from room temperature to Compound (1-B) or compound (1-C) is obtained by condensation with compound (5) at reflux temperature for 1 to 24 hours.

（式中、各記号は前記と同義である。）
化合物（６）と化合物（７）との反応は、方法２と同様に実施することができる。化合物（６）と化合物（８）との反応は、方法２（１）の酸ハライドの反応と同様に実施することができる。 Method 3: Compound (1) in which Z is —CON (R ¹³ ) — or —SO ₂ N (R ¹³ ) — is prepared by the following method.

(In the formula, each symbol has the same meaning as described above.)
The reaction of compound (6) and compound (7) can be carried out in the same manner as in Method 2. The reaction between the compound (6) and the compound (8) can be carried out in the same manner as the acid halide reaction in the method 2 (1).

（式中、各記号は前記と同義である。） Method 4: Compound (1) wherein Z is —N (R ¹⁴ ) CON (R ¹⁵ ) — and R ¹⁵ is hydrogen is prepared by the following method.

(In the formula, each symbol has the same meaning as described above.)

Compound (6-a) in compound (9-a) and solvent (chloroform, dichloromethane, DMF, DMSO, dioxane, THF, etc.) or without solvent, base (triethylamine, diisopropylethylamine, 4-methylmorpholine, pyridine, etc.) Compound (1-E) is obtained by reacting in the presence of. This reaction suitably proceeds at −40 to 100 ° C. for 1 to 48 hours.
In addition, compound (1-F) is obtained by reacting compound (6-a) with compound (9-b) in a solvent (chloroform, dichloromethane, DMF, DMSO, dioxane, THF, etc.). This reaction suitably proceeds at −40 to 100 ° C. for 1 to 48 hours.

（式中、Ａｌｋは１〜３個のオキソで置換されていてもよく、１〜３個の窒素原子、酸素原子または硫黄原子が介在していてもよいＣ２〜Ｃ６アルキレンを示し、環Ｄは置換されていてもよいピロリジン、置換されていてもよいピペリジン、置換されていてもよいピペラジン、置換されていてもよいモルホリン、置換されていてもよいチオモルホリン、置換されていてもよいイミダゾリジン、置換されていてもよいチアゾリジン、置換されていてもよいイソチアゾリジンなどの５〜７員の飽和含窒素複素環式基を示し、他の記号は前記と同義である。） Method 5: A compound in which Z is a single bond and R ³ is a 5- to 7-membered saturated nitrogen-containing heterocyclic group is prepared by the following method.

(In the formula, Alk represents C2 to C6 alkylene which may be substituted with 1 to 3 oxo and may be intervened with 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms, and ring D represents An optionally substituted pyrrolidine, an optionally substituted piperidine, an optionally substituted piperazine, an optionally substituted morpholine, an optionally substituted thiomorpholine, an optionally substituted imidazolidine, This represents a 5- to 7-membered saturated nitrogen-containing heterocyclic group such as optionally substituted thiazolidine and optionally substituted isothiazolidine, and other symbols are as defined above.

  Compound (1-G) can be produced by treating compound (10) with a base (sodium hydride, potassium tert-butoxide, etc.) in a solvent (DMF, DMSO, N, N-dimethylacetamide, etc.). it can. This reaction suitably proceeds at 0 to 100 ° C. for 1 to 48 hours.

（式中、Ｒ^1a、Ｒ^1bは、それぞれＲ¹と同義であり、Ｌｖはアルキル、置換されていてもよいフェニルまたは置換されていてもよいベンジルを示し、ＶはＣＨまたはＮを示し、Ｘ¹は−Ｎ（Ｒ⁵）−または−Ｏ−を示し、他の記号は前記と同義である。） Method 6: Compound (1) wherein ring A is group (I) and X is —N (R ⁵ ) — or —O— is prepared by the following method.

Wherein R ^1a and R ^1b have the same meanings as R ¹ , Lv represents alkyl, optionally substituted phenyl or optionally substituted benzyl, V represents CH or N, and X ¹ represents —N (R ⁵ ) — or —O—, and the other symbols are as defined above.

Compound (11) in 3-aminopyrazole and a solvent (methanol, ethanol, isopropyl alcohol, THF, dioxane, etc.) or without solvent, in the presence of an acid (such as a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid). By reacting, the compound (12) is obtained.
Compound (12) can be used in a solvent (benzene, toluene, xylene, chloroform, methylene chloride, acetonitrile, DMF, etc.) or without solvent, and in the presence of a base (dimethylaniline, diethylaniline, triethylamine, etc.) as necessary from room temperature. By reacting with a halogenating agent (phosphorus oxychloride, phosphorus oxybromide, etc.) for 1 to 12 hours at the reflux temperature of the solvent, compound (13) is obtained.

  Compound (13) is mixed with compound (14) and a solvent (THF, dioxane, diethyl ether, DMF, DMSO, methanol, ethanol, ethylene glycol, etc.) with a base (triethylamine, diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide, Compound (1-H) is obtained by reacting at 0 to 150 ° C. for 1 to 24 hours in the presence of sodium carbonate, potassium carbonate and the like.

（式中、Ｐ³はハロゲンを示し、他の記号は前記と同義である。）
化合物（１５）と化合物（１４−ａ）との反応は、方法６と同様に実施することができる。 Method 7: Compound (2) wherein X is —N (R ⁵ ) — or —O— is prepared by the following method.

(Wherein P ³ represents halogen, and other symbols are as defined above.)
The reaction of compound (15) and compound (14-a) can be carried out in the same manner as in Method 6.

（式中、Ｒ^Aは水素またはアルキルを示し、他の記号は前記と同義である。）
化合物（１６）を常法によりアンモニア水と処理して化合物（１７）とした後、化合物（１７）を、溶媒（例えば、水、メタノール、エタノール、tert−ブチルアルコール、ＴＨＦ、ジオキサン、酢酸エチル、酢酸、キシレン、ＤＭＦ、ＤＭＳＯまたはそれらの混合物）中、還元することにより化合物（１８）が得られる。還元反応は、例えば水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化アルミニウムリチウム等の還元剤を用いるか、金属（鉄、亜鉛、スズ等）を用いるか、または遷移金属（パラジウム−炭素、酸化白金、ラネーニッケル、ロジウム、ルテニウム等）を用いた接触還元などによっても行うことができる。なお、接触還元を行う場合、水素源はギ酸、ギ酸アンモニウム、１，４−シクロヘキサジエン等であってもよい。本反応は、通常−２０〜１５０℃で、通常３０分間から４８時間で進行する。 Method 8: Compound (15) wherein ring A ¹ is group (C) is prepared by the following method.

(Wherein R ^A represents hydrogen or alkyl, and other symbols are as defined above.)
Compound (16) is treated with aqueous ammonia by a conventional method to obtain compound (17), and then compound (17) is converted into a solvent (for example, water, methanol, ethanol, tert-butyl alcohol, THF, dioxane, ethyl acetate, Compound (18) is obtained by reduction in acetic acid, xylene, DMF, DMSO or a mixture thereof. For the reduction reaction, for example, a reducing agent such as sodium borohydride, lithium borohydride, lithium aluminum hydride or the like, a metal (iron, zinc, tin, etc.) or a transition metal (palladium-carbon, platinum oxide) is used. , Raney nickel, rhodium, ruthenium, etc.). When performing catalytic reduction, the hydrogen source may be formic acid, ammonium formate, 1,4-cyclohexadiene, or the like. This reaction usually proceeds at −20 to 150 ° C., usually 30 minutes to 48 hours.

Compound (19) is obtained by reacting compound (18) with urea at 100 to 250 ° C. for 1 to 12 hours.
Compound (19) is used in a solvent (benzene, toluene, xylene, chloroform, methylene chloride, acetonitrile, DMF, etc.) or without a solvent, and if necessary, a base (dimethylaniline, diethylaniline, triethylamine, collidine, pyridine, diisopropylethylamine) Etc.) in the presence of a halogenating agent (phosphorus oxychloride, phosphorus oxybromide, etc.) at room temperature to the reflux temperature of the solvent for 1 to 12 hours to give compound (15-A).

（式中、Ｒ^BおよびＲ^4aはそれぞれアルキルを示し、他の記号は前記と同義である。）
化合物（２０）を溶媒（メタノール、エタノールなど）中、強塩基（ナトリウムメトキシド、カリウムメトキシド、ナトリウムエトキシド、カリウムエトキシドなど）で処理することにより生成する３−オキソプロピオニトリル誘導体と、化合物（２１）とを弱塩基（酢酸ナトリウム、酢酸カリウム、炭酸ナトリウム、炭酸カリウムなど）の存在下で反応させることにより、化合物（２２）が得られる。 Method 9: Compound (15) wherein ring A ¹ is group (D) is prepared by the following method.

(In the formula, R ^B and R ^4a each represents alkyl, and other symbols are as defined above.)
A 3-oxopropionitrile derivative produced by treating compound (20) with a strong base (sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, etc.) in a solvent (methanol, ethanol, etc.); Compound (22) is obtained by reacting compound (21) in the presence of a weak base (sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, etc.).

Compound (23) is obtained by reacting compound (22) with cyanate (sodium cyanate, potassium cyanate, etc.) in a solvent (such as methanol, ethanol, acetic acid, water or a mixture thereof). This reaction suitably proceeds at 0 to 100 ° C., preferably at room temperature, for 1 to 12 hours.
Compound (24) is obtained by treating compound (23) with a base (sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.) in a solvent (water, methanol, ethanol, DMSO, DMF, etc.). . This reaction suitably proceeds at 0 to 150 ° C., preferably at the reflux temperature of the solvent, for 1 to 12 hours.
Compound (15) can be obtained by reacting compound (24) with a halogenating agent in the same manner as in Method 8. Furthermore, a compound (15-B-2) is obtained by making a compound (15-B-1) react with an alkyl halide by a conventional method.

（式中、ＶはＣＨまたはＮを示し、他の記号は前記と同義である。）
化合物（２５）をマロン酸ジアルキルエステルと溶媒（メタノール、エタノール、イソプロピルアルコールなど）中、塩基（ナトリウムメトキシド、ナトリウムエトキシド、カリウムメトキシドなど）の存在下、室温から溶媒の還流温度で１〜４８時間反応させることにより、化合物（２６）が得られる。
化合物（２６）を方法８のハロゲン化反応と同様に反応させることにより化合物（１５−Ｃ）が得られる。 Method 10: Compound (15) wherein ring A is group (I) or (J) is prepared by the following method.

(In the formula, V represents CH or N, and other symbols are as defined above.)
The compound (25) is diluted with malonic acid dialkyl ester and a solvent (methanol, ethanol, isopropyl alcohol, etc.) in the presence of a base (sodium methoxide, sodium ethoxide, potassium methoxide, etc.) at room temperature to the reflux temperature of the solvent. Compound (26) is obtained by reacting for 48 hours.
Compound (15-C) is obtained by reacting Compound (26) in the same manner as in the halogenation reaction of Method 8.

（式中、各記号は前記と同義である。） Method 11: Compound (15) wherein ring A is group (A) or (B) is prepared by the following method.

(In the formula, each symbol has the same meaning as described above.)

Compound (28-a) or compound (28-b) is obtained by reacting compound (27-a) or compound (27-b) with urea at 100 to 250 ° C. for 1 to 12 hours.
Compound (15-D) or Compound (15-E) is obtained by reacting Compound (28-a) or Compound (28-b) in the same manner as in the halogenation reaction of Method 8.

（式中、Ｇはカルボキシまたはシアノを示し、他の記号は前記と同義である。）
化合物（２９）は、Tetrahedron, 58, (2002) 3155-3158またはＷＯ９５／３２２０５に記載の方法に準じて調製される。すなわち、（１）Ｇがシアノである化合物（２９）を二酸化炭素と溶媒（ＤＭＦ、ＤＭＳＯ、ＴＨＦなど）中、過剰量の塩基（ＤＢＵ、ＤＢＮなど）の存在下、室温から１００℃で１〜４８時間反応させるか、または（２）Ｇがカルボキシである化合物（２９）を尿素と１００〜２５０℃で１〜１２時間反応させることにより、化合物（３０）が得られる。
化合物（３０）を方法８のハロゲン化反応と同様に反応させることにより、化合物（１５−Ｆ）が得られる。 Method 12: Compound (15) wherein ring A is group (F) is prepared by the following method.

(In the formula, G represents carboxy or cyano, and other symbols are as defined above.)
Compound (29) is prepared according to the method described in Tetrahedron, 58, (2002) 3155-3158 or WO95 / 32205. (1) A compound (29) in which G is cyano is dissolved in carbon dioxide and a solvent (DMF, DMSO, THF, etc.) in the presence of an excess amount of a base (DBU, DBN, etc.) at room temperature to 100 ° C. Compound (30) is obtained by reacting for 48 hours or (2) reacting compound (29) in which G is carboxy with urea at 100 to 250 ° C. for 1 to 12 hours.
Compound (15-F) is obtained by reacting Compound (30) in the same manner as in the halogenation reaction of Method 8.

（式中、各記号は前記と同義である。） Method 13: Compound (15) wherein ring A is group (E) is prepared by the following method.

(In the formula, each symbol has the same meaning as described above.)

This reaction is prepared according to the method described in JP-A-58-146586. That is, compound (31) is converted into compound (32) or a salt thereof (hydrochloride, sulfate, etc.) and a solvent (methanol, ethanol, isopropyl alcohol, DMF, DMSO, etc.) in a base (sodium hydroxide, potassium hydroxide, carbonate). Compound (33) is obtained by reacting at room temperature to 100 ° C. for 1 to 12 hours in the presence of sodium, potassium carbonate, sodium hydride, sodium methoxide, sodium ethoxide and the like.
Compound (33) in a solvent (hydrous methanol, hydrous ethanol, water, etc.), acid (acetic acid, hydrochloric acid, sulfuric acid, etc.) or alkali (sodium hydroxide, potassium hydroxide, etc.) and room temperature to solvent reflux temperature from 1 hour The compound (34) is obtained by reacting for 3 days.
Compound (15-G) is obtained by reacting Compound (34) in the same manner as in the halogenation reaction of Method 8.

（式中、各記号は前記と同義である。）
化合物（３５）を溶媒（ベンゼン、トルエン、キシレン、クロロホルム、塩化メチレンなど）中、アクリロニトリルと室温から溶媒の還流温度で１〜２４時間反応させることにより、化合物（３６）が得られる。
化合物（３６）を三フッ化ホウ素・ジエチルエーテル錯体と好ましくは還流温度で１〜１２時間反応させることにより、化合物（２９−ａ）が得られる。 Method 14: Compound (29) wherein G is cyano and R ^1a is alkoxycarbonyl is prepared by the following method.

(In the formula, each symbol has the same meaning as described above.)
Compound (36) is obtained by reacting compound (35) in a solvent (benzene, toluene, xylene, chloroform, methylene chloride, etc.) with acrylonitrile at room temperature to the reflux temperature of the solvent for 1 to 24 hours.
Compound (29-a) is obtained by reacting compound (36) with boron trifluoride-diethyl ether complex, preferably at reflux temperature for 1 to 12 hours.

（式中、Ｒ^Cは脱離基（トリフルオロメタンスルホニル等）を示し、他の記号は前記と同義である。） Method 15: Compound (1) in which Ring A is the group (G), X is —N (R ⁷ ) — or —O—, and Y is —C (R ¹⁰ ) (R ¹¹ ) — It is prepared by the following method.

(In the formula, R ^C represents a leaving group (such as trifluoromethanesulfonyl), and other symbols are as defined above.)

Compound (37) is treated with a base (n-butyllithium, LDA, etc.) in a solvent (THF, diethyl ether, dioxane, etc.) from −78 ° C. under ice cooling, and then carbon dioxide at the same temperature for 1-12 hours. To give compound (38).
Compound (40) is obtained by reacting compound (38) with compound (39) in the same manner as in Method 6.
The reaction of compound (40) with R ⁴ NH ₂ can be carried out in the same manner as in Method 2. The acid halide of compound (40) is prepared by treating with a halogenating agent (such as thionyl chloride) by a conventional method.
The compound (42) is obtained by reacting the compound (41) with ammonia in a solvent (THF, diethyl ether, dioxane, etc.) from 0 ° C. to the reflux temperature of the solvent for 1 hour to 10 days.
The compound (42) is reacted at room temperature to 150 ° C. in the presence of trialkyl orthoformate (trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, tributyl orthoformate, etc.) and an acid (acetic acid, acetic anhydride, hydrochloric acid, sulfuric acid, etc.). A compound (43) is obtained by making it react for 1 to 12 hours.

The compound (43) is hydrolyzed in the same manner as in Method 13 to give a compound in which R ^C is hydrogen, and then treated with trifluoromethanesulfonic anhydride or the like by a conventional method to convert it into a leaving group, whereby the compound (44) Is obtained.
Compound (1-I) is obtained by reacting compound (44) with compound (45) in the same manner as in Method 1.

（式中、各記号は前記と同義である。） Method 16: Ring A is a group (H), X is -N (R ⁷⁾ - or a -O-, Y is ^{-C (R 10) (R 11} ) - , Compound (1) It is prepared by the following method.

(In the formula, each symbol has the same meaning as described above.)

Compound (47) is obtained by reacting compound (46) with DMF and phosphorus oxychloride or phosphorus oxybromide at room temperature to the reflux temperature of the solvent for 1 to 12 hours.
The reaction of compound (47) and compound (48) can be carried out in the same manner as in Method 6.

Compound (49) may be converted into compound (50) and a solvent (methanol, ethanol, isopropyl alcohol, chloroform, methylene chloride, DMF, DMSO, THF, dioxane, etc.) with an acid (hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid) as necessary. In the presence of a reducing agent (sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc.), compound (51) is obtained. This reaction can be carried out at room temperature to the reflux temperature of the solvent for 30 minutes to 2 days.
Compound (51) is dissolved in a solvent (THF, dioxane, diethyl ether, DMF, DMSO, etc.) in the presence of a base (triethylamine, pyridine, sodium hydride, potassium t-butoxide, sodium t-butoxide, etc.) from room temperature to the solvent. The compound (52) is obtained by treating at reflux temperature for 1 to 24 hours.
Compound (53) is obtained by reacting compound (52) in the same manner as in Method 15.
In the same manner as in Method 1, compound (1-J) is obtained by reacting compound (53) with compound (54).

（式中、Ｐ⁴はカルボキシ、アルコキシカルボニル、アミノまたは脱離基（ハロゲン、メタンスルホニル、トリフルオロメタンスルホニルなど）などを示し、他の記号は前記と同義である。）
なお、化合物（５５）は、対応する原料化合物を用いて、上記製造法と同様に反応させることにより調製される。 Method 17: Compound (1) can also be used to prepare compound (1) of the present invention by converting the functional group usually used in the field of organic synthetic chemistry using the following compound (55). .

(Wherein P ⁴ represents carboxy, alkoxycarbonyl, amino, a leaving group (halogen, methanesulfonyl, trifluoromethanesulfonyl, etc.), etc., and other symbols are as defined above.)
In addition, a compound (55) is prepared by making it react like the said manufacturing method using a corresponding raw material compound.

Method 18: In the above method, when the compound of the present invention, intermediate compound, raw material compound or the like has a functional group (hydroxyl group, amino, carboxy, etc.), Protective Groups in Organic Synthesis ”TW Greene, PMG Wuts, John Wiley and Sons According to the method described in 1991, the target compound can be obtained by protecting with a protective group usually used in organic synthetic chemistry, and removing the protective group after the reaction. Examples of the protecting group usually used in the described organic synthetic chemistry include, for example, a hydroxyl protecting group such as tetrahydropyranyl, trimethylsilyl, tert-butyldimethylsilyl, benzyl, methoxymethyl, acetyl, and the like. Examples of the protecting group include tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenyl. Butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, tert- amyloxycarbonyl, and the like, as the protective group for carboxy, for example, methyl, alkyl of ethyl, and the like, benzyl and the like.
Moreover, after manufacturing this invention compound and an intermediate compound according to the said method, a functional group can also be converted or modified according to a conventional method. Specifically, the following methods are mentioned.

(1) Conversion of amino to amide It can be converted to the corresponding amide by reacting amino with an acyl halide or reacting carboxy with an amine in the presence of a condensing agent.
(2) Conversion of carboxy or its ester to carbamoyl By converting carboxy to acyl halide and reacting with amine, reacting carboxy with amine in the presence of a condensing agent, or reacting the ester with amine Can be converted to the corresponding carbamoyl.
(3) Hydrolysis of ester The ester can be converted to the corresponding carboxy by hydrolysis with an alkali (sodium hydroxide, potassium hydroxide, etc.) or acid (hydrochloric acid, sulfuric acid, etc.).
(4) Conversion of carbamoyl to nitrile Carbamoyl can be converted to the corresponding nitrile by reacting it with phosphorus oxychloride or trifluoroacetic anhydride.

(5) N-alkylation, N-phenylation By reacting amino with alkyl halide or phenyl halide, it can be converted to the corresponding mono- or dialkyl-substituted amino or phenyl-substituted amino.
(6) N-sulfonylation Amino can be converted to the corresponding alkylsulfonylamino or phenylsulfonylamino by reacting it with an alkylsulfonyl halide or phenylsulfonyl halide. Alternatively, amino can be converted to the corresponding mono- or dialkyl-substituted amino by subjecting it to a reductive amination reaction.
(7) Conversion of amino to ureido By reacting amino with alkyl isocyanate, it can be converted to alkylureido. It can also be converted to ureido by reacting amino with carbamoyl halide or by reacting amino with isocyanate and then amine.

(8) Conversion of aromatic nitro to aromatic amine Aromatic nitro is converted into a reducing agent [for example, a metal reducing reagent such as sodium borohydride, lithium borohydride, lithium aluminum hydride, metal (iron, Zinc, tin, tin (II) chloride, titanium, etc.) and reduction with a transition metal (palladium-carbon, platinum, Raney nickel, etc.)] can be converted to an aromatic amine. In the case of performing catalytic reduction, ammonium formate, hydrazine, or the like can be used as a hydrogen source.
In the production described above, the produced compound of the present invention and each intermediate can be purified by usual methods such as column chromatography, recrystallization and the like. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic solvents such as toluene, ketone solvents such as acetone, and hydrocarbons such as hexane. A solvent, water, etc., or these mixed solvents are mentioned. In addition, the compound of the present invention can be converted into a pharmaceutically acceptable salt according to a conventional method, followed by recrystallization and the like.

  Since the compound of the present invention or a pharmaceutically acceptable salt thereof has a function-regulating action of CCR4 or TARC / CCL17 and / or MDC / CCL22, allergic diseases, inflammatory diseases, autoimmune diseases or cancer diseases [for example, Asthma (such as bronchial asthma), allergic rhinitis, allergic conjunctivitis, hay fever, dermatitis (such as atopic dermatitis, contact dermatitis), psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, insulin dependent Diabetes mellitus (IDDM), rejection during organ transplantation, inflammatory bowel disease (ulcerative colitis, Crohn's disease, etc.), interstitial cystitis, glomerulonephritis, sepsis, pain, adult T-cell leukemia (ATL), malignant Tumor, pulmonary fibrosis, eosinophilic pneumonia, pulmonary eosinophilic granuloma, cutaneous T-cell lymphoma, ankylosing spondylitis, coronary artery disease, pemphigoid, hojiki It is useful as a prophylactic or therapeutic drug for such diseases.

  The compound of the present invention or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include diluents, binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone), excipients (lactose, sucrose, corn starch, potassium phosphate, sorbit, glycine), A lubricant (magnesium stearate, talc, polyethylene glycol, silica), a disintegrant (potato starch), a wetting agent (sodium lauryl sulfate) and the like can be mentioned.

The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and can be used as an appropriate pharmaceutical preparation. Suitable pharmaceutical preparations for oral administration include, for example, solid preparations such as tablets, granules, capsules, powders, solution preparations, suspension preparations or emulsion preparations. Suitable pharmaceutical preparations for parenteral administration include suppositories, injectable or instilled preparations using distilled water for injection, physiological saline or aqueous dextrose, or inhalants.
The dose of the compound of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration method, patient age, body weight, and condition, but is usually about 0.003 to 100 mg / kg per day, preferably about 0.00. It is preferable to set it to 01-30 mg / kg, especially about 0.05-10 mg / kg.

  EXAMPLES Hereinafter, although an Example and a reference example demonstrate this invention in detail, this invention is not limited at all by these.

（１）テレフタル酸モノメチルエステル１０ｇのＴＨＦ１８５ｍｌ溶液に氷冷下でＮ，Ｎ’−カルボニルジイミダゾール９．９ｇを加え、室温下で終夜攪拌した。反応液に氷冷下でマロン酸モノ（ｐ‐ニトロベンジル）エステルマグネシウム塩３０．６ｇを加え、５０〜６０℃で４時間攪拌した。反応液に酢酸エチル５００ｍｌを加え、塩酸、水、飽和重曹水および飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を留去した。残渣にジイソプロピルエーテルとヘキサンを加えて固化した。固形物を濾取し、ヘキサン／酢酸エチル（４／１）で洗浄して乾燥し、４−［２−（４−ニトロ−ベンジルオキシカルボニル）−アセチル］−ベンゼンカルボン酸メチルエステル１７．２ｇを無色粉末として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３５８［Ｍ＋Ｈ］⁺

Example 1

(1) To a solution of 10 g of terephthalic acid monomethyl ester in 185 ml of THF was added 9.9 g of N, N′-carbonyldiimidazole under ice cooling, and the mixture was stirred overnight at room temperature. 30.6 g of malonic acid mono (p-nitrobenzyl) ester magnesium salt was added to the reaction solution under ice cooling, and the mixture was stirred at 50 to 60 ° C. for 4 hours. To the reaction mixture was added 500 ml of ethyl acetate, washed with hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was evaporated. Diisopropyl ether and hexane were added to the residue and solidified. The solid was collected by filtration, washed with hexane / ethyl acetate (4/1) and dried to give 17.2 g of 4- [2- (4-nitro-benzyloxycarbonyl) -acetyl] -benzenecarboxylic acid methyl ester. Obtained as a colorless powder.
APCI-MS (m / e): 358 [M + H] ⁺

(2) A solution of 17.2 g of 4- [2- (4-nitro-benzyloxycarbonyl) -acetyl] -benzenecarboxylic acid methyl ester and 3.8 g of 3-aminopyrazole in 82 ml of acetic acid is heated under reflux for 2.5 hours. Stir. The reaction solution was allowed to stand at room temperature overnight and then stirred again for 2.5 hours under heating and reflux. The reaction mixture was concentrated under reduced pressure, 200 ml of ethyl acetate was added, insoluble matter was collected by filtration, dried under reduced pressure, and 4- (7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidine-5- Yl) -benzenecarboxylic acid methyl ester (12.3 g) was obtained as a light brown powder.
APCI-MS (m / e): 270 [M + H] ⁺

(3) 4- (7-oxo-4,7-dihydro-pyrazolo [1,5-a] pyrimidin-5-yl) -benzenecarboxylic acid methyl ester (7.1 g) with diethylaniline (8.5 ml) and phosphorus oxychloride (20) 0.6 g was added and stirred at 80 ° C. for 3 hours. The reaction solution was allowed to cool and diethyl ether was added to wash insolubles. The insoluble material was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The precipitated crystals were washed with diethyl ether and dried under reduced pressure to obtain 6.30 g of 4- (7-chloro-pyrazolo [1,5-a] pyrimidin-5-yl) -benzenecarboxylic acid methyl ester as a yellow powder. .
APCI-MS (m / e): 288/290 [M + H] ⁺

(4) 2,4-Dichlorobenzylamine 4 in 1,4-dioxane 40 ml solution of 6.3 g of 4- (7-chloro-pyrazolo [1,5-a] pyrimidin-5-yl) -benzenecarboxylic acid methyl ester 0.6 g and diisopropylethylamine 3.8 ml were added, and the mixture was stirred at 60 ° C. for 3 hours and at 90 ° C. for 4 hours. After allowing to cool, chloroform was added to the reaction mixture, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was evaporated. After adding diisopropyl ether to the residue, the crystals were collected by filtration and dried under reduced pressure to give 4- [7- (2,4-dichloro-benzylamino) -pyrazolo [1,5-a] pyrimidin-5-yl]- 9.1 g of benzenecarboxylic acid methyl ester was obtained as a pale yellow powder.
APCI-MS (m / e) : 427/429 [M + H] +

(5) 2- [7- (2,4-Dichloro-benzylamino) -pyrazolo [1,5-a] pyrimidin-5-yl] -benzenecarboxylic acid methyl ester in a methanol 250 ml solution with 2N hydroxide 50 ml of an aqueous sodium solution was added, and the mixture was stirred at 50-60 ° C. overnight. The reaction solution was allowed to cool, poured into 100 g of citric acid / 1.5 L of an aqueous solution, and stirred for 30 minutes. The insoluble material was collected by filtration, washed with water and ethyl acetate / diisopropyl ether, and dried to give 4- [7- (2,4-dichloro-benzylamino) -pyrazolo [1,5-a] pyrimidin-5-yl. 8.4 g of benzenecarboxylic acid was obtained as a light brown powder.
APCI-MS (m / e): 413/415 [M + H] ⁺

(6) 4- [7- (2,4-dichloro-benzylamino) -pyrazolo [1,5-a] pyrimidin-5-yl] -benzenecarboxylic acid 124 mg, methylpiperazine 50 mg in DMF 1.5 ml solution at room temperature Then, 79 mg of diethylphosphorocyanidate and 51 mg of triethylamine were added dropwise and stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. Recrystallization from ethyl acetate / diisopropyl ether yields {4- [7- (2,4-dichloro-benzylamino) -pyrazolo [1,5-a] pyrimidin-5-yl] -phenyl}-(4-methyl- 148 mg of piperazin-1-yl) -methanone were obtained as pale yellow crystals.
APCI-MS (m / e): 495/497 [M + H] ⁺

Examples 2-29
The following compounds were obtained by reacting and treating in the same manner as in the examples and reference examples described above and below.

［５−（４−アミノ−フェニル）−ピラゾロ［１，５−ａ］ピリミジン−７−イル］−（２，４−ジクロロ−ベンジル）−アミン１００ｍｇ、（Ｒ）−ピログルタミン酸３４ｍｇをＤＭＦ１ｍｌに溶かし、氷冷下で１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩６５ｍｇ、１−ヒドロキシベンゾトリアゾール・１水和物５１ｍｇを加え、室温下で終夜攪拌した。反応液にクロロホルムを加え、飽和重曹水および飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１００／０→９５／５）で精製し、５−オキソ−ピロリジン−２−カルボン酸｛４−［７−（２，４−ジクロロ−ベンジルアミノ）−ピラゾロ［１，５−ａ］ピリミジン−５−イル］−フェニル｝−アミド８６ｍｇを淡黄色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４９５／４９７［Ｍ＋Ｈ］⁺ Example 30

100 mg of [5- (4-amino-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl]-(2,4-dichloro-benzyl) -amine and 34 mg of (R) -pyroglutamic acid were dissolved in 1 ml of DMF. Under ice-cooling, 65 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 51 mg of 1-hydroxybenzotriazole monohydrate were added, and the mixture was stirred overnight at room temperature. Chloroform was added to the reaction mixture, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform / methanol = 100/0 → 95/5) to give 5-oxo-pyrrolidine-2-carboxylic acid {4- [7- (2,4-dichloro-benzylamino)- 86 mg of pyrazolo [1,5-a] pyrimidin-5-yl] -phenyl} -amide was obtained as a pale yellow solid.
APCI-MS (m / e): 495/497 [M + H] ⁺

実施例３０と同様に反応、処理することにより、上記化合物を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４８２／４８４［Ｍ＋Ｈ］⁺ Example 31

The above compound was obtained by reacting and treating in the same manner as in Example 30.
APCI-MS (m / e): 482/484 [M + H] ⁺

（１）［５−（４−アミノ−フェニル）−ピラゾロ［１，５−ａ］ピリミジン−７−イル］−（２，４−ジクロロ−ベンジル）−アミン２００ｍｇのＤＭＦ１ｍｌ溶液に２−クロロエチルイソシアネート８８μｌを加え、室温で４日間攪拌した。反応液にクロロホルムを加え、飽和重曹水および飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を留去した。残渣固形物に酢酸エチルおよびジエチルエーテルを加えて粉砕後、乾燥し、１−（２−クロロ−エチル）−３−｛４−［７−（２，４−ジクロロ−ベンジルアミノ）−ピラゾロ［１，５−ａ］ピリミジン−５−イル］−フェニル｝−ウレア１２８ｍｇを淡黄色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４８９／４９１［Ｍ＋Ｈ］⁺

Example 32

(1) 2-chloroethyl isocyanate in a solution of 200 mg of [5- (4-amino-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl]-(2,4-dichloro-benzyl) -amine in 1 ml of DMF 88 μl was added and stirred at room temperature for 4 days. Chloroform was added to the reaction mixture, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residual solid was crushed by adding ethyl acetate and diethyl ether, dried, 1- (2-chloro-ethyl) -3- {4- [7- (2,4-dichloro-benzylamino) -pyrazolo [1 , 5-a] pyrimidin-5-yl] -phenyl} -urea was obtained as a pale yellow solid.
APCI-MS (m / e): 489/491 [M + H] ⁺

(2) 1- (2-Chloro-ethyl) -3- {4- [7- (2,4-dichloro-benzylamino) -pyrazolo [1,5-a] pyrimidin-5-yl] -phenyl}- 120 mg of urea was dissolved in 2 ml of DMF, 50 mg of sodium hydride (60%) was added under ice cooling, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over sodium sulfate, and the solvent was distilled off. The residual solid was triturated with methanol and diethyl ether and 1- {4- [7- (2,4-dichloro-benzylamino) -pyrazolo [1,5-a] pyrimidin-5-yl] -phenyl} -64 mg of imidazolidin-2-one was obtained as a pale yellow solid.
APCI-MS (m / e): 453/455 [M + H] ⁺

（１）［５−（４−アミノ−フェニル）−ピラゾロ［１，５−ａ］ピリミジン−７−イル］−（２，４−ジクロロ−ベンジル）−アミン９６ｍｇのＴＨＦ５ｍｌ溶液に３−クロロプロピルスルホニルクロリド８８５ｍｇを加え、４０℃で１日間攪拌した。反応液に酢酸エチルを加え、水洗し、硫酸マグネシウムで乾燥後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１００／０→６０／４０）で精製し、酢酸エチル／ヘキサンで結晶化した後、乾燥させ、３−クロロ−プロパン−１−スルホン酸｛４−［７−（２，４−ジクロロ−ベンジルアミノ）−ピラゾロ［１，５−ａ］ピリミジン−５−イル］−フェニル｝−アミド２３ｍｇを微黄色結晶として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５２４／５２６［Ｍ＋Ｈ］⁺

（２）化合物（１）を実施例３２（２）と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４８８／４９０［Ｍ＋Ｈ］⁺ Example 33

(1) [5- (4-Amino-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl]-(2,4-dichloro-benzyl) -amine in a solution of 96 mg of THF in 3-chloropropylsulfonyl 885 mg of chloride was added and stirred at 40 ° C. for 1 day. Ethyl acetate was added to the reaction solution, washed with water and dried over magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100/0 → 60/40), crystallized from ethyl acetate / hexane, dried, and 3-chloro-propane-1-sulfonic acid {4- 23 mg of [7- (2,4-dichloro-benzylamino) -pyrazolo [1,5-a] pyrimidin-5-yl] -phenyl} -amide was obtained as slightly yellow crystals.
APCI-MS (m / e): 524/526 [M + H] ⁺

(2) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Example 32 (2).
APCI-MS (m / e): 488/490 [M + H] ⁺

［５−（４−アミノ−フェニル）−ピラゾロ［１，５−ａ］ピリミジン−７−イル］−（２，４−ジクロロ−ベンジル）−アミン１１５ｍｇのピリジン１ｍｌ溶液にジメチルアミノカルバモイルクロリド１２９ｍｇを加え、室温下で１日間攪拌した。反応液に酢酸エチルを加え、クエン酸水溶液、水、飽和重曹水および飽和食塩水で順次洗浄し、硫酸マグネシウムで乾燥後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９０／１０→２０／８０）で精製し、酢酸エチル／ヘキサンで固化した後、乾燥させ、３−｛４−［７−（２，４−ジクロロ−ベンジルアミノ）−ピラゾロ［１，５−ａ］ピリミジン−５−イル］−フェニル｝−１，１−ジメチル−ウレア６２ｍｇを淡褐色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４５５／４５７［Ｍ＋Ｈ］⁺ Example 34

To a solution of 115 mg of [5- (4-amino-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl]-(2,4-dichloro-benzyl) -amine in 1 ml of pyridine was added 129 mg of dimethylaminocarbamoyl chloride. And stirred at room temperature for 1 day. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 90/10 → 20/80), solidified with ethyl acetate / hexane, dried, and 3- {4- [7- (2,4-dichloro). 62 mg of -benzylamino) -pyrazolo [1,5-a] pyrimidin-5-yl] -phenyl} -1,1-dimethyl-urea were obtained as a light brown solid.
APCI-MS (m / e): 455/457 [M + H] ⁺

Examples 35-43
The following compounds were obtained by reacting and treating in the same manner as in the examples and reference examples described above and below.

（２−クロロ−チエノ［３，２−ｄ］ピリミジン−４−イル）−（２，４−ジクロロ−ベンジル）−アミン１５０ｍｇ、４−（４−エチル−モルホリン−２−イル）ボロン酸１３５ｍｇをジメトキシエタン７ｍｌおよびエタノール１ｍｌの混液に溶かし、この溶液に窒素雰囲気下、テトラキストリフェニルホスフィンパラジウム２０３ｍｇおよび１Ｍ炭酸ナトリウム水溶液１ｍｌを加え、８０℃で終夜攪拌した。放冷後、反応液に２Ｎ塩酸を加えて弱酸性とし、炭酸カリウムを加えて液性を塩基性に戻した後に酢酸エチルで３回抽出した。有機層を合わせ、硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（Ｓｉカラム：ヘキサン／酢酸エチル＝７０／３０→０／１００，ＮＨカラム：ヘキサン／酢酸エチル＝１００／０→６０／４０）で２回精製し、（２，４−ジクロロ−ベンジル）−｛２−［４−（４−エチル−モルホリン−２−イル）−フェニル］−チエノ［３，２−ｄ］ピリミジン−４−イル｝−アミン９４ｍｇを白色固体として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４９９／５０１［Ｍ＋Ｈ］⁺ Example 44

150 mg of (2-chloro-thieno [3,2-d] pyrimidin-4-yl)-(2,4-dichloro-benzyl) -amine, 135 mg of 4- (4-ethyl-morpholin-2-yl) boronic acid Dissolved in a mixed solution of 7 ml of dimethoxyethane and 1 ml of ethanol, 203 mg of tetrakistriphenylphosphine palladium and 1 ml of 1M aqueous sodium carbonate solution were added to this solution under a nitrogen atmosphere and stirred at 80 ° C. overnight. After allowing to cool, the reaction solution was made weakly acidic by adding 2N hydrochloric acid, and potassium carbonate was added to return the solution to basic, followed by extraction with ethyl acetate three times. The organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified twice by silica gel column chromatography (Si column: hexane / ethyl acetate = 70/30 → 0/100, NH column: hexane / ethyl acetate = 100/0 → 60/40) (2,4- 94 mg of dichloro-benzyl)-{2- [4- (4-ethyl-morpholin-2-yl) -phenyl] -thieno [3,2-d] pyrimidin-4-yl} -amine were obtained as a white solid.
APCI-MS (m / e) : 499/501 [M + H] +

化合物（１）を実施例４４と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５１３／５１５［Ｍ＋Ｈ］⁺ Example 45

Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Example 44.
APCI-MS (m / e): 513/515 [M + H] ⁺

（１）化合物（１）を実施例４４と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５８２／５８４［Ｍ＋Ｈ］⁺

Example 46

(1) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Example 44.
APCI-MS (m / e): 582/584 [M + H] ⁺

(2) (2,4-Dichloro-benzyl)-{5- [4- (4-ethyl-morpholin-2-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl} -carbamine 122 mg of acid tert-butyl ester was dissolved in 2 ml of methylene chloride, 1 ml of trifluoroacetic acid was added under ice cooling, and the mixture was stirred for 2 hours. Further, 1 ml of trifluoroacetic acid was added and stirred for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layers were combined and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate 100/0 → 50/50) and (2,4-dichloro-benzyl)-{5- [4- (4-ethyl-morpholin-2-yl) 77 mg of -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl} -amine were obtained as a pale yellow oil.
APCI-MS (m / e): 482/484 [M + H] ⁺

（１）化合物（１）を実施例４４と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４３０／４３２［Ｍ＋Ｈ］⁺

Example 47

(1) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Example 44.
APCI-MS (m / e): 430/432 [M + H] ⁺

（３）化合物（１）を実施例１（４）と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４８３／４８５［Ｍ＋Ｈ］⁺ (2) 2- {4- [4- (2,4-Dichloro-benzylamino) -thieno [3,2-d] pyrimidin-2-yl] phenyl} -ethanol in 76 ml of THF at 0 ° C. in methane chloride 21 μM sulfonyl and 49 μl triethylamine were added, and the mixture was stirred at room temperature for 1 hour. Methanesulfonyl chloride (10.5 μM) and triethylamine (30 μl) were added, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. Ethyl acetate was added to the residual solid, which was pulverized and then dried. Methanesulfonic acid 2- {4- [4- (2,4-dichloro-benzylamino) -thieno [3,2-d] pyrimidine 65 mg of -2-yl] phenyl} -ethyl ester were obtained as a colorless solid.
APCI-MS (m / e): 508/510 [M + H] ⁺

(3) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Example 1 (4).
APCI-MS (m / e): 483/485 [M + H] ⁺

Examples 48-62
The following compounds were obtained by reacting and treating in the same manner as in the examples and reference examples described above and below.

（１）イソキサゾール７５ｇのエタノール３００溶液ｍｌに、ナトリウムエトキシド（２１ｗ％エタノール溶液）３６９ｇを８℃以下で２時間かけてゆっくり加え、そのまま４５分攪拌した。反応液に４〜６℃で酢酸２２．５ｇ、２−アミノマロン酸ジエチル塩酸塩１４３ｇおよび酢酸ナトリウム６１．４ｇを順次加え、室温で終夜攪拌した。減圧濃縮後、残渣にクロロホルムを加えて水洗後、乾燥した。残渣にエタノール１．１４Ｌ、ナトリウムエトキシド（２１ｗ％エタノール溶液）２６２ｍｌを加え、終夜攪拌した。反応液に酢酸４２．２ｇを加えて減圧濃縮した。残渣に水を加えた後、飽和重曹水を加えてpH７とし、クロロホルムを用いて抽出した後、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）で精製し、３−アミノ−１Ｈ−ピロール−２−カルボン酸エチルエステルを６０．７ｇ得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：１５５（Ｍ＋Ｈ）⁺

Example 63

(1) To a solution of 75 g of isoxazole in 300 ml of ethanol, 369 g of sodium ethoxide (21 w% ethanol solution) was slowly added at 8 ° C. or less over 2 hours, and stirred as it was for 45 minutes. To the reaction solution, 22.5 g of acetic acid, 143 g of 2-aminomalonic acid diethyl hydrochloride and 61.4 g of sodium acetate were sequentially added at 4 to 6 ° C., and the mixture was stirred at room temperature overnight. After concentration under reduced pressure, chloroform was added to the residue, washed with water, and dried. To the residue, 1.14 L of ethanol and 262 ml of sodium ethoxide (21 w% ethanol solution) were added and stirred overnight. To the reaction solution, 42.2 g of acetic acid was added and concentrated under reduced pressure. Water was added to the residue, saturated aqueous sodium hydrogen carbonate was added to adjust the pH to 7, and the mixture was extracted with chloroform, purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and 3-amino-1H-pyrrole. 60.7 g of 2-carboxylic acid ethyl ester was obtained.
APCI-MS (m / e): 155 (M + H) ⁺

（３）３−ウレイド−１Ｈ−ピロロ−２−カルボン酸エチルエステル６９．４ｇに６％水酸化ナトリウム水溶液９５０ｍｌを加え、加熱還流下で３０分攪拌した。放冷後、反応液に濃塩酸を加えてｐＨ６とし、攪拌後に析出物をろ取した。少量の水とメタノールで洗浄後、減圧濃縮し、トルエンで共沸し、１，５−ジヒドロ−ピロロ［３，２−ｄ］ピリミジン−２，４−ジオンを３２．０ｇ得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：１５２（Ｍ＋Ｈ）⁺

(2) 3-Amino-1H-pyrrole-2-carboxylic acid ethyl ester (82.6 g) was dissolved in a solution of 500 ml of acetic acid and 50 ml of water, and a 250 ml aqueous solution of 130.4 g of potassium cyanate was added over 1 hour. For 1 hour. After concentration under reduced pressure, 500 ml of water and 200 ml of ethyl acetate were added, followed by neutralization with potassium carbonate. The precipitate was collected by filtration, washed with water and ethyl acetate, and dried to obtain 63.8 g of 3-ureido-1H-pyrrolo-2-carboxylic acid ethyl ester.
APCI-MS (m / e): 198 (M + H) ⁺

(3) 950 ml of 6% aqueous sodium hydroxide solution was added to 69.4 g of 3-ureido-1H-pyrrolo-2-carboxylic acid ethyl ester, and the mixture was stirred for 30 minutes under heating to reflux. After allowing to cool, concentrated hydrochloric acid was added to the reaction solution to adjust to pH 6. After stirring, the precipitate was collected by filtration. After washing with a small amount of water and methanol, the mixture was concentrated under reduced pressure and azeotroped with toluene to obtain 32.0 g of 1,5-dihydro-pyrrolo [3,2-d] pyrimidine-2,4-dione.
APCI-MS (m / e): 152 (M + H) ⁺

(4) 231 ml of 1N aqueous sodium hydroxide solution was added to 35.0 g of 1,5-dihydro-pyrrolo [3,2-d] pyrimidine-2,4-dione, stirred for a while and then concentrated under reduced pressure, and toluene was added to the residue. Azeotropic. After slowly adding 239 g of phenylphosphonic dichloride to the residue, the temperature was raised to 180 ° C., and the mixture was stirred for 3 hours. Further, 100 g of phenylphosphonic dichloride was slowly added and stirred overnight. The reaction solution was slowly poured into stirring ice water and extracted by adding ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate, dried and concentrated under reduced pressure. The residue was crystallized by adding ethyl acetate / diisopropyl ether to obtain 19.96 g of 2,4-dichloro-5H-pyrrolo [3,2-d] pyrimidine.
APCI-MS (m / e): 188/190 (M + H) ⁺

（６）２，４−ジクロロ−５−メチル−５Ｈ−ピロロ［３，２−ｄ］ピリミジンを実施例１（３）と同様に反応・処理することにより、（２−クロロ−５−メチル−５Ｈ−ピロロ［３，２−ｄ］ピリミジン−４−イル）−（２，４−ジクロロ−ベンジル）−アミンを２０．６ｇ得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３４１／３４３（Ｍ＋Ｈ）⁺

(5) To a solution of 19.9 g of 2,4-dichloro-5H-pyrrolo [3,2-d] pyrimidine in 530 ml of acetonitrile, slowly add 5.08 g of 60% sodium hydride under ice cooling, and stir at room temperature for 30 minutes. did. To the reaction solution, 18.03 g of methyl iodide was added dropwise at 8 ° C. and stirred overnight at room temperature. The insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether to obtain 11.0 g of 2,4-dichloro-5-methyl-5H-pyrrolo [3,2-d] pyrimidine.
APCI-MS (m / e): 202/204 (M + H) ⁺

(6) By reacting and treating 2,4-dichloro-5-methyl-5H-pyrrolo [3,2-d] pyrimidine in the same manner as in Example 1 (3), (2-chloro-5-methyl- 20.6 g of 5H-pyrrolo [3,2-d] pyrimidin-4-yl)-(2,4-dichloro-benzyl) -amine was obtained.
APCI-MS (m / e): 341/343 (M + H) ⁺

（８）化合物（１）を実施例１（５）と同様に反応、処理して、対応するカルボン酸化合物とした後、実施例１（６）と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５２３／５２５（Ｍ＋Ｈ）⁺ (7) Compound (3) was obtained by reacting and treating compound (1) and compound (2) in the same manner as in Example 44.
APCI-MS (m / e): 441/443 (M + H) ⁺

(8) The compound (1) is reacted and treated in the same manner as in Example 1 (5) to give the corresponding carboxylic acid compound, and then reacted and treated in the same manner as in Example 1 (6) to give the compound ( 2) was obtained.
APCI-MS (m / e): 523/525 (M + H) ⁺

（１）４−ニトロ−３−ピラゾール（１）５１．０６ｇのメタノール５１５ｍｌ懸濁液に、濃硫酸１０．１ｍｌを加え、加熱還流下で終夜攪拌した。反応液を氷冷し、飽和重曹水を加えて液性をアルカリ性とし、溶液中のメタノールを減圧留去した。残渣から酢酸エチルで６回抽出し、有機層を合わせて乾燥後、溶媒留去した。残渣を酢酸エチル／ヘキサンで粉砕し、乾燥し、化合物（２）４７．６１ｇを無色粉末として得た。
ＥＳＩ−ＭＳ（ｍ／ｅ）：１７０（Ｍ−Ｈ）^-

Example 64

(1) 4-Nitro-3-pyrazole (1) To a suspension of 51.06 g of methanol in 515 ml of methanol was added 10.1 ml of concentrated sulfuric acid, and the mixture was stirred overnight with heating under reflux. The reaction solution was ice-cooled, saturated aqueous sodium hydrogen carbonate was added to make the solution alkaline, and methanol in the solution was distilled off under reduced pressure. The residue was extracted 6 times with ethyl acetate, and the organic layers were combined, dried and evaporated. The residue was pulverized with ethyl acetate / hexane and dried to obtain 47.61 g of Compound (2) as a colorless powder.
ESI-MS (m / e): 170 (M−H) ⁻

(2) 6.71 g of metallic sodium was carefully and slowly added to 830 ml of dried methanol, and the metal sodium piece was dissolved and then ice-cooled. Compound (1) 43.61g was added to this solution, then methyl iodide 43.64ml was added, and it stirred at 60-70 degreeC for 4 hours. The reaction mixture was concentrated under reduced pressure, chloroform was added to the residue, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 1) to obtain 17.0 g of compound (2) as a yellow oil and 26.8 g of compound (3) as a colorless powder. .
Compound (2):
APCI-MS (m / e): 186 (M + H) ^{+
_{1 HNMR (500MH Z / DMSO-}} d 6) δ (ppm): 3.95 (s, 3H), 4.00 (s, 3H), 8.37 (s, 1H)
Compound (3):
APCI-MS (m / e): 186 (M + H) ^{+
_{1 HNMR (500MH Z / DMSO-}} d 6) δ (ppm): 3.94 (s, 3H), 4.00 (s, 3H), 8.95 (s, 1H)

（４）化合物（１）１９．８ｇのメタノール３５０ｍｌ懸濁液に、１０％パラジウム−炭素を加え、中圧還元装置を用いて、室温、水素ガス下（５０psi）で終夜攪拌した。４Ｎ塩酸／酢酸エチル１２０ｍｌに反応液を注ぎ、不溶物をセライトを用いてろ過した。ろ液を減圧濃縮し、残渣に酢酸エチルを加えて粉砕、乾燥し、化合物（２）１９．９５ｇを淡橙色粉末として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：１４１（Ｍ＋Ｈ）⁺

(3) 17.0 g of compound (1) was added to 285 ml of 28% aqueous ammonia, and the mixture was stirred at 60 ° C. for 6 hours. The reaction solution was allowed to cool and concentrated under reduced pressure to obtain 16.0 g of Compound (2) as a colorless solid.
ESI-MS (m / e): 169 (M−H) ⁻

(4) Compound (1) 10% palladium-carbon was added to a suspension of 19.8 g of methanol in 350 ml, and the mixture was stirred overnight at room temperature under hydrogen gas (50 psi) using a medium pressure reduction apparatus. The reaction solution was poured into 120 ml of 4N hydrochloric acid / ethyl acetate, and the insoluble material was filtered through celite. The filtrate was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was pulverized and dried to obtain 19.95 g of Compound (2) as a pale orange powder.
APCI-MS (m / e): 141 (M + H) ⁺

（６）化合物（１）１４．０ｇとオキシ塩化リン８４ｍｌの懸濁液に、ジエチルアニリン１６．９ｍｌをゆっくり加え、加熱還流下で２２時間攪拌した。反応液を放冷し、減圧濃縮し、トルエンで２回共沸した。残渣を氷水中にゆっくり注ぎ、クロロホルムを加えて攪拌した。混合物を分液し、クロロホルム層を飽和食塩水で洗浄し、乾燥後、溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１→２：１）で精製し、化合物（２）１５．３ｇを黄色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２０３／２０５（Ｍ＋Ｈ）⁺

(5) 17.3 g of compound (1) and 32.9 g of urea were added to the reaction vessel and stirred at 200 ° C. for 1 hour while heating. After allowing to cool, 330 ml of warm 1N aqueous sodium hydroxide solution was added, and the raw materials were dissolved, then ice-cooled, and 55 ml of acetic acid was added to adjust the liquidity to pH 4. The precipitated crystals were collected by filtration, washed 3 times with water and once with diethyl ether, and dried to obtain 12.6 g of compound (2) as a colorless powder.
APCI-MS (m / e): 189 (M + Na) ⁺

(6) 16.9 ml of diethylaniline was slowly added to a suspension of 14.0 g of compound (1) and 84 ml of phosphorus oxychloride, and the mixture was stirred for 22 hours with heating under reflux. The reaction was allowed to cool, concentrated under reduced pressure, and azeotroped twice with toluene. The residue was slowly poured into ice water, and chloroform was added and stirred. The mixture was separated, and the chloroform layer was washed with saturated brine, dried and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 2: 1) to obtain 15.3 g of Compound (2) as a yellow solid.
APCI-MS (m / e): 203/205 (M + H) ⁺

（８）化合物（１）および化合物（２）を実施例４４と同様に反応、処理することにより、化合物（３）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４４２／４４４（Ｍ＋Ｈ）⁺

(7) To a solution of 14.3 g of compound (1) in 260 ml of 1,4-dioxane, 18.6 g of 2,4-dichlorobenzylamine (2) and 17.8 g of triethylamine were sequentially added under ice cooling, and the mixture was stirred at room temperature for 4 hours. Stir. Ethyl acetate was added to the reaction mixture, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 2). Trituration with diethyl ether and drying gave 20.0 g of compound (2) as a colorless powder.
APCI-MS (m / e): 342/344 (M + H) ⁺

(8) Compound (3) was obtained by reacting and treating compound (1) and compound (2) in the same manner as in Example 44.
APCI-MS (m / e): 442/444 (M + H) ⁺

(9) Compound (1) is reacted and treated in the same manner as in Example 1 (5) to give the corresponding carboxylic acid compound, and then reacted with 2 (S) -cyanopyrrolidine in the same manner as in Example 1 (6). The compound (2) was obtained by processing.
APCI-MS (m / e): 524/526 (M + H) ⁺

Examples 65-72
The following compounds were obtained by reacting and treating in the same manner as in the examples and reference examples described above and below.

（１）試薬（３）７．８ｍｇ、化合物（４）６．７ｍｇおよびｔｅｒｔ−ブトキシナトリウム１５ｍｇに、窒素置換下で、化合物（１）５０ｍｇ、化合物（２）４１μｌの１，４−ジオキサン３ｍｌ溶液を滴下後、８０℃で終夜攪拌した。放冷後、反応液に酢酸エチルを加え、水、飽和食塩水で洗浄後に乾燥し、溶媒留去した。ＮＨ−シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８３：１７→６５：３５）で精製し、化合物（５）３１ｍｇを黄色アモルファスとして得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５９７／５９９（Ｍ＋Ｈ）⁺

（２）化合物（１）を実施例４６と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４９７／４９９（Ｍ＋Ｈ）⁺ Example 73

(1) Reagent (3) 7.8 mg, Compound (4) 6.7 mg and tert-butoxy sodium 15 mg under nitrogen substitution, Compound (1) 50 mg, Compound (2) 41 μl of 1,4-dioxane 3 ml solution After dropwise addition, the mixture was stirred at 80 ° C. overnight. After allowing to cool, ethyl acetate was added to the reaction mixture, washed with water and saturated brine, dried, and the solvent was evaporated. Purification by NH-silica gel column chromatography (hexane: ethyl acetate = 83: 17 → 65: 35) gave 31 mg of compound (5) as a yellow amorphous.
APCI-MS (m / e): 597/599 (M + H) ⁺

(2) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Example 46.
APCI-MS (m / e): 497/499 (M + H) ⁺

化合物（１）１００ｍｇをＴＨＦ２ｍｌおよび塩化メチレン２ｍｌの溶液に溶解し、ヨウ化メチル７１ｍｇを加えて、室温で２日間攪拌した。反応液を減圧濃縮し、黄色固形物を得た。メタノール／酢酸エチルから再結晶を行い、化合物（２）９２ｍｇを無色結晶として得た。
ＥＳＩ−ＭＳ（ｍ／ｅ）：４８２／４８４（Ｍ−Ｈ）^- Example 74

100 mg of compound (1) was dissolved in a solution of 2 ml of THF and 2 ml of methylene chloride, 71 mg of methyl iodide was added, and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure to obtain a yellow solid. Recrystallization from methanol / ethyl acetate gave 92 mg of compound (2) as colorless crystals.
ESI-MS (m / e): 482/484 (MH) ⁻

Examples 75-82
The following compounds were obtained by reacting and treating in the same manner as in the examples and reference examples described above and below.

化合物（１）９４ｍｇのエタノール０．８ｍｌおよび水０．２ｍｌの溶液にビス（２−クロロエチル）エーテル２８μｌ、ヨウ化ナトリウム３１ｍｇ、炭酸カリウム８３ｍｇを加え、マイクロウエーブ装置を用い、１５０℃で２時間照射した。反応液を濃縮後、残渣にクロロホルムを加えて水洗し、乾燥後に溶媒留去した。薄層シリカゲルプレート精製（クロロホルム：メタノール＝９：１）を行い、化合物（２）３６ｍｇを淡緑色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５５１／５５３（Ｍ＋Ｈ）⁺ Example 83

Compound (1) To a solution of 94 mg of ethanol 0.8 ml and water 0.2 ml was added 28 μl of bis (2-chloroethyl) ether, 31 mg of sodium iodide, 83 mg of potassium carbonate, and irradiated at 150 ° C. for 2 hours using a microwave apparatus. did. After concentrating the reaction solution, chloroform was added to the residue and washed with water. After drying, the solvent was distilled off. Thin layer silica gel plate purification (chloroform: methanol = 9: 1) was performed to obtain 36 mg of compound (2) as a pale green solid.
APCI-MS (m / e): 551/553 (M + H) ⁺

（１）化合物（１）を実施例４４と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４９５／４９７（Ｍ＋Ｈ）⁺

（２）化合物（１）１２０ｍｇの１，４―ジオキサン２ｍｌ溶液に、濃塩酸２ｍｌを加え、６０℃で終夜攪拌した。更に１００℃で終夜攪拌した。反応液減圧濃縮し、ジイソプロピルエーテル／エタノールで粉砕し、化合物（２）９５ｍｇを橙色粉末として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４１４／４１６（Ｍ−Ｈ）^―

（３）化合物（１）４５ｍｇ、（Ｌ）−プロリンアミド１３．７ｍｇのＤＭＦ２ｍｌ溶液に、室温でジエチルホスホロシアニデート２４．５ｍｇ、トリエチルアミン２４．５ｍｇを順次加え、終夜攪拌した。反応液に酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄、乾燥し、溶媒留去した。ＮＨ−シリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０→９５：５）にて精製し、化合物（２）３８．２ｍｇを黄色粉末として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５１０／５１２（Ｍ＋Ｈ）⁺ Example 84

(1) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Example 44.
APCI-MS (m / e): 495/497 (M + H) ⁺

(2) Compound (1) To a solution of 120 mg of 1,4-dioxane in 2 ml was added 2 ml of concentrated hydrochloric acid, and the mixture was stirred at 60 ° C. overnight. The mixture was further stirred at 100 ° C. overnight. The reaction mixture was concentrated under reduced pressure and triturated with diisopropyl ether / ethanol to obtain 95 mg of Compound (2) as an orange powder.
APCI-MS (m / e): 414/416 (M−H) ⁻

(3) To a solution of 45 mg of compound (1) and 13.7 mg of (L) -prolinamide in 2 ml of DMF, 24.5 mg of diethylphosphorocyanidate and 24.5 mg of triethylamine were sequentially added at room temperature and stirred overnight. Ethyl acetate was added to the reaction mixture, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried, and the solvent was evaporated. Purification by NH-silica gel column chromatography (chloroform: methanol = 100: 0 → 95: 5) gave 38.2 mg of compound (2) as a yellow powder.
APCI-MS (m / e): 510/512 (M + H) ⁺

Examples 85 to 128
The following compounds were obtained by reacting and treating in the same manner as in the examples and reference examples described above and below.

２，４−ジクロロベンジルアルコール３９ｍｇのＴＨＦ１ｍｌ溶液に６０％水素化ナトリウム１４ｍｇを０℃で加え、１時間攪拌した。反応液に化合物（１）５０ｍｇのＴＨＦ１ｍｌ溶液を加え、室温で終夜攪拌した。反応液に重曹水を加えて酢酸エチルで抽出し、乾燥し、溶媒留去した。シリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０→９２：８）で精製し、化合物（２）３２ｍｇを無色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４８２／４８４（Ｍ＋Ｈ）⁺ Example 129

To a solution of 39 mg of 2,4-dichlorobenzyl alcohol in 1 ml of THF, 14 mg of 60% sodium hydride was added at 0 ° C. and stirred for 1 hour. To the reaction solution was added 50 mg of compound (1) in 1 ml of THF, and the mixture was stirred at room temperature overnight. Sodium bicarbonate water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried and evaporated. Purification by silica gel column chromatography (chloroform: methanol = 100: 0 → 92: 8) gave 32 mg of compound (2) as a colorless solid.
APCI-MS (m / e): 482/484 (M + H) ⁺

Examples 130-153
The following compounds were obtained by reacting and treating in the same manner as in the examples and reference examples described above and below.

参考例３０の化合物（１）７０mg、（１−エトキシシクロプロポキシ）トリメチルシラン１２３μｌのメタノール２ｍｌ溶液に酢酸９０μｌ、水素化シアノホウ素ナトリウム３８．６ｍｇ、モレキュラーシーブMS３Aを加え、加熱還流下で４時間攪拌した。放冷後、反応液に酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄、乾燥し、溶媒留去した。残渣をNH−シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８０：２０→６７：３３）で精製し、化合物（２）３５．６ｍｇを微黄色粉末として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４９５／４９７（Ｍ＋Ｈ）⁺ Example 154

90 mg of acetic acid, 38.6 mg of sodium cyanoborohydride, and molecular sieve MS3A were added to 2 ml of methanol in 70 mg of the compound (1) of Reference Example 30 and 123 μl of (1-ethoxycyclopropoxy) trimethylsilane, and the mixture was stirred for 4 hours while heating under reflux. did. After allowing to cool, ethyl acetate was added to the reaction mixture, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried, and the solvent was evaporated. The residue was purified by NH-silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 67: 33) to obtain 35.6 mg of compound (2) as a slightly yellow powder.
APCI-MS (m / e): 495/497 (M + H) ⁺

（１）５−ブロモ−２−クロロピリミジン（１）３．８７ｇのエタノール５０ｍｌ溶液に、ナトリウムメタンチオレート１．６８ｇを加え、室温で４時間、６０℃で２．５時間攪拌した。反応液を減圧濃縮し、残渣に酢酸エチルを加え、水、飽和食塩水で洗浄後、乾燥し、溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→９１：９）で精製し、化合物（２）３．０２ｇを無色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２０５／２０７（Ｍ＋Ｈ）⁺

Example 155

(1) To a solution of 3.87 g of 5-bromo-2-chloropyrimidine (1) in 50 ml of ethanol was added 1.68 g of sodium methanethiolate, and the mixture was stirred at room temperature for 4 hours and at 60 ° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, washed with water and saturated brine, dried and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 91: 9) to obtain 3.02 g of compound (2) as a colorless solid.
APCI-MS (m / e): 205/207 (M + H) ⁺

（３）化合物（１）、化合物（２）を実施例４４と同様に反応、処理することにより、化合物（３）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５１７／５１９（Ｍ＋Ｈ）⁺

（４）化合物（１）２．０７ｇの塩化メチレン４０ｍｌ溶液にメタ−クロロ過安息香酸（２５％含水）２．３０ｇを加え、室温で２．５時間攪拌した。メタ−クロロ過安息香酸（２５％含水）０．４５ｇを追加し、室温で１時間攪拌した。反応液に塩化メチレンを加え、飽和重曹水、飽和食塩水で洗浄し、乾燥後に溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝７５：２５→６０：４０）で精製し、化合物（２）１．２３ｇを黄色粉末として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５４９／５５１（Ｍ＋Ｈ）⁺

(2) The compound (2) was obtained by reacting and treating the compound (1) in the same manner as in Reference Example 22 (2).
APCI-MS (m / e) : 253 (M + H) +

(3) Compound (3) was obtained by reacting and treating compound (1) and compound (2) in the same manner as in Example 44.
APCI-MS (m / e): 517/519 (M + H) ⁺

(4) To a solution of 2.07 g of compound (1) in 40 ml of methylene chloride, 2.30 g of meta-chloroperbenzoic acid (containing 25% water) was added and stirred at room temperature for 2.5 hours. 0.45 g of meta-chloroperbenzoic acid (containing 25% water) was added, and the mixture was stirred at room temperature for 1 hour. Methylene chloride was added to the reaction mixture, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 75: 25 → 60: 40) to obtain 1.23 g of compound (2) as a yellow powder.
APCI-MS (m / e): 549/551 (M + H) ⁺

（６）化合物（１）を実施例４６（２）と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４８３／４８５（Ｍ＋Ｈ）⁺ (5) Compound (1) 18.7 mg of 3-dimethylaminopyrrolidine was added to a solution of 45 mg of 1,4-dioxane in 3 ml and stirred at 80 ° C. overnight. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, dried and evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol = 96: 4 → 92: 8) to obtain 42 mg of compound (2) as a brown amorphous substance.
APCI-MS (m / e): 583/585 (M + H) ⁺

(6) The compound (2) was obtained by reacting and treating the compound (1) in the same manner as in Example 46 (2).
APCI-MS (m / e): 483/485 (M + H) ⁺

Examples 156-171
The following compounds were obtained by reacting and treating in the same manner as in the examples and reference examples described above and below.

（１）化合物（１）、化合物（２）を実施例４４と同様に反応、処理することにより、化合物（３）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：６３９／６４１（Ｍ＋Ｈ）⁺

Example 172

(1) Compound (3) was obtained by reacting and treating compound (1) and compound (2) in the same manner as in Example 44.
APCI-MS (m / e): 639/641 (M + H) ⁺

（３）化合物（１）１００ｍｇのＴＨＦ５ｍｌ溶液にＮ，Ｎ’−カルボニルジイミダゾール１６２ｍｇを加え、室温で１４時間攪拌した。反応液に２８％アンモニア水５ｍｌを加え、室温で３時間激しく攪拌した。反応液に酢酸エチルを加え、飽和食塩水で洗浄後、乾燥し、溶媒留去した。残渣に４Ｎ塩酸／１，４−ジオキサン１０ｍｌを加えて、室温で５時間攪拌した。反応液を減圧濃縮し、残渣に重曹水を加えて、酢酸エチルで抽出後、乾燥し、溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０→９４：６）で精製し、酢酸エチル／イソプロピルエーテルから再結晶し、化合物（２）３６ｍｇを無色結晶として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５２４／５２６（Ｍ＋Ｈ）⁺ (2) The compound (2) was obtained by reacting and treating the compound (1) in the same manner as in Example 1 (5).
APCI-MS (m / e): 625/627 (M + H) ⁺

(3) Compound (1) To a solution of 100 mg of THF in 5 ml was added 162 mg of N, N′-carbonyldiimidazole, and the mixture was stirred at room temperature for 14 hours. To the reaction solution, 5 ml of 28% aqueous ammonia was added and stirred vigorously at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, washed with saturated brine, dried and the solvent was distilled off. To the residue, 10 ml of 4N hydrochloric acid / 1,4-dioxane was added and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, aqueous sodium bicarbonate was added to the residue, extracted with ethyl acetate, dried and evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 → 94: 6) and recrystallized from ethyl acetate / isopropyl ether to obtain 36 mg of compound (2) as colorless crystals.
APCI-MS (m / e): 524/526 (M + H) ⁺

（１）化合物（１）２５０ｍｇ、化合物（２）１６８ｍｇ、グリシン１５．８ｍｇ、ヨウ化銅（Ｉ）およびリン酸カリウム粉末２２２ｍｇを１，４−ジオキサン０．８４ｍｌに加えて、１００℃で終夜攪拌した。放冷後に不溶物をろ去し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝７０：３０→４５：５５）で精製し、化合物（３）１５８ｍｇを淡黄色アモルファスとして得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：６６７／６６９（Ｍ＋Ｈ）⁺

Example 173

(1) 250 mg of compound (1), 168 mg of compound (2), 15.8 mg of glycine, copper (I) iodide and 222 mg of potassium phosphate powder are added to 0.84 ml of 1,4-dioxane and stirred at 100 ° C. overnight. did. After standing to cool, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70: 30 → 45: 55) to obtain 158 mg of compound (3) as a pale yellow amorphous.
APCI-MS (m / e): 667/669 (M + H) ⁺

（３）化合物（１）５０ｍｇの塩化メチレン３ｍｌ溶液に、酢酸６．１μｌ、水素化トリアセトキシホウ素ナトリウム６８ｍｇ、アセトアルデヒド１２μｌを室温で順次加え、３時間攪拌した。反応液に酢酸エチルを加え、飽和重曹水、飽和食塩水で洗浄し、乾燥後に溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール１００：０→９５：５）にて精製し、ｔｅｒｔ−ブタノールを用いて凍結乾燥し、化合物（２）２４ｍｇを微黄色粉末として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４９５／４９７（Ｍ＋Ｈ）⁺ (2) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Example 46.
APCI-MS (m / e): 467/469 (M + H) ⁺

(3) Compound (1) To a solution of 50 mg of methylene chloride in 3 ml of methylene chloride, 6.1 μl of acetic acid, 68 mg of sodium triacetoxyborohydride and 12 μl of acetaldehyde were sequentially added at room temperature and stirred for 3 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried and evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol 100: 0 → 95: 5) and lyophilized using tert-butanol to obtain 24 mg of compound (2) as a slightly yellow powder.
APCI-MS (m / e): 495/497 (M + H) ⁺

（１）化合物（１）および化合物（２）を実施例７３と同様に反応、処理することにより、化合物（３）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：６３７／６３９（Ｍ＋Ｈ）⁺

（２）化合物（１）を実施例４６と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４３７／４３９（Ｍ＋Ｈ）⁺ Example 174

(1) Compound (3) was obtained by reacting and treating compound (1) and compound (2) in the same manner as in Example 73.
APCI-MS (m / e): 637/639 (M + H) ⁺

(2) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Example 46.
APCI-MS (m / e) : 437/439 (M + H) +

化合物（１）を実施例４６と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４８１／４８３（Ｍ＋Ｈ）⁺ Example 175

Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Example 46.
APCI-MS (m / e): 481/483 (M + H) ⁺

Examples 176-189
The following compounds were obtained by reacting and treating in the same manner as in the above Examples and Reference Examples.

４−クロロスルホニル−ベンゼンカルボン酸９．１９ｇのＴＨＦ１００ｍｌ溶液に、氷冷下でエチルピペラジン５．１４ｇおよび炭酸カリウム５．５３ｇの水溶液１００ｍｌを加え、氷冷下で２時間激しく攪拌した。反応液を減圧濃縮し、残渣に塩酸を加えて中和し、析出結晶を濾取した。結晶を水、メタノールおよびジエチルエーテルで順次洗浄後、乾燥させて、４−（４−エチル−ピペラジン−１−スルホニル）−ベンゼンカルボン酸９．０８ｇを無色粉末として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２９９［Ｍ＋Ｈ］⁺ Reference example 1

To a solution of 9.19 g of 4-chlorosulfonyl-benzenecarboxylic acid in 100 ml of THF, 5.14 g of ethyl piperazine and 100 ml of an aqueous solution of 5.53 g of potassium carbonate were added under ice cooling, and vigorously stirred for 2 hours under ice cooling. The reaction solution was concentrated under reduced pressure, the residue was neutralized with hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed successively with water, methanol and diethyl ether and dried to give 9.08 g of 4- (4-ethyl-piperazine-1-sulfonyl) -benzenecarboxylic acid as a colorless powder.
APCI-MS (m / e): 299 [M + H] ⁺

化合物（１）を参考例１と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２９９［Ｍ＋Ｈ］⁺ Reference example 2

Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Reference Example 1.
APCI-MS (m / e): 299 [M + H] ⁺

モノメチルイソフタレート５ｇのＴＨＦ１００ｍｌ溶液に氷冷下でＮ，Ｎ’−カルボニルジイミダゾール４．８７ｇを加え、室温下で２時間攪拌した。反応液に氷冷下でマロン酸モノエチルエステル マグネシウム塩３０．６ｇを加え、室温下で終夜攪拌した。反応液を濃縮し、残渣に酢酸エチルを加え、塩酸、水、飽和重曹水および飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を瑠去した。放置により固化し、３−（２−エトキシカルボニル−アセチル）−ベンゼンカルボン酸メチルエステル３．５５ｇを微黄色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２５１［Ｍ＋Ｈ］⁺ Reference example 3

To a solution of monomethylisophthalate 5 g in THF 100 ml was added 4.87 g of N, N′-carbonyldiimidazole under ice cooling, and the mixture was stirred at room temperature for 2 hours. 30.6 g of malonic acid monoethyl ester magnesium salt was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, ethyl acetate was added to the residue, washed with hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was removed. Solidifying by standing, 3.55 g of 3- (2-ethoxycarbonyl-acetyl) -benzenecarboxylic acid methyl ester was obtained as a slightly yellow solid.
APCI-MS (m / e): 251 [M + H] ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３６９［Ｍ＋Ｈ］⁺ The following compounds were obtained by reacting and treating in the same manner as in Reference Example 3 above.
Reference example 4

APCI-MS (m / e): 369 [M + H] ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３６９［Ｍ＋Ｈ］⁺
実施例１（２）と同様に反応、処理することにより、以下の化合物を得た。 Reference Example 5

APCI-MS (m / e): 369 [M + H] ⁺
The following compounds were obtained by reacting and treating in the same manner as in Example 1 (2).

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２７０［Ｍ＋Ｈ］⁺ Reference Example 6

APCI-MS (m / e): 270 [M + H] ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３８８［Ｍ＋Ｈ］⁺
参考例８

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３８８［Ｍ＋Ｈ］⁺ Reference Example 7

APCI-MS (m / e): 388 [M + H] ⁺
Reference Example 8

APCI-MS (m / e): 388 [M + H] ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２５７［Ｍ＋Ｈ］⁺
参考例１０

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２５７［Ｍ＋Ｈ］⁺ Reference Example 9

APCI-MS (m / e): 257 [M + H] ⁺
Reference Example 10

APCI-MS (m / e): 257 [M + H] ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２８８／２９０［Ｍ＋Ｈ］⁺
参考例１２

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４０６／４０８［Ｍ＋Ｈ］⁺ The following compounds were obtained by reacting and treating in the same manner as in Example 1 (3).
Reference Example 11

APCI-MS (m / e): 288/290 [M + H] ⁺
Reference Example 12

APCI-MS (m / e): 406/408 [M + H] ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４０６／４０８［Ｍ＋Ｈ］⁺
参考例１４

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２７５／２７７［Ｍ＋Ｈ］⁺ Reference Example 13

APCI-MS (m / e): 406/408 [M + H] ⁺
Reference Example 14

APCI-MS (m / e): 275/277 [M + H] ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２７５／２７７［Ｍ＋Ｈ］⁺ Reference Example 15

APCI-MS (m / e): 275/277 [M + H] ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４２７／４２９［Ｍ＋Ｈ］⁺
参考例１７

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４１４／４１６［Ｍ＋Ｈ］⁺ The following compounds were obtained by reacting and treating in the same manner as in Example 1 (4).
Reference Example 16

APCI-MS (m / e) : 427/429 [M + H] +
Reference Example 17

APCI-MS (m / e): 414/416 [M + H] ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４１４／４１６［Ｍ＋Ｈ］⁺
参考例１９

実施例１（５）と同様に反応、処理することにより、上記化合物を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４１３／４１５［Ｍ＋Ｈ］⁺ Reference Example 18

APCI-MS (m / e): 414/416 [M + H] ⁺
Reference Example 19

The above compound was obtained by reacting and treating in the same manner as in Example 1 (5).
APCI-MS (m / e): 413/415 [M + H] ⁺

（２，４−ジクロロ−ベンジル）−［５−（４−ニトロ−フェニル）−ピラゾロ［１，５−ａ］ピリミジン−７−イル］−アミン６．６０ｇ、塩化第一スズ１２．６ｇにエタノール１６０ｍｌを加え、加熱還流下で１．５時間攪拌した。室温まで冷却後、反応液に飽和重曹水を加え、不溶物をセライトで濾去した。濾液にクロロホルム５００ｍｌを加え、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を留去した。酢酸エチルで結晶化し、得られた結晶を少量のメタノールとクロロホルムで洗浄後、乾燥させ、［５−（４−アミノ−フェニル）−ピラゾロ［１，５−ａ］ピリミジン−７−イル］−（２，４−ジクロロ−ベンジル）−アミン２．５０ｇを淡黄色結晶として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３８４／３８６［Ｍ＋Ｈ］⁺ Reference Example 20

6.60 g of (2,4-dichloro-benzyl)-[5- (4-nitro-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl] -amine, 12.6 g of stannous chloride and ethanol. 160 ml was added, and the mixture was stirred for 1.5 hours under reflux with heating. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the insoluble material was filtered off through celite. To the filtrate, 500 ml of chloroform was added, washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. Crystallization with ethyl acetate was performed, and the obtained crystals were washed with a small amount of methanol and chloroform, dried, and [5- (4-amino-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl]-( 2,50 g of 2,4-dichloro-benzyl) -amine was obtained as pale yellow crystals.
APCI-MS (m / e): 384/386 [M + H] ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３８４／３８６［Ｍ＋Ｈ］⁺ Reference Example 21
The following compounds were obtained by reacting and treating in the same manner as in Reference Example 20.

APCI-MS (m / e): 384/386 [M + H] ⁺

（１）Ｎ−エチルアミノエタノールに氷冷下でギ酸をゆっくり加え、これに４‐ブロモフェナシルブロミド９．３７ｇを加え、１００〜１１０℃で終夜攪拌した。反応液を放冷し、酢酸エチルと水を加えて分液した。水層に炭酸カリウムを加え、酢酸エチルで３回抽出した。有機層を合わせた後、硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をＮＨ−シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１００／０→９０／１０）で精製し、２−（４−ブロモ−フェニル）−４−エチル−モルホリン５．９０ｇを淡黄色油状物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２７０／２７２［Ｍ＋Ｈ］⁺

Reference Example 22

(1) Formic acid was slowly added to N-ethylaminoethanol under ice cooling, 9.37 g of 4-bromophenacyl bromide was added thereto, and the mixture was stirred at 100 to 110 ° C. overnight. The reaction solution was allowed to cool, and ethyl acetate and water were added for liquid separation. Potassium carbonate was added to the aqueous layer and extracted three times with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by NH-silica gel column chromatography (hexane / ethyl acetate = 100/0 → 90/10) to give 5.90 g of 2- (4-bromo-phenyl) -4-ethyl-morpholine as a pale yellow oil. Obtained.
APCI-MS (m / e): 270/272 [M + H] ⁺

(2) 3.0 g of 2- (4-bromo-phenyl) -4-ethyl-morpholine, 1,1′-bis (diphenylphosphino) ferrocene palladium (II) chloride 272 mg, potassium acetate 3.27 g, bis (pinacolate) ) 30 ml of DMSO was added to 4.23 g of diborane, and the mixture was stirred at 80 ° C. for 4 hours and at 100 ° C. overnight under a nitrogen atmosphere. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and the solvent was distilled off. The residue was purified twice by NH-silica gel column chromatography (hexane / ethyl acetate = 100/0 → 70/30), and 4-ethyl-2- “4- (4,4,5,5-tetramethyl- [ 1.44 g of 1,3,2] dioxaborolan-2-yl) -phenyl ”-morpholine was obtained as a pale yellow oil.
¹ HNMR (400 Mz / CDCl ₃ ) δ (ppm): 1.10 (t, 3H, J = 7.2 Hz), 1.34 (s, 12H), 1.99 (t, 1H, J = 10.5 Hz) ), 2.21 (dt, 1H, J = 3.4, 11.5 Hz), 2.44 (d, 2H), 2.83 (d, 1H), 2.95 (d, 1H), 3. 85 (dt, 1H, J = 2.3, 10.2 Hz), 4.06 (br d, 1H), 4.59 (dd, 1H, J = 2.3, 10.2 Hz), 7.37 ( d, 2H), 7.78 (d, 2H)

２−（４−ブロモ−フェニル）−４−エチル−モルホリン２．９９ｇのＴＨＦ溶液３０ｍｌに窒素雰囲気下、−７８℃でｎ−ブチルリチウム（１．７Ｍヘキサン溶液）７．２ｍｌをゆっくり滴下し、３０分攪拌した。反応液にトリメチルボレート２．４８ｍｌをゆっくり加えた後攪拌し、その後ゆっくりと室温まで上昇し、終夜攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、室温で１時間攪拌した。リン酸緩衝液（０．５Ｍ、ｐＨ８．０）を加え、酢酸エチルで３回抽出した。有機層を合わせた後、硫酸マグネシウムで乾燥し、溶媒を留去した。残渣にジエチルエーテルを加えて固化し、乾燥させ、４−（４−エチル−モルホリン−２−イル）ボロン酸７９５ｍｇを橙色固形物として得た。この粗生成物は、精製せずに実施例４４の反応に使用した。
¹ＨＮＭＲ（４００Ｍｚ／ＣＤＣｌ₃）δ（ｐｐｍ）：１．１１（ｔ，３Ｈ），２．０７（ｂｒ，１Ｈ），２．２３（ｔ，１Ｈ，Ｊ＝１１．０Ｈｚ），２．４８（ｄ，２Ｈ，Ｊ＝５．６Ｈｚ），２．８４（ｄ，１Ｈ，Ｊ＝１０．２Ｈｚ），２．９７（ｄ，１Ｈ，Ｊ＝１０．２Ｈｚ），３．８４（ｔ，１Ｈ，Ｊ＝１１．３Ｈｚ），３．８７（ｂｒ，１Ｈ），４．５９（ｄ，１Ｈ，Ｊ＝１０．０Ｈｚ），７．３３（ｂｒ ｓ，３Ｈ），７．７４（ｂｒ ｓ，１Ｈ），７．７９（ｂｒ ｓ，２Ｈ） Reference Example 23

To 30 ml of THF solution of 2.99 g of 2- (4-bromo-phenyl) -4-ethyl-morpholine, 7.2 ml of n-butyllithium (1.7 M hexane solution) was slowly added dropwise at −78 ° C. in a nitrogen atmosphere, Stir for 30 minutes. To the reaction solution, 2.48 ml of trimethyl borate was slowly added and stirred, and then slowly raised to room temperature and stirred overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Phosphate buffer (0.5M, pH 8.0) was added and extracted three times with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off. Diethyl ether was added to the residue to solidify, and dried to obtain 795 mg of 4- (4-ethyl-morpholin-2-yl) boronic acid as an orange solid. This crude product was used in the reaction of Example 44 without purification.
¹ HNMR (400 Mz / CDCl ₃ ) δ (ppm): 1.11 (t, 3H), 2.07 (br, 1H), 2.23 (t, 1H, J = 11.0 Hz), 2.48 ( d, 2H, J = 5.6 Hz), 2.84 (d, 1H, J = 10.2 Hz), 2.97 (d, 1H, J = 10.2 Hz), 3.84 (t, 1H, J = 11.3 Hz), 3.87 (br, 1 H), 4.59 (d, 1 H, J = 10.0 Hz), 7.33 (br s, 3 H), 7.74 (br s, 1 H), 7.79 (br s, 2H)

（１）４−ヨードベンゼンスルホニルクロリド４．５４ｇのクロロホルム溶液３０ｍｌに０℃でエチルピペラジン１．８３ｇおよびトリエチルアミン２．０２ｇのクロロホルム溶液２０ｍｌをゆっくりと滴下し、０℃で１時間、室温で終夜攪拌した。反応液にクロロホルムを加え、飽和重曹水および飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１００／０→９０／１０）で精製し、酢酸エチルから再結晶を行い、１−エチル−４−（４−ヨード−ベンゼンスルホニル）−ピペラジン５．３６ｇを無色結晶として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３８１［Ｍ＋Ｈ］⁺

（２）化合物（１）を参考例２３と同様に反応、処理することにより、化合物（２）を得た。
¹ＨＮＭＲ（４００Ｍｚ／ＤＭＳＯ−ｄ₆）δ（ｐｐｍ）：０．９４（ｔ，３Ｈ，Ｊ＝６．６Ｈｚ），２．２３−２．６０（ｂｒ，６Ｈ），２．８５（ｂｒ ｓ，４Ｈ），７．６９（ｄ，２Ｈ，Ｊ＝８．２Ｈｚ），８．０２（ｄ，２Ｈ，Ｊ＝８．２Ｈｚ），８．４６（ｓ，２Ｈ） Reference Example 24

(1) To 30 ml of chloroform solution of 4.54 g of 4-iodobenzenesulfonyl chloride, 1.83 g of ethyl piperazine and 20 ml of chloroform solution of 2.02 g of triethylamine were slowly added dropwise at 0 ° C. and stirred at 0 ° C. for 1 hour and at room temperature overnight. did. Chloroform was added to the reaction mixture, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform / methanol = 100/0 → 90/10), recrystallized from ethyl acetate, and 5.36 g of 1-ethyl-4- (4-iodo-benzenesulfonyl) -piperazine. Was obtained as colorless crystals.
APCI-MS (m / e): 381 [M + H] ⁺

(2) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Reference Example 23.
¹ HNMR (400 Mz / DMSO-d ₆ ) δ (ppm): 0.94 (t, 3H, J = 6.6 Hz), 2.23 to 2.60 (br, 6H), 2.85 (br s, 4H), 7.69 (d, 2H, J = 8.2 Hz), 8.02 (d, 2H, J = 8.2 Hz), 8.46 (s, 2H)

化合物（１）を参考例２２（２）と同様に反応、処理することにより、化合物（２）を得た。
¹ＨＮＭＲ（４００Ｍｚ／ＣＤＣｌ₃）δ（ｐｐｍ）：１．３４（ｓ，１２Ｈ），２．８９（ｔ，２Ｈ，Ｊ＝６．７Ｈｚ），３．８６（ｔ，２Ｈ，Ｊ＝６．７Ｈｚ），７．２５（ｄ，２Ｈ，Ｊ＝７．９Ｈｚ），７．７７（ｄ，２Ｈ，Ｊ＝７．９Ｈｚ） Reference Example 25

Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Reference Example 22 (2).
¹ HNMR (400 Mz / CDCl ₃ ) δ (ppm): 1.34 (s, 12H), 2.89 (t, 2H, J = 6.7 Hz), 3.86 (t, 2H, J = 6.7 Hz) ), 7.25 (d, 2H, J = 7.9 Hz), 7.77 (d, 2H, J = 7.9 Hz)

（１）４−ブロモベンゾイルクロリド３７．３７ｇを塩化メチレン１５０ｍｌ／ＴＨＦ５０ｍｌ混液に溶かし、氷冷下でメチルピペリジン１８．９５ｇのＴＨＦ１０ｍｌ溶液およびトリエチルアミン４７ｍｌをゆっくり加え、３０分間攪拌した。反応液に炭酸カリウム水溶液を加え、クロロホルム／メタノール（９／１）で３回抽出した。有機層を合わせ、硫酸マグネシウムで乾燥後、溶媒を留去した。残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル１００／０→５０／５０）で２回精製を行い、（４−ブロモフェニル）−（４−メチル−ピペラジン−１−イル）−メタノン４５．５１ｇを淡黄色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２８３／２８５［Ｍ＋Ｈ］⁺

Reference Example 26

(1) 37.37 g of 4-bromobenzoyl chloride was dissolved in a mixture of 150 ml of methylene chloride / 50 ml of THF, and a solution of 18.95 g of methylpiperidine in 10 ml of THF and 47 ml of triethylamine was slowly added under ice-cooling and stirred for 30 minutes. A potassium carbonate aqueous solution was added to the reaction solution, and the mixture was extracted 3 times with chloroform / methanol (9/1). The organic layers were combined and dried over magnesium sulfate, and then the solvent was distilled off. The residue was purified twice by NH silica gel column chromatography (hexane / ethyl acetate 100/0 → 50/50) to give (4-bromophenyl)-(4-methyl-piperazin-1-yl) -methanone 45.51 g. Was obtained as a pale yellow solid.
APCI-MS (m / e): 283/285 [M + H] ⁺

(2) The compound (2) was obtained by reacting and treating the compound (1) in the same manner as in Reference Example 22 (2). The obtained crude product of compound (2) was used in the reaction of Example 51 without purification.
¹ HNMR (400 Mz / CDCl ₃ ) δ (ppm): 1.35 (s, 12H), 2.31 (s, 3H), 2.48 (brs, 2H), 2.62 (s, 2H), 3.39 (br s, 2H), 3.80 (br s, 2H), 7.38 (d, 2H, J = 8.2 Hz), 7.84 (d, 2H, J = 8.2 Hz)

（１）（５−クロロピラゾロ［１、５−ａ］ピリミジン−７−イル）−（２、４−ジクロロベンジル）アミン６５５ｍｇのクロロホルム７ｍｌ溶液にジ−ｔｅｒｔ−ブチルジカルボネート４３７ｍｇおよび４−ジメチルアミノピリジン２４ｍｇを加え、還流下、１．５時間攪拌した。さらに反応液にジ−ｔｅｒｔ−ブチルジカルボネート８３ｍｇを加え、還流下、３０分攪拌した後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：０→１０：１）にて精製し、（５−クロロ−ピラゾロ［１，５−a］ピリミジン−７−イル）−（２，４−ジクロロ−ベンジル）−カルバミン酸 ｔｅｒｔ−ブチルエステル９５３．３ｍｇを無色粘体として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４２７／４２９［Ｍ＋Ｈ］⁺

Reference Example 27

(1) (5-chloropyrazolo [1,5-a] pyrimidin-7-yl)-(2,4-dichlorobenzyl) amine (655 mg) in chloroform (7 ml) in chloroform (7 ml) and di-tert-butyl dicarbonate (437 mg) and 4-dimethylaminopyridine 24 mg was added and stirred under reflux for 1.5 hours. Further, 83 mg of di-tert-butyl dicarbonate was added to the reaction solution and stirred for 30 minutes under reflux, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 0 → 10: 1) to give (5-chloro-pyrazolo [1,5-a] pyrimidin-7-yl)-(2,4- Dichloro-benzyl) -carbamic acid tert-butyl ester (953.3 mg) was obtained as a colorless viscous body.
APCI-MS (m / e) : 427/429 [M + H] +

（３）化合物（１）を実施例４６（２）と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３６９／３７１［Ｍ＋Ｈ］⁺ (2) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Example 44.
APCI-MS (m / e): 469/471 [M + H] ⁺

(3) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Example 46 (2).
APCI-MS (m / e): 369/371 [M + H] ⁺

（１）アミノピラゾール１６ｇおよびマロン酸ジメチル２６．４ｇのメタノール５００ｍｌ溶液に、ナトリウムメトキシド（２８％メタノール溶液）７７．２ｇを滴下し、加熱還流下で１８時間攪拌した。反応液を放冷した後、減圧濃縮し、析出物をろ取して少量のメタノールで洗浄した。得られた粉末を水５００ｍｌに溶かし、濃塩酸を加えてｐＨ３〜４とし、析出結晶をろ取した。水、エタノールおよびジエチルエーテルで洗浄後に乾燥し、４Ｈ−ピラゾロ［１，５−a］ピリミジン−５，７−ジオンを無色粉末２２．１ｇとして得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：１５２（Ｍ＋Ｈ）⁺

（２）化合物（１）を実施例１（３）と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：１８８／１９０（Ｍ＋Ｈ）⁺ Reference Example 28

(1) 77.2 g of sodium methoxide (28% methanol solution) was added dropwise to a solution of 16 g of aminopyrazole and 26.4 g of dimethyl malonate in 500 ml of methanol, and the mixture was stirred for 18 hours with heating under reflux. The reaction solution was allowed to cool and then concentrated under reduced pressure. The precipitate was collected by filtration and washed with a small amount of methanol. The obtained powder was dissolved in 500 ml of water, concentrated hydrochloric acid was added to adjust the pH to 3 to 4, and the precipitated crystals were collected by filtration. The extract was washed with water, ethanol and diethyl ether and dried to give 4H-pyrazolo [1,5-a] pyrimidine-5,7-dione as 22.1 g of a colorless powder.
APCI-MS (m / e): 152 (M + H) ⁺

(2) The compound (2) was obtained by reacting and treating the compound (1) in the same manner as in Example 1 (3).
APCI-MS (m / e): 188/190 (M + H) ⁺

（３）化合物（１）１０．８５ｇの１，４−ジオキサン２００ｍｌ溶液に２，４−ジクロロベンジルアミン１５．２ｇ、トリエチルアミン１４．６ｇを室温下で加え、終夜攪拌した。反応液を減圧濃縮し、残渣に酢酸エチルを加えた。混合物を飽和重曹水、飽和食塩水で洗浄し、乾燥後、溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）で精製し、化合物（２）１８．０ｇを無色粉末として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３２７／３２９（Ｍ＋Ｈ）⁺

(3) To a solution of 10.85 g of compound (1) in 200 ml of 1,4-dioxane, 15.2 g of 2,4-dichlorobenzylamine and 14.6 g of triethylamine were added at room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 18.0 g of Compound (2) as a colorless powder.
APCI-MS (m / e): 327/329 (M + H) ⁺

（１）化合物（１）を参考例３４と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：１５１（Ｍ＋Ｈ）⁺

（２）化合物（１）を実施例１（３）と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：１８７／１８９（Ｍ＋Ｈ）⁺ Reference Example 29

(1) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Reference Example 34.
APCI-MS (m / e): 151 (M + H) ⁺

(2) The compound (2) was obtained by reacting and treating the compound (1) in the same manner as in Example 1 (3).
APCI-MS (m / e): 187/189 (M + H) ⁺

（１）化合物（１）を参考例３４と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２２４（Ｍ＋Ｈ）⁺

（２）化合物（１）を実施例１（３）と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２６０／２６２（Ｍ＋Ｈ）⁺
上記参考例と同様にして、以下の化合物を得た。 Reference Example 30

(1) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Reference Example 34.
APCI-MS (m / e): 224 (M + H) ⁺

(2) The compound (2) was obtained by reacting and treating the compound (1) in the same manner as in Example 1 (3).
APCI-MS (m / e): 260/262 (M + H) ⁺
The following compounds were obtained in the same manner as in the above Reference Example.

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３４１／３４３（Ｍ＋Ｈ）⁺
参考例３２

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３１１／３１３（Ｍ＋Ｈ）⁺ Reference Example 31

APCI-MS (m / e): 341/343 (M + H) ⁺
Reference Example 32

APCI-MS (m / e): 311/313 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３２８／３３０（Ｍ＋Ｈ）⁺
参考例３４

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３１０／３１２（Ｍ＋Ｈ）⁺ Reference Example 33

APCI-MS (m / e): 328/330 (M + H) ⁺
Reference Example 34

APCI-MS (m / e): 310/312 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３８３／３８５（Ｍ＋Ｈ）⁺
上記参考例と同様に反応、処理することにより、以下の化合物を得た。 Reference Example 35

APCI-MS (m / e): 383/385 (M + H) ⁺
The following compounds were obtained by reacting and treating in the same manner as in the above Reference Example.

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４２７／４２９（Ｍ＋Ｈ）⁺ Reference Example 36

APCI-MS (m / e): 427/429 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４４１／４４３（Ｍ＋Ｈ）⁺
参考例３８

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４１１／４１３（Ｍ＋Ｈ）⁺
参考例３９

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４２８／４３０（Ｍ＋Ｈ）⁺ Reference Example 37

APCI-MS (m / e): 441/443 (M + H) ⁺
Reference Example 38

APCI-MS (m / e): 411/413 (M + H) ⁺
Reference Example 39

APCI-MS (m / e): 428/430 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４１２／４１４（Ｍ＋Ｈ）⁺
参考例４１

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４８３／４８５（Ｍ＋Ｈ）⁺ Reference Example 40

APCI-MS (m / e): 412/414 (M + H) ⁺
Reference Example 41

APCI-MS (m / e): 483/485 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：６３７／６３９（Ｍ＋Ｈ）⁺
参考例４３

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５２９／５３１（Ｍ−Ｈ）^-
参考例４４

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５４５／５４７（Ｍ−Ｈ）^- Reference Example 42

APCI-MS (m / e): 637/639 (M + H) ⁺
Reference Example 43

APCI-MS (m / e): 529/531 (M−H) ⁻
Reference Example 44

APCI-MS (m / e): 545/547 (M−H) ⁻

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５４５／５４７（Ｍ＋Ｈ）⁺
参考例４６

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５３１／５３３（Ｍ＋Ｈ）⁺ Reference Example 45

APCI-MS (m / e): 545/547 (M + H) ⁺
Reference Example 46

APCI-MS (m / e): 531/533 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４３１／４３３（Ｍ＋Ｈ）⁺
参考例４８

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５４１／５４３（Ｍ＋Ｈ）⁺
参考例４９

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５２７／５２９（Ｍ＋Ｈ）⁺ Reference Example 47

APCI-MS (m / e): 431/433 (M + H) ⁺
Reference Example 48

APCI-MS (m / e): 541/543 (M + H) ⁺
Reference Example 49

APCI-MS (m / e): 527/529 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４２７／４２９（Ｍ＋Ｈ）⁺
参考例５１

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４３０／４３２（Ｍ＋Ｈ）⁺ Reference Example 50

APCI-MS (m / e): 427/429 (M + H) ⁺
Reference Example 51

APCI-MS (m / e): 430/432 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４４４／４４６（Ｍ＋Ｈ）⁺ Reference Example 52

APCI-MS (m / e): 444/446 (M + H) ⁺

（１）化合物（１）を実施例６８（１）と同様に反応、処理することにより、化合物（２）を得た。
¹ＨＮＭＲ（４００ＭＨ_Z／ＣＤＣｌ₃）δ（ｐｐｍ）：３．９４（ｓ，３Ｈ），７．７７（ｄｄ，１Ｈ，Ｊ＝１．８Ｈｚ，９．０Ｈｚ），７．７１（ｄｄ，１Ｈ，Ｊ＝１．８Ｈｚ，１０．２Ｈｚ），７．６４（ｄｄ，１Ｈ，Ｊ＝６．７Ｈｚ，８．５Ｈｚ）

（２）化合物（１）を参考例２２（２）と同様に反応、処理することにより、化合物（２）を得た。
¹ＨＮＭＲ（４００ＭＨ_Z／ＣＤＣｌ₃）δ（ｐｐｍ）：１．３７（ｓ，１２Ｈ），３．９３（ｓ， ３Ｈ）， ７．８６（ｄ，１Ｈ，Ｊ＝１０．０Ｈｚ），７．８０−７．８１（ｍ，２Ｈ） Reference Example 53

(1) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Example 68 (1).
^{_{1 HNMR (400MH Z / CDCl 3}} ) δ (ppm): 3.94 (s, 3H), 7.77 (dd, 1H, J = 1.8Hz, 9.0Hz), 7.71 (dd, 1H, J = 1.8 Hz, 10.2 Hz), 7.64 (dd, 1 H, J = 6.7 Hz, 8.5 Hz)

(2) The compound (2) was obtained by reacting and treating the compound (1) in the same manner as in Reference Example 22 (2).
^{_{1 HNMR (400MH Z / CDCl 3}} ) δ (ppm): 1.37 (s, 12H), 3.93 (s, 3H), 7.86 (d, 1H, J = 10.0Hz), 7.80 -7.81 (m, 2H)

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２７７（Ｍ＋Ｈ）⁺
参考例５５

（１）４−ブロモ−ヨードベンゼン４０．０ｇ、Ｎ−エチルピペラジン３２．３ｇの２−プロパノール４００ｍｌ溶液に、エチレングリコール２６．３ｇ、ヨウ化銅（Ｉ）５．３９ｇ、リン酸カリウム粉末９１．９ｇを加え、加熱還流下で終夜攪拌した。放冷後、不溶物をろ去し、ろ液を減圧濃縮した。残渣に酢酸エチルを加え、飽和重曹水で洗浄、乾燥し、溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０→９５：５）で精製し、１−（４−ブロモ−フェニル）−４−エチル−ピペラジン（２）３０．１ｇを無色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２６９／２７１（Ｍ＋Ｈ）⁺

（２）化合物（１）を参考例２３と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２３５（Ｍ＋Ｈ）⁺ Reference Example 54

APCI-MS (m / e): 277 (M + H) ⁺
Reference Example 55

(1) A solution of 40.0 g of 4-bromo-iodobenzene and 32.3 g of N-ethylpiperazine in 400 ml of 2-propanol, 26.3 g of ethylene glycol, 5.39 g of copper (I) iodide, and 91. potassium phosphate powder. 9 g was added and stirred overnight under reflux with heating. After allowing to cool, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with saturated aqueous sodium hydrogen carbonate, dried and evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 → 95: 5) to obtain 30.1 g of 1- (4-bromo-phenyl) -4-ethyl-piperazine (2) as a colorless solid. It was.
APCI-MS (m / e): 269/271 (M + H) ⁺

(2) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Reference Example 23.
APCI-MS (m / e): 235 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３０７（Ｍ＋Ｈ）⁺
参考例５７

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３３８（Ｍ＋Ｈ）⁺ Reference Example 56

APCI-MS (m / e): 307 (M + H) ⁺
Reference Example 57

APCI-MS (m / e): 338 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３３９（Ｍ＋Ｈ）⁺
参考例５９

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３５６／３５８（Ｍ＋Ｈ）⁺ Reference Example 58

APCI-MS (m / e): 339 (M + H) ⁺
Reference Example 59

APCI-MS (m / e): 356/358 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３５７／３５９（Ｍ＋Ｈ）⁺
参考例６１

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４９５／４９７（Ｍ＋Ｈ）⁺ Reference Example 60

APCI-MS (m / e): 357/359 (M + H) ⁺
Reference Example 61

APCI-MS (m / e): 495/497 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：５９５／５９７（Ｍ＋Ｈ）⁺ Reference Example 62

APCI-MS (m / e): 595/597 (M + H) ⁺

メチルアクリロニトリル４０ｇに４５℃で臭素を２時間かけてゆっくり滴下し、更に２時間攪拌した。水酸化カリウム６７．４ｇのメタノール５００ｍｌ溶液に、０℃で先の反応液を３０分かけてゆっくり滴下し、２時間後に室温に昇温し、１日攪拌した。反応液を減圧濃縮し、残渣に水を加え、ジエチルエーテルで２回抽出した。有機層を合わせ、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、濾過し、溶媒を留去した。残渣にエタノール５０ｍｌ、飽水ヒドラジン３５．８ｇを加え、８０℃で１日攪拌した。ヒドラジン１０ｇを追加し、８０℃で更に１日攪拌した。反応液を減圧濃縮後、残渣をクロロホルム／メタノール（９／１）混液に溶解し、シリカゲルを加えて放置後に濾過した。濾液を減圧濃縮し、４−メチル−１Ｈ−ピラゾール−３−イルアミンを暗紫色油状物４６．７ｇとして得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：９８［Ｍ＋Ｈ］⁺ Reference Example 63

Bromine was slowly dropped into 40 g of methylacrylonitrile at 45 ° C. over 2 hours, and the mixture was further stirred for 2 hours. The above reaction solution was slowly added dropwise to a solution of 67.4 g of potassium hydroxide in 500 ml of methanol at 0 ° C. over 30 minutes, and the temperature was raised to room temperature after 2 hours and stirred for 1 day. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted twice with diethyl ether. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated. To the residue were added 50 ml of ethanol and 35.8 g of saturated hydrazine, and the mixture was stirred at 80 ° C. for 1 day. 10 g of hydrazine was added, and the mixture was further stirred at 80 ° C. for 1 day. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in a chloroform / methanol (9/1) mixed solution, added with silica gel, and allowed to stand, followed by filtration. The filtrate was concentrated under reduced pressure to give 4-methyl-1H-pyrazol-3-ylamine as 46.7 g of a dark purple oil.
APCI-MS (m / e): 98 [M + H] ⁺

（１）化合物（１）２０．０ｇ、化合物（２）３２．０ｇのジメチルアセトアミド９０ｍｌ溶液に炭酸カリウム粉末２７．６ｇを加え、１５０℃で終夜攪拌した。反応液を放冷後、酢酸エチルを加え、水、飽和食塩水で洗浄、乾燥し、溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０→９５：５）にて精製し、黄橙色固形物を得た。ジイソプロピルエーテル／ヘキサンから再結晶を行い、化合物（３）２５．８ｇを黄色晶として得た。化合物（３）を６Ｎ塩酸１２０ｍｌに溶解し、加熱還流下で９時間攪拌した。反応液を氷冷し、２時間放置後、析出結晶をろ取し、少量の冷水で洗浄後乾燥し、化合物（４）１５．９ｇを淡黄色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２３５（Ｍ＋Ｈ）⁺

Reference Example 64

(1) To a solution of 20.0 g of compound (1) and 32.0 g of compound (2) in 90 ml of dimethylacetamide was added 27.6 g of potassium carbonate powder, and the mixture was stirred at 150 ° C. overnight. The reaction mixture was allowed to cool, ethyl acetate was added, washed with water and saturated brine, dried, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 → 95: 5) to obtain a yellow-orange solid. Recrystallization from diisopropyl ether / hexane gave 25.8 g of Compound (3) as yellow crystals. Compound (3) was dissolved in 120 ml of 6N hydrochloric acid and stirred for 9 hours under heating and reflux. The reaction mixture was ice-cooled and allowed to stand for 2 hours. The precipitated crystals were collected by filtration, washed with a small amount of cold water and dried to obtain 15.9 g of Compound (4) as a pale yellow solid.
APCI-MS (m / e): 235 (M + H) ⁺

（３）化合物（１）を実施例１（２）と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３３８（Ｍ＋Ｈ）⁺

（４）化合物（１）を実施例１（３）と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３５６／３５８（Ｍ＋Ｈ）⁺ (2) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Reference Example 3.
APCI-MS (m / e): 305 (M + H) ⁺

(3) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Example 1 (2).
APCI-MS (m / e): 338 (M + H) ⁺

(4) The compound (2) was obtained by reacting and treating the compound (1) in the same manner as in Example 1 (3).
APCI-MS (m / e): 356/358 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３３８（Ｍ＋Ｈ）⁺
参考例６６

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３２４（Ｍ＋Ｈ）⁺ The following compounds were obtained in the same manner as in the above Reference Example.
Reference Example 65

APCI-MS (m / e): 338 (M + H) ⁺
Reference Example 66

APCI-MS (m / e): 324 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３３９（Ｍ＋Ｈ）⁺
参考例６８

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３５６／３５８（Ｍ＋Ｈ）⁺ Reference Example 67

APCI-MS (m / e): 339 (M + H) ⁺
Reference Example 68

APCI-MS (m / e): 356/358 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３４２／３４４（Ｍ＋Ｈ）⁺ Reference Example 69

APCI-MS (m / e): 342/344 (M + H) ⁺

化合物（１）６２４ｍｇのＴＨＦ３０ｍｌ溶液に６０％水素化ナトリウム１４５ｍｇを加えて３０分攪拌後、イミノジカルボン酸−ジ-ｔｅｒｔ-ブチルエステル７８８ｍｇを加え、５５℃で１時間攪拌した。さらに、イミノジカルボン酸−ジ−ｔｅｒｔ−ブチルエステル７８８ｍｇを加えて、５５℃で終夜攪拌した。反応液を放冷後、酢酸エチルを加え、水洗後、乾燥し、溶媒留去した。シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→９５：５）で精製し油状物を得た。得られた油状物の酢酸エチル溶液に４Ｎ塩酸／酢酸エチル２０ｍｌを加えて、室温で１．５時間攪拌し、反応液を減圧濃縮した。残渣にジエチルエーテル／ヘキサンを加えて固形物を粉砕し、乾燥させて、化合物（２）４９０ｍｇを無色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：１９４／１９６（Ｍ＋Ｈ）⁺ Reference Example 70

To a solution of compound (1) 624 mg in THF 30 ml, 60% sodium hydride 145 mg was added and stirred for 30 minutes, then iminodicarboxylic acid-di-tert-butyl ester 788 mg was added and stirred at 55 ° C. for 1 hour. Further, 788 mg of iminodicarboxylic acid-di-tert-butyl ester was added, and the mixture was stirred at 55 ° C. overnight. The reaction mixture was allowed to cool, ethyl acetate was added, the mixture was washed with water, dried and the solvent was distilled off. Purification by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 95: 5) gave an oil. To the obtained oily ethyl acetate solution was added 4N hydrochloric acid / ethyl acetate (20 ml), and the mixture was stirred at room temperature for 1.5 hours, and the reaction mixture was concentrated under reduced pressure. Diethyl ether / hexane was added to the residue, and the solid was pulverized and dried to obtain 490 mg of Compound (2) as a colorless solid.
APCI-MS (m / e): 194/196 (M + H) ⁺

（１）５−クロロ−２−メチルベンゾニトリル７．８ｇの四塩化炭素５０ｍｌ溶液にＮ−ブロモスクシンイミド９．２６ｇ、過酸化ベンゾイル５１５ｍｇを加え、加熱還流下で終夜攪拌した。反応液を放冷し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３０：１）で精製し、化合物（２）８．８７ｇを黄色透明油状物として得た。
¹ＨＮＭＲ（４００ＭＨ_Z／ＣＤＣｌ₃）δ（ｐｐｍ）：４．６０（ｓ，２Ｈ），７．５０（ｄ，１Ｈ，Ｊ＝８．５Ｈ_Z），７．５７（ｄｄ，１Ｈ，Ｊ＝２．３，８．５Ｈ_Z），７．６５（ｄ，１Ｈ，Ｊ＝２．３Ｈ_Z）

（２）化合物（１）を参考例７０と同様に反応、処理し、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：１６７／１６９（Ｍ＋Ｈ）⁺ Reference Example 71

(1) To a solution of 7.8 g of 5-chloro-2-methylbenzonitrile in 50 ml of carbon tetrachloride were added 9.26 g of N-bromosuccinimide and 515 mg of benzoyl peroxide, and the mixture was stirred overnight with heating under reflux. The reaction solution was allowed to cool and purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to obtain 8.87 g of Compound (2) as a yellow transparent oil.
^{_{1 HNMR (400MH Z / CDCl 3}} ) δ (ppm): 4.60 (s, 2H), 7.50 (d, 1H, J = 8.5H Z), 7.57 (dd, 1H, J = 2 .3, 8.5 H _Z ), 7.65 (d, 1 H, J = 2.3 H _Z )

(2) The compound (1) was reacted and treated in the same manner as in Reference Example 70 to obtain the compound (2).
APCI-MS (m / e): 167/169 (M + H) ⁺

（１）４−クロロ−２−フルオロベンズアルデヒド２６．２ｇ、（Ｓ）（−）−２−メチル−２−プロパンスルホンアミド２１．０ｇのＴＨＦ９４０ｍｌ溶液に室温下でチタニウム（IV）エトキシド８０．９ｇをゆっくり滴下し、加熱還流下で２．５時間攪拌した。放冷後、反応液を冷した飽和食塩水に攪拌しながらゆっくり注ぎ、セライトを用いて不溶物をろ去した。ろ液に塩化メチレン１８００ｍｌを加えて分液し、乾燥後、溶媒留去し、化合物（２）４２．３ｇを無色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２６２／２６４（Ｍ＋Ｈ）⁺

（２）メチルマグネシウムブロミド（ジエチルエーテル３M溶液）８１ｍｌに窒素置換下、ドライアイス／アセトン浴で冷却下（内温：−３０〜―５℃）で、化合物（１）４２．３ｇのＴＨＦ１．２L溶液を４０分かけて滴下し、室温まで昇温しながら終夜攪拌した。反応液に塩化アンモニウム水溶液を氷冷下でゆっくり加え、塩化メチレンで抽出し、乾燥後、溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１→１：０）で精製し、ヘキサンから再結晶を行うことにより、化合物（２）４４．５ｇを無色晶として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２７８／２８０（Ｍ＋Ｈ）⁺

（３）化合物（１）３６．９ｇのメタノール２１６ｍｌ溶液に、氷冷下で４N塩酸／１，４−ジオキサン溶液２１６ｍｌを加え、室温で２時間攪拌した。反応液を濃縮し、残渣にジエチルエーテルを加えて粉砕後、乾燥し、化合物（２）２７．７ｇを無色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：１７４／１７６（Ｍ＋Ｈ）⁺ Reference Example 72

(1) 80.9 g of titanium (IV) ethoxide was added to a solution of 26.2 g of 4-chloro-2-fluorobenzaldehyde and 21.0 g of (S) (−)-2-methyl-2-propanesulfonamide in 940 ml of THF at room temperature. The solution was slowly added dropwise and stirred for 2.5 hours while heating under reflux. After allowing to cool, the reaction solution was slowly poured into a cooled saturated saline solution with stirring, and insoluble materials were removed by filtration through Celite. The filtrate was added with 1800 ml of methylene chloride, separated, dried, and then the solvent was distilled off to obtain 42.3 g of Compound (2) as a colorless solid.
APCI-MS (m / e): 262/264 (M + H) ⁺

(2) Methylmagnesium bromide (diethyl ether 3M solution) was replaced with nitrogen, and cooled in a dry ice / acetone bath (internal temperature: -30 to -5 ° C), 42.3 g of THF (1.2 L) of compound (1) The solution was added dropwise over 40 minutes and stirred overnight while warming to room temperature. An aqueous ammonium chloride solution was slowly added to the reaction solution under ice-cooling, extracted with methylene chloride, dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 0) and recrystallized from hexane to obtain 44.5 g of Compound (2) as colorless crystals.
APCI-MS (m / e): 278/280 (M + H) ⁺

(3) To a solution of 36.9 g of compound (1) in methanol (216 ml) was added 4N hydrochloric acid / 1,4-dioxane solution (216 ml) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, diethyl ether was added to the residue, and the mixture was pulverized and dried to obtain 27.7 g of Compound (2) as a colorless solid.
APCI-MS (m / e): 174/176 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：１７６（Ｍ＋Ｈ）⁺ The following compounds were obtained in the same manner as in the above Reference Example.
Reference Example 73

APCI-MS (m / e): 176 (M + H) ⁺

（１）化合物（１）を参考例２７と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３７５／３７７（Ｍ＋Ｈ）⁺

（２）化合物（１）５２５ｍｇの１,４−ジオキサン８．４ｍｌ溶液に、ビス（ピナコレート）ジボラン４９８mg、ビス（ジベンジリデンアセトン）パラジウム４８．３ｍｇ、トリシクロヘキシルホスフィンテトラフルオロボレート６８ｍｇ、酢酸カリウム２０７ｍｇを加え、窒素置換下、８０℃で終夜攪拌した。反応液に水および酢酸エチルを加え、不溶物をろ去した。ろ液を酢酸エチルで抽出し、乾燥後に溶媒留去した。残渣をジエチルエーテル／イソプロピルエーテルで結晶化し、目的物（２）４５９ｍｇを無色晶として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４６７（Ｍ＋Ｈ）⁺ Reference Example 74

(1) Compound (2) was obtained by reacting and treating compound (1) in the same manner as in Reference Example 27.
APCI-MS (m / e): 375/377 (M + H) ⁺

(2) 8.4 mg of bis (pinacolato) diborane, 498 mg of bis (dibenzylideneacetone) palladium, 68 mg of tricyclohexylphosphine tetrafluoroborate and 207 mg of potassium acetate are added to 8.4 ml of 525 mg of compound (1). In addition, the mixture was stirred overnight at 80 ° C. under nitrogen substitution. Water and ethyl acetate were added to the reaction solution, and the insoluble material was removed by filtration. The filtrate was extracted with ethyl acetate, dried and evaporated. The residue was crystallized from diethyl ether / isopropyl ether to obtain 459 mg of the desired product (2) as colorless crystals.
APCI-MS (m / e): 467 (M + H) ⁺

ＡＰＣＩ−ＭＳ（ｍ／ｅ）：４３４（Ｍ＋Ｈ）⁺ The following compounds were obtained in the same manner as in the above Reference Example.
Reference Example 75

APCI-MS (m / e): 434 (M + H) ⁺

（１）化合物（１）３．０ｇにピペラジン７．８３ｇ、N，Ｎ−ジメチルアセトアミド１０ｍｌを加え、１３０℃で終夜攪拌した。反応液を減圧濃縮し、残渣にジエチルエーテルを加えて粉砕後、少量の水で洗浄後に乾燥し、化合物（２）３．１１ｇを黄色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３１３／３１５（Ｍ＋Ｈ）⁺

（２）化合物（１）３．０３ｇのメタノール２５０ｍｌ溶液に濃硫酸１０ｍｌを加え、加熱還流下で４時間攪拌した。反応液を減圧濃縮し、残渣に水、炭酸カリウムを加え、液性をｐH９とした。ジエチルエーテルで２回抽出し、乾燥した後、溶媒を留去し、化合物（２）２．６１ｇを淡褐色カラメルとして得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３２７／３２９（Ｍ＋Ｈ）⁺

（３）化合物（１）を参考例２２（２）と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３７５（Ｍ＋Ｈ）⁺ Reference Example 76

(1) Piperazine (7.83 g) and N, N-dimethylacetamide (10 ml) were added to compound (1) (3.0 g), and the mixture was stirred at 130 ° C overnight. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the mixture was pulverized, washed with a small amount of water and dried to give 3.11 g of Compound (2) as a yellow solid.
APCI-MS (m / e): 313/315 (M + H) ⁺

(2) 10 ml of concentrated sulfuric acid was added to a solution of 3.03 g of the compound (1) in 250 ml of methanol, and the mixture was stirred for 4 hours with heating under reflux. The reaction mixture was concentrated under reduced pressure, and water and potassium carbonate were added to the residue to adjust the liquidity to pH 9. After extracting twice with diethyl ether and drying, the solvent was distilled off to obtain 2.61 g of Compound (2) as a light brown caramel.
APCI-MS (m / e): 327/329 (M + H) ⁺

(3) The compound (2) was obtained by reacting and treating the compound (1) in the same manner as in Reference Example 22 (2).
APCI-MS (m / e): 375 (M + H) ⁺

（１）５−ブロモ−２−クロロピリミジン２．９０ｇ、１−ｔｅｒｔ−ブトキシカルボニルピペラジン４．１９ｇの１，４−ジオキサン７０ｍｌ溶液に炭酸カリウム３．７３ｇを加え、加熱還流下で１．５時間攪拌した。反応液に水を加え、ジエチルエーテルで２回抽出した。有機層を合わせて乾燥し、溶媒留去した。シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１５：１→８：１）で精製し、化合物（２）５．０９ｇを無色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３４３／３４５（Ｍ＋Ｈ）⁺

（２）化合物（１）を参考例２２（２）と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３９１（Ｍ＋Ｈ）⁺ Reference Example 77

(1) To a solution of 2.90 g of 5-bromo-2-chloropyrimidine and 4.19 g of 1-tert-butoxycarbonylpiperazine in 70 ml of 1,4-dioxane, 3.73 g of potassium carbonate was added and heated under reflux for 1.5 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted twice with diethyl ether. The organic layers were combined, dried and evaporated. Purification by silica gel column chromatography (hexane: ethyl acetate = 15: 1 → 8: 1) gave 5.09 g of Compound (2) as a colorless solid.
APCI-MS (m / e): 343/345 (M + H) ⁺

(2) The compound (2) was obtained by reacting and treating the compound (1) in the same manner as in Reference Example 22 (2).
APCI-MS (m / e): 391 (M + H) ⁺

（１）化合物（１）２９．６ｇ、エチルピペラジン１１．４ｇのトルエン１５０ｍｌ溶液に、トリス（ジベンジリデンアセトン）ジパラジウム１．８３ｇ、キサントフォス３．４６ｇ、ｔｅｒｔ‐ブトキシナトリウム１４．９ｇを加え、窒素置換下、１００℃で３時間攪拌した。反応液を放冷後、酢酸エチルを加えて水洗した。有機層を塩酸で２回抽出し、先の水層を合わせてジエチルエーテルで２回洗浄後、炭酸カリウムを加えて液性を弱アルカリ性とした後に、酢酸エチルで２回抽出した。有機層を合わせて乾燥後、溶媒留去し、化合物（２）１８．１ｇを淡橙色固形物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２７０／２７２（Ｍ＋Ｈ）⁺

（２）化合物（１）を参考例２２（２）と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３１８（Ｍ＋Ｈ）⁺ Reference Example 78

(1) To a solution of 29.6 g of compound (1) and 11.4 g of ethylpiperazine in 150 ml of toluene was added 1.83 g of tris (dibenzylideneacetone) dipalladium, 3.46 g of xantphos, and 14.9 g of tert-butoxy sodium, and nitrogen was added. It stirred at 100 degreeC for 3 hours under substitution. The reaction solution was allowed to cool, and then ethyl acetate was added and washed with water. The organic layer was extracted twice with hydrochloric acid, and the previous aqueous layer was combined and washed twice with diethyl ether. After adding potassium carbonate to make the solution weakly alkaline, the mixture was extracted twice with ethyl acetate. The organic layers were combined and dried, and then the solvent was distilled off to obtain 18.1 g of Compound (2) as a pale orange solid.
APCI-MS (m / e): 270/272 (M + H) ⁺

(2) The compound (2) was obtained by reacting and treating the compound (1) in the same manner as in Reference Example 22 (2).
APCI-MS (m / e): 318 (M + H) ⁺

（１）化合物（１）４．０ｇのＤＭＳＯ６０ｍｌ溶液に氷冷下、６０％水素化ナトリウム１．３５ｇをゆっくりと加え、０℃で１時間攪拌した。反応液にN‐ｔｅｒｔ−ブトキシカルボニル−Ｎ，N−ビス（２−クロロエチル）アミン４．５９ｇのＤＭＳＯ３０ｍｌ溶液を滴下し、室温で３時間攪拌した。反応液を氷水中に注ぎ、塩化メチレンで抽出し、水洗し、乾燥し、溶媒留去した。残渣をＮＨ−シリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝１００／０→１００／２０）で精製し、化合物（２）２．０３ｇを黄色油状物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２６５／２６７（Ｍ＋２Ｈ―ＢＯＣ）⁺

（２）化合物（１）１．０ｇの塩化メチレン６．０ｍｌ溶液に、トリフルオロ酢酸３．０ｍｌを加え、室温下で終夜攪拌した。反応液を減圧濃縮後、残渣に飽和重曹水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、乾燥し、溶媒留去した。残渣のＤＭＦ１０ｍｌ溶液に、０℃で６０％水素化ナトリウム１３４ｍｇを加え、室温で３０分攪拌した後、０℃でヨウ化エチル５９２μlを加え、室温で終夜攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を乾燥後、溶媒留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１００／０→９１／９）で精製し、化合物（２）４０３ｍｇを無色油状物として得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：２９３／２９５（Ｍ＋Ｈ）⁺

（３）化合物（１）を参考例２２（２）と同様に反応、処理することにより、化合物（２）を得た。
ＡＰＣＩ−ＭＳ（ｍ／ｅ）：３４１（Ｍ＋Ｈ）⁺ Reference Example 79

(1) Compound (1) To a solution of 4.0 g of DMSO in 60 ml of DMSO was slowly added 1.35 g of 60% sodium hydride under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. A solution of 4.59 g of N-tert-butoxycarbonyl-N, N-bis (2-chloroethyl) amine in 30 ml of DMSO was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, extracted with methylene chloride, washed with water, dried and evaporated. The residue was purified by NH-silica gel chromatography (hexane / ethyl acetate = 100/0 → 100/20) to obtain 2.03 g of Compound (2) as a yellow oil.
APCI-MS (m / e): 265/267 (M + 2H-BOC) ⁺

(2) To a solution of 1.0 g of compound (1) in 6.0 ml of methylene chloride was added 3.0 ml of trifluoroacetic acid, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. To a solution of the residue in DMF (10 ml) was added 60% sodium hydride (134 mg) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Then, ethyl iodide (592 μl) was added at 0 ° C. and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After the organic layer was dried, the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform / methanol = 100/0 → 91/9) to obtain 403 mg of compound (2) as a colorless oil.
APCI-MS (m / e): 293/295 (M + H) ⁺

(3) The compound (2) was obtained by reacting and treating the compound (1) in the same manner as in Reference Example 22 (2).
APCI-MS (m / e): 341 (M + H) ⁺

Experimental Example 1: Inhibitory action on MDC-induced mouse T cell migration The spleen excised from a mouse (male Balb / c) was ground in RPMI-1640 medium containing 2% FBS to obtain a spleen cell suspension. Red blood cells in the spleen cell suspension were removed by hemolysis of ammonium chloride, and further purified to T cells using a mouse T cell separation column (R & D Systems). Purified T cells were suspended in 10% FCS-containing RPMI-1640 medium containing IL-2 (20 ng / mL, R & D Systems), and the anti-CD3 antibody was immobilized on a 6-well plate at 37 ° C., 5% Cultivation was carried out for 4 days under CO ₂ conditions. After completion of the culture, T cells were suspended in RPMI-1640 medium (assay buffer) containing 0.5% bovine serum albumin and 25 mM HEPES to obtain a T cell suspension.
A test compound dissolved in dimethyl sulfoxide (DMSO) and diluted with an assay buffer and a T cell suspension (5 × 10 ⁵ cells / well) were added to the upper chamber of a 24-well transwell plate (Corning). The transwell used was preliminarily immobilized with gelatin (Nitta gelatin) and fibronectin (Sigma). To the lower chamber, a test compound prepared to have the same concentration as the upper chamber and mouse MDC dissolved in assay buffer (final concentration 30 ng / mL) were added. The upper chamber was overlapped with the lower chamber, and reacted at 37 ° C. and 5% CO ₂ for 90 minutes. After completion of the reaction, the number of cells that migrated to the lower chamber was counted using a flow cytometer (Becton Dickinson).
The inhibition rate (%) for the migration reaction of the test compound was calculated from the following formula.

Binding inhibition rate (%) = {1− (A−B) / (C−B)} × 100
A: Number of cells in a well to which MDC was added in the presence of a test compound B: Number of cells in a well to which MDC was not added in the absence of a test compound C: Number of cells in a well to which MDC was added in the absence of a test compound

The inhibition rate at each concentration of the test compound was calculated, and the compound concentration (IC ₅₀ value) showing the inhibition rate of 50% was determined from the inhibition curve. The results are shown in Table 1.

  The compound of the present invention or a pharmaceutically acceptable salt thereof has an excellent CCR4 or TARC and / or MDC function regulating action, and includes allergic diseases such as bronchial asthma and atopic dermatitis, inflammatory diseases and autoimmune diseases, etc. It is useful as a prophylactic or therapeutic drug.

Claims (6)

Formula (1)

Wherein ring A is a group selected from the group consisting of

Indicate
Ring B represents an optionally substituted aromatic carbocycle or an optionally substituted heterocycle;
G ¹ , G ² , G ³ , G ⁴ and G ⁵ are the same or different and each represents CH or N (provided that ^{two of} G ¹ , G ² , G ³ , G ⁴ and G ⁵ The above shows CH.)
Q represents an oxygen atom, a sulfur atom or —N (R ⁶ ) —,
m represents 1 or 2, n represents an integer of 1 to 3, w represents 0, 1 or 2,
X represents —N (R ⁷ ) —, —O— or —C (R ⁸ ) (R ⁹ ) —,
Y represents —C (R ¹⁰ ) (R ¹¹ ) —, —CO— or —SO ₂ —;
Z represents a single bond, —CO—, —SO ₂ —, —N (R ¹² ) —, —CON (R ¹³ ) —, —SO ₂ N (R ¹³ ) —, —N (R ¹³ ) CO—, — N (R ¹³ ) SO ₂ —, —N (R ¹⁴ ) CON (R ¹⁵ ) — or —N (R ¹⁴ ) SO ₂ N (R ¹⁵ ) —
R ¹ represents hydrogen, alkyl, alkoxy, halogen, carboxy, alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted amino, nitro, or optionally substituted ureido;
R ² represents hydrogen, alkyl, alkoxy, halogen, haloalkyl, carboxy, alkoxycarbonyl, optionally substituted carbamoyl or optionally substituted amino;
R ³ represents an optionally substituted carbocyclic group, an optionally substituted heterocyclic group or an optionally substituted alkyl;
R ⁴ represents hydrogen or alkyl,
R ⁵ represents hydrogen, alkyl or alkanoyl which may be substituted;
R ⁶ represents hydrogen, alkyl or an optionally substituted alkanoyl;
R ⁷ represents hydrogen or alkyl,
R ⁸ and R ⁹ and R ¹⁰ and R ¹¹ are the same or different and each represents hydrogen or alkyl;
R ¹² represents hydrogen, alkyl, alkanoyl or carboxyalkyl;
R ¹³ represents hydrogen or alkyl, and R ¹⁴ and R ¹⁵ are the same or different and each represents hydrogen or alkyl. )
A pharmaceutical comprising an aromatic compound represented by the formula: or a pharmaceutically acceptable salt thereof. The pharmaceutical according to claim 1, wherein ring A is a group selected from the group consisting of the following formulae.

(In the formula, each symbol has the same meaning as in claim 1.) The medicament according to claim 1 or 2, wherein ring A is a group selected from the group consisting of the following formulae.

(In the formula, each symbol has the same meaning as in claim 1.)   The pharmaceutical according to any one of claims 1 to 3, wherein Z is a single bond, -CONH-, -NHCO- or -CO-. R ³ is (1) (a) oxo, (b) hydroxymethyl, (c) alkyl, (d) amino optionally substituted mono- or di-substituted with alkyl, or (e) mono- or di-substituted with alkyl Pyrrolidine optionally substituted with carbamoyl, (2) alkyl, alkanoyl, cyano, piperidine optionally substituted with mono or disubstituted amino or oxo with alkyl, (3) alkyl substituted The pharmaceutical according to any one of claims 1 to 4, which is piperazine which may be substituted, (4) morpholine which may be substituted with alkyl, or (5) tetrahydropyridine which may be substituted with alkyl. 1 or X in which X is —NH—, Y is —CH ₂ —, —CH (CH ₃ ) — or —C (CH ₃ ) ₂ —, and ring B is selected from the group consisting of halogen, alkyl and haloalkyl. The medicine according to any one of claims 1 to 5, which is benzene substituted with two groups.