JP2006241089A - Pyrroloprymidine derivative or its salt - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound which can be used for preventing and treating respiratory diseases related to STAT6, especially asthma, chronic obstructive pulmonary diseases, and the like. <P>SOLUTION: This pyrroloprymidine derivative represented by general formula (I) [A: =CH-, =N-, or the like; R<SP>1</SP>is a lower alkyl, a heterocyclic group, or the like; R<SP>2</SP>is -H, -O- lower alkyl, or the like; or R<SP>1</SP>and R<SP>2</SP>together form a *-lower alkylene-, *-O-lower alkylene- or the like; R<SP>3</SP>is -H, a lower alkyl, or the like; R<SP>4</SP>is -H, -C(O)OR<SP>0</SP>, or the like; R<SP>5</SP>is a lower alkyl, a lower alkylene-aryl, or the like], or its salt. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a pyrrolopyrimidine derivative useful as a therapeutic agent for respiratory diseases involving pharmaceuticals, particularly STAT6 (Signal transducer and activator of transcription 6).

  Asthma is a disease characterized by chronic inflammation of the respiratory tract and reversible airway obstruction accompanied by overreaction, and it is known that CD4 positive T cells, especially type 2 helper T cells (Th2) cells, play an important role. It has been. Th2 cells are induced to differentiate from naive helper T cells (Thp) cells by interleukin-4 (IL-4). IL-4 and IL-13 produced by Th2 cells directly or indirectly induce airway contraction by inducing immunoglobulin E (IgE) antibody production, eosinophil activation / infiltration and increased mucus secretion And cause chronic inflammation of the respiratory tract. Furthermore, IL-13 is airway epithelial thickening observed in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), subepithelial fibrosis (Non-Patent Document 1) and alveolar destruction (Non-Patent Document 2). It has been reported that it is also involved in such organic changes.

  STAT6 is mediated by intracellular signal transduction of IL-4 and IL-13. Differentiation from Thp cells to Th2 cells does not occur due to deficiency of STAT6 (Non-patent Document 3), and in the asthma model of STAT6 deficient mice, IgE production, airway responsiveness, eosinophil infiltration into the airways and lungs (Non-patent Document 4) has been reported, suggesting the involvement of STAT6 in inflammatory respiratory diseases such as asthma.

  Moreover, STAT6 and IL-4 mRNA in the nasal mucosa are elevated by antigen administration to patients with allergic rhinitis (Non-patent Documents 5 and 6), and further, overexpression of IL-4 in mice causes inflammation in the skin. It has been reported that dermatitis-like symptoms such as cell infiltration are induced (Non-Patent Document 7), suggesting that STAT6 is involved in allergic rhinitis and dermatitis.

  STAT6 binds to the GYKXF motif of IL-4 receptor α chain (IL-4Rα) which is a component of IL-4 receptor and IL-13 receptor (Non-patent Document 8). Also binds JAK family kinases. When IL-4 or IL-13 binds to a receptor, STAT6 is tyrosine phosphorylated by a JAK family kinase, dimerizes, moves into the nucleus, and functions as a transcription factor (Non-patent Document 7). Therefore, if any of these processes, for example, tyrosine phosphorylation of STAT6 can be inhibited, the function of STAT6 as a transcription factor can be suppressed, and various diseases involving IL-4 and IL-13 can be suppressed. Expected to be effective for treatment.

  Syk tyrosine kinase (non-patent document 9), which is a Zap / Syk (zeta-associated protein / Spleen tyrosine kinase) family kinase, is classified as an antibody receptor (FcεRI). , FcγR) and signals from antigen receptors (B cell receptor (BCR), T cell receptor (TCR)) and granulocyte / macrophage colony-stimulating factor (GM-CSF) Therefore, it has been reported that Syk inhibitors are expected as inflammation or allergic diseases including asthma (for example, Patent Document 1). However, there are no reports showing that Syk is involved in IL-4 or IL-13 signals. Syk inhibitors suppress all antigen-mediated activation of B and T cells, inhibit antibody production regardless of subclass for antibodies, and nonspecifically helper T cells for T cell subsets It is thought that the effect is expressed by suppressing differentiation. That is, it is predicted that Syk inhibitors are necessarily accompanied by suppressive actions such as infection protection and immune function. STAT6 inhibitors, on the other hand, specifically suppress ILE production in antibodies and Th2 differentiation in T cell subsets because STAT6 functions are specific to IL-4 and IL-13. Therefore, STAT6 inhibitors are expected to be effective as therapeutic agents for allergies or inflammatory respiratory diseases that have little effect on infection defense, immune function, and the like (Non-patent Document 10).

（式中の記号は公報参照） In Patent Document 2, a dihydrothiadiazole derivative represented by the following general formula (A) (Patent Document 2) is reported as a STAT6 activation inhibitor. However, the structure is different from the pyrrolopyrimidine derivative which is the compound of the present invention.

(See the official gazette for symbols in the formula)

（式中の記号は公報参照） Patent Document 3 reports an imidazopyrimidine derivative represented by the following general formula (B) as a STAT6 activation inhibitor. However, the structure is different from the pyrrolopyrimidine derivative which is the compound of the present invention.

(See the official gazette for symbols in the formula)

（式中の記号は公報参照） Patent Document 4 reports a benzofuran derivative represented by the following general formula (C) as a STAT6 activation inhibitor. However, the structure is different from the pyrrolopyrimidine derivative which is the compound of the present invention.

(See the official gazette for symbols in the formula)

（式中の記号は公報参照） Patent Document 5 reports an imidazo [2,1-b] thiazole derivative represented by the following general formula (D) as a STAT6 activation inhibitor. However, the structure is different from the pyrrolopyrimidine derivative which is the compound of the present invention.

(See the official gazette for symbols in the formula)

（式中の記号は公報参照） Patent Document 6 reports a tetrahydroquinoline derivative represented by the following general formula (E) as a STAT6 activation inhibitor. However, the structure is different from the pyrrolopyrimidine derivative which is the compound of the present invention.

(See the official gazette for symbols in the formula)

（式中の記号は公報参照） Patent Document 7 reports a pyrimidinecarboxamide derivative represented by the following general formula (F) as a STAT6 activation inhibitor. However, the structure is different from the pyrrolopyrimidine derivative which is the compound of the present invention.

(See the official gazette for symbols in the formula)

（式中のA、Y、R及びXは以下の意味を示す。
A：NまたはCH。X：O、NR³またはS。Y：結合、O、N(R’)、C(=O)、CH(OR’)、CHR’またはS(O)n。R：アリールまたはヘテロアリール。他の式中の記号は公報参照） Patent Document 8 reports a derivative represented by the following general formula (G) as a p38 kinase inhibitor useful for the treatment of inflammatory / allergic diseases, immune diseases and the like. However, the structure differs from the pyrrolopyrimidine derivative of the compound of the present invention in that the structure at the 6-position is bonded to aryl or heteroaryl via a bond. In addition, not only the action on STAT6 but also the action on IL-4 and IL-13 is not disclosed.

(In the formula, A, Y, R and X have the following meanings.
A: N or CH. X: O, NR ³ or S. Y: a bond, O, N (R ′), C (═O), CH (OR ′), CHR ′ or S (O) n. R: aryl or heteroaryl. Refer to the gazette for symbols in other formulas)

（式中のZはNまたはCHを示す。他の式中の記号は公報参照） Patent Document 9 reports a derivative represented by the following general formula (H) as a compound that inhibits a cyclin-dependent kinase useful as a therapeutic agent for inflammatory / allergic diseases, immune diseases and the like. Yes. However, what is described as examples is limited to purine derivatives, and pyrrolo [2,3-d] pyrimidine derivatives are not specifically described as examples. In addition, not only the action on STAT6 but also the action on IL-4 and IL-13 is not disclosed.

(Z in the formula represents N or CH. Refer to the gazette for symbols in other formulas)

（式中のA、B、C、D、Ｘ及びＹは以下の意味を示す。
A、B、C、D：それぞれ独立して窒素原子あるいは炭素原子。X：窒素原子あるいは炭素原子。Y：窒素原子あるいは炭素原子等。他の式中の記号は公報参照）
Patent Document 10 reports a derivative represented by the general formula (J) as a compound that suppresses adhesion molecule expression from vascular endothelial cells useful as an anti-inflammatory agent / anti-allergic agent or anti-rheumatic agent. However, pyrrolo [2,3-d] pyrimidine derivatives in which A, C and Y are carbon atoms and B, D and X are nitrogen atoms are not specifically described as examples. In addition, not only the action on STAT6 but also the action on IL-4 and IL-13 is not disclosed.

(A, B, C, D, X and Y in the formula have the following meanings.
A, B, C, D: each independently a nitrogen atom or carbon atom. X: Nitrogen atom or carbon atom. Y: Nitrogen atom or carbon atom. Refer to the gazette for symbols in other formulas)

"The Journal of Clinical Investigation" (USA), 1999, 103, 6, p. 779-788 "The Journal of Clinical Investigation" (USA), 2000, 106, 9, p.1081-1093 “Immunity” (USA), 1996, Volume 4, pages 313-319 "The Journal of Experimental Medicine" (USA), 1998, Vol. 187, No. 9, p.1537-1542 “Clinical and Experimental Allergy” (UK), Volume 30, pages 86-93 “Clinical and Experimental Allergy” (UK), Volume 30, pages 1709-1716 “The Journal of Investigative Dermatology” (USA), 2001, Vol. 117, No. 4, pp.977-983 “Science” (USA), 1994, Volume 165, pp. 1265-1267 “Genome Biology”, (UK), Volume 3, research0043.1-0043.12 “The Journal of Clinical Investigation” (USA), 2002, 109, pp. 1279-1283 International Publication No. 99/31073 Pamphlet JP 2000-229959 A International Publication No. 02/14321 Pamphlet WO 02/53550 pamphlet JP-A-11-106340 International Publication No. 02/79165 Pamphlet International Publication No. 2004/002964 Pamphlet International Publication No. 03/74530 Pamphlet International Publication No. 01/49688 Pamphlet JP-A-9-176116

  Existing therapeutic agents for respiratory diseases such as asthma and COPD are not satisfactory in terms of efficacy and safety, and are effective in treating asthma and respiratory diseases such as COPD with excellent efficacy and safety. The offer of is anxious.

  As mentioned above, having STAT6 inhibitory activity is expected to be useful as a therapeutic agent for respiratory diseases such as asthma and COPD, and other inflammatory and allergic diseases, which have little effect on immunosuppressive function. it can. Therefore, the present inventors have provided a novel compound useful for the treatment of respiratory diseases and the like with few side effects, and further, for the purpose of providing a medicament containing these compounds, a compound having an activity of inhibiting the activation of STAT6. Researched earnestly. As a result, the inventors discovered that a novel pyrrolopyrimidine derivative has a potent and selective STAT6 inhibitory action, and completed the present invention.

［式中の記号は以下の意味を示す。
A：=C(R⁰)-、または=N-。
R⁰ _、R^0a _、R^0b _、R^0c：同一または互いに異なって、-Hまたは低級アルキル。

R¹：-H、-R^x、ハロゲン、-CN、ヘテロ環または-L-R^1aで示される基。ただし、ヘテロ環はP群より選択される基で置換されていてもよい。

L：*-O-、*-NR⁰-、*-S-、*-S(O)₂-、*-C(O)-、*-C(O)O-、*-OC(O)-、*-C(O)NR⁰-、*-NR⁰C(O)-、*-NR⁰-C(O)NR^0a-、*-O-C(O)NR⁰-、*-NR⁰-C(O)O-、*-O-低級アルキレン、*-NR⁰-低級アルキレン、*-S-低級アルキレン、*-SO₂-低級アルキレン、*-C(O)-低級アルキレン、*-C(O)O-低級アルキレン、*-OC(O)-低級アルキレン、*-C(O)NR⁰-低級アルキレンまたは*-NR⁰C(O)-低級アルキレン。ただし、*はR^1aへの結合を示す。

R^1a：-H、-R^1b、シクロアルキル、低級アルキレン-シクロアルキル、アリール、低級アルキレン-アリール、ヘテロ環、低級アルキレン-へテロ環または低級アルキレン-NR⁰-へテロ環。
ただし、シクロアルキル及び低級アルキレン-シクロアルキルのシクロアルキル部分はQ群より選択される基で置換されていてもよく、アリール及び低級アルキレン-アリールのアリール部分、並びにヘテロ環、低級アルキレン-へテロ環及び低級アルキレン-NR⁰-へテロ環のヘテロ環部分はP群から選択される基で置換されていてもよい。

R^1b:G¹群から選択される基で置換されていてもよい低級アルキル。
G¹群：ハロゲン、-CN、-OR⁰、-O-低級アルキレン-OR⁰、-S-低級アルキル、-S(O)-低級アルキル、-S(O)₂-低級アルキル、-NR⁰R^0a、-NR⁰-低級アルキレン-OR^0a、-N(低級アルキレン-OR⁰)(低級アルキレン-OR^0a)、-Si(低級アルキル)₃、-C(O)OR⁰、-C(O)NR⁰R^0a、-C(O)NR⁰-ハロゲノ低級アルキル、-C(O)NR⁰-低級アルキレン-OR^0a、-C(O)NR⁰-低級アルキレン-NR^0aR^0b、-C(O)NR⁰-低級アルキレン-C(O)OR^0a、-OC(O)R⁰、-NR⁰C(O)-R^0a、-NR⁰S(O)₂-低級アルキル及び-NR⁰S(O)₂-アリール。ただし-NR⁰S(O)₂-アリールのアリール部分は、低級アルキル、ハロゲン、-OH、-O-低級アルキル、-O-ハロゲノ低級アルキルまたはオキソで置換されていてもよい。

P群：-R^X、ハロゲンで置換されていてもよい低級アルケニル、-ハロゲン、-OH、-O-R^X、オキソ、-CN、-ニトロ、-NH₂、-NH-R^X、-NR^XR^Xa、-C(O)H、-C(O)-R^X、-C(O)OH、-C(O)O-R^X、-C(O)NH₂、-C(O)NH-R^X、-C(O)NR^XR^Xa、-NR⁰C(O)-R^X、-NR⁰C(O)NR^0aR^0b、-NR⁰C(=NR^0a)NR^0bR^0c、-NR⁰S(O)₂-低級アルキル、-S-低級アルキル、-S(O)-低級アルキル、-S(O)₂-低級アルキル、シクロアルキル、アリール及びヘテロ環。
ただし、アリール及びヘテロ環は、低級アルキル、ハロゲノ低級アルキル、ハロゲン、-OH、-O-低級アルキル、-O-ハロゲノ低級アルキルまたはオキソで置換されていてもよい。

Q群：低級アルキル、低級アルキレン-OR⁰、低級アルキレン-C(O)OR⁰、低級アルキレン-C(O)NR⁰R^0a、-OR⁰、オキソ、-NR⁰R^0a、-C(O)OR⁰、-C(O)NR⁰R^0a、-NHC(O)-低級アルキル、-C(O)-低級アルキル、アリール及びヘテロ環。
ただしアリール及びヘテロ環は低級アルキル、ハロゲノ低級アルキル、ハロゲン、-OH、-O-低級アルキル、-O-ハロゲノ低級アルキルまたはオキソで置換されていてもよい。

R^X、R^Xa:同一または互いに異なって、G²群から選択される基で置換されていてもよい低級アルキル。
G²群：ハロゲン、-CN、-OR⁰、-O-低級アルキレン-OR⁰、-S-低級アルキル、-S(O)-低級アルキル、-S(O)₂-低級アルキル、-NR⁰R^0a、-NR⁰-低級アルキレン-OR^0a、-N(低級アルキレン-OR⁰)(低級アルキレン-OR^0a)、-Si(低級アルキル)₃、-C(O)OR⁰、-C(O)NR⁰R^0a、-C(O)NR⁰-ハロゲノ低級アルキル、-C(O)NR⁰-低級アルキレン-OR^0a、-C(O)NR⁰-低級アルキレン-NR^0aR^0b、-C(O)NR⁰-低級アルキレン-C(O)OR^0a、-OC(O)R⁰、-NR⁰C(O)-R^0a、-NR⁰S(O)₂-低級アルキル、-NR⁰S(O)₂-アリール、シクロアルキル、アリール及びヘテロ環。
ただしアリール、-NR⁰S(O)₂-アリールのアリール部分及びヘテロ環は、低級アルキル、ハロゲン、-OH、-O-低級アルキル、-O-ハロゲノ低級アルキルまたはオキソで置換されていてもよい。

R²：-H、-CN、低級アルキル、ハロゲノ低級アルキル、低級アルキレン-OR⁰、ハロゲン、-OR⁰、-O-ハロゲノ低級アルキル、-O-低級アルキレン-OR⁰、-O-低級アルキレン-NR⁰R^0a、-O-低級アルキレン-C(O)OR⁰、-O-低級アルキレン-C(O)NR⁰R^0a、-NR⁰R^0a、-NR⁰C(O)-R^0a、-C(O)R⁰、-C(O)OR⁰、-C(O)NR⁰R^0a、-C(O)NR⁰-低級アルキレン-NR^0aR^0b、-S-低級アルキル、-S(O)-低級アルキル、-S(O)₂-低級アルキル、シクロアルキル、-O-シクロアルキル、-O-低級アルキレン-シクロアルキル、アリール、-O-アリール、-O-低級アルキレン-アリール、-NR⁰-アリール、-C(O)NR⁰-アリール、-NR⁰C(O)-アリール、ヘテロ環、-O-ヘテロ環、-O-低級アルキレン-ヘテロ環、-NR⁰-ヘテロ環、-C(O)NR⁰-ヘテロ環、-NR⁰C(O)-ヘテロ環または-C(O)NR⁰-低級アルキレン-ヘテロ環。
ただし、アリール、-O-アリール、-O-低級アルキレン-アリール、-NR⁰-アリール、-C(O)NR⁰-アリール及び-NR⁰C(O)-アリールのアリール部分、並びに、ヘテロ環、-O-ヘテロ環、-O-低級アルキレン-ヘテロ環、-NR⁰-ヘテロ環、-C(O)NR⁰-ヘテロ環、-NR⁰C(O)-ヘテロ環及び-C(O)NR⁰-低級アルキレン-ヘテロ環のヘテロ環部分は低級アルキル、ハロゲン、-OH、-O-低級アルキル、-O-ハロゲノ低級アルキル、オキソ、-NR⁰R^0a、-SR⁰、-SO₂R⁰、-C(O)R⁰、-C(O)OR⁰、-C(O)NR⁰R^0a、-CNまたは-NR⁰C(O)-R^0aで置換されていてもよい。

或いは、R¹、R²が一体となって*-低級アルキレン-、*-O-低級アルキレン-、*-低級アルキレン-O-、*-低級アルキレン-O-低級アルキレン-、*-O-低級アルキレン-O-、*-N(R⁶)-低級アルキレン-、*-低級アルキレン-N(R⁶)-、*-低級アルキレン-N(R⁶)-低級アルキレン-、*-N(R⁶)-CH=CH-、*-CH=CH-N(R⁶)-、*-N=CH-CH=CH-、*-CH=N-CH=CH-、*-CH=CH-N=CH-、*-CH=CH-CH=N-、*-N=CH-CH=N-、*-CH=N-N=CH-、*-N(R⁶)-N=CH-、*-CH=N-N(R⁶)-、*-CH=CH-C(O)-O-、*-N(R⁶)-C(R⁰)=N-、*-N=C(R⁰)-N(R⁶)-、*-N=C(ハロゲノ低級アルキル)-N(R⁶)-または*-N(R⁶)-C(ハロゲノ低級アルキル)=N-を形成していてもよい（ただし、*はR¹で示す位置への結合を示す。）。ただし、*-低級アルキレン-、*-O-低級アルキレン-、*-低級アルキレン-O-、*-低級アルキレン-O-低級アルキレン-、*-O-低級アルキレン-O-、*-N(R⁶)-低級アルキレン、*-低級アルキレン-N(R⁶)-及び*-低級アルキレン-N(R⁶)-低級アルキレン-の低級アルキレン部分はハロゲン、-OR⁰またはオキソで置換されていてもよい。

R⁶：-H、低級アルキル、-C(O)-低級アルキル、-C(O)-へテロ環、-C(O)O-低級アルキル、低級アルキレン-OR⁰、低級アルキレン-O-低級アルキレン-OR⁰、低級アルキレン-C(O)OR⁰または低級アルキレン-C(O)NR⁰R^0a。

R³：-H、低級アルキル、ハロゲン、-OR⁰、-NR⁰R^0a、低級アルキレン-OR⁰、低級アルキレン-NR⁰R^0aまたは-NR⁰C(O)-R^0a。
R⁴：-H、-C(O)OR⁰または-C(O)NR⁰R^0a。
R⁵：低級アルキル、アリール、低級アルキレン-アリールまたは低級アルキレン-ヘテロ環。
ただし、アリール及び低級アルキレン-アリールのアリール部分及び低級アルキレン-ヘテロ環のヘテロ環部分は低級アルキル、ハロゲン、-OH、-O-低級アルキル、-O-ハロゲノ低級アルキル、-NR⁰R^0a、-SR⁰、-S(O)₂R⁰、-C(O)R⁰、-C(O)OR⁰、-C(O)NR⁰R^0a、-CNまたは-NR⁰C(O)-R^0aで置換されていてもよい。］
That is, the present invention relates to a novel pyrrolopyrimidine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, and a medicament containing these as active ingredients.

[The symbols in the formula have the following meanings.
A: = C (R ⁰ )-or = N-.
R ⁰ _, R ^0a _, R ^0b _, R ^0c : the same or different from each other, —H or lower alkyl.

R ¹ : a group represented by —H, —R ^x , halogen, —CN, heterocycle or —LR ^1a . However, the heterocycle may be substituted with a group selected from the P group.

L: * -O-, * -NR ^0- , * -S-, * -S (O) _2- , * -C (O)-, * -C (O) O-, * -OC (O) -, * -C (O) NR ^0- , * -NR ⁰ C (O)-, * -NR ⁰ -C (O) NR ^0a- , * -OC (O) NR ^0- , * -NR ^0- C (O) O-, * -O-lower alkylene, * -NR ⁰ -lower alkylene, * -S-lower alkylene, * -SO ₂ -lower alkylene, * -C (O) -lower alkylene, * -C (O) O-lower alkylene, * -OC (O) -lower alkylene, * -C (O) NR ⁰ -lower alkylene or * -NR ⁰ C (O) -lower alkylene. However, * shows the coupling ^| bonding to R1a.

R ^1a : —H, —R ^1b , cycloalkyl, lower alkylene-cycloalkyl, aryl, lower alkylene-aryl, heterocycle, lower alkylene-heterocycle or lower alkylene-NR ⁰ -heterocycle.
However, the cycloalkyl part of cycloalkyl and lower alkylene-cycloalkyl may be substituted with a group selected from group Q, the aryl part of aryl and lower alkylene-aryl, and the heterocycle, lower alkylene-heterocycle And the heterocyclic portion of the lower alkylene-NR ⁰ -heterocycle may be substituted with a group selected from the group P.

R ^1b : lower alkyl optionally substituted with a group selected from group G ¹ .
G ¹ group: halogen, —CN, —OR ⁰ , —O-lower alkylene —OR ⁰ , —S-lower alkyl, —S (O) -lower alkyl, —S (O) ₂ -lower alkyl, —NR ⁰ R ^0a , -NR ⁰ -lower alkylene-OR ^0a , -N (lower alkylene-OR ⁰ ) (lower alkylene-OR ^0a ), ^-Si (lower alkyl) ₃ , -C (O) OR ⁰ , -C (O ) NR ⁰ R ^0a , -C (O) NR ⁰ -halogeno lower alkyl, -C (O) NR ⁰ -lower alkylene-OR ^0a , -C (O) NR ⁰ -lower alkylene-NR ^0a R ^0b , -C (O) NR ⁰ -lower alkylene-C (O) OR ^0a , -OC (O) R ⁰ , -NR ⁰ C (O) -R ^0a , -NR ⁰ S (O) ₂ -lower alkyl and -NR ⁰ S (O) ₂ -aryl. However, the aryl part of —NR ⁰ S (O) ₂ -aryl may be substituted with lower alkyl, halogen, —OH, —O-lower alkyl, —O-halogeno lower alkyl or oxo.

Group P: —R ^X , lower alkenyl optionally substituted with halogen, —halogen, —OH, —OR ^X , oxo, —CN, —nitro, —NH ₂ , —NH—R ^X , —NR ^X R ^{xa, -C (O) H,} -C (O) -R X, -C (O) OH, -C (O) OR X, -C (O) NH 2, -C (O) NH-R X , -C (O) NR ^X R ^Xa , -NR ⁰ C (O) -R ^X , -NR ⁰ C (O) NR ^0a R ^0b , -NR ⁰ C (= NR ^0a ) NR ^0b R ^0c , -NR ⁰ S (O) ₂ -lower alkyl, -S-lower alkyl, -S (O) -lower alkyl, -S (O) ₂ -lower alkyl, cycloalkyl, aryl and heterocycle.
However, the aryl and heterocycle may be substituted with lower alkyl, halogeno lower alkyl, halogen, —OH, —O-lower alkyl, —O-halogeno lower alkyl or oxo.

Q group: lower alkyl, lower alkylene-OR ⁰ , lower alkylene-C (O) OR ⁰ , lower alkylene-C (O) NR ⁰ R ^0a , —OR ⁰ , oxo, —NR ⁰ R ^0a , —C (O ) OR ⁰ , —C (O) NR ⁰ R ^0a , —NHC (O) -lower alkyl, —C (O) -lower alkyl, aryl and heterocycle.
However, the aryl and heterocycle may be substituted with lower alkyl, halogeno lower alkyl, halogen, —OH, —O-lower alkyl, —O-halogeno lower alkyl or oxo.

R ^X , R ^Xa : lower alkyl which may be the same or different from each other and may be substituted with a group selected from Group G ² .
Group G ² : halogen, —CN, —OR ⁰ , —O-lower alkylene —OR ⁰ , —S-lower alkyl, —S (O) -lower alkyl, —S (O) ₂ -lower alkyl, —NR ⁰ R ^0a , -NR ⁰ -lower alkylene-OR ^0a , -N (lower alkylene-OR ⁰ ) (lower alkylene-OR ^0a ), ^-Si (lower alkyl) ₃ , -C (O) OR ⁰ , -C (O ) NR ⁰ R ^0a , -C (O) NR ⁰ -halogeno lower alkyl, -C (O) NR ⁰ -lower alkylene-OR ^0a , -C (O) NR ⁰ -lower alkylene-NR ^0a R ^0b , -C (O) NR ⁰ -lower alkylene-C (O) OR ^0a , -OC (O) R ⁰ , -NR ⁰ C (O) -R ^0a , -NR ⁰ S (O) ₂ -lower alkyl, -NR ⁰ S (O) ₂ -aryl, cycloalkyl, aryl and heterocycle.
Provided that the aryl moiety and the heterocycle of aryl, —NR ⁰ S (O) ₂ -aryl may be substituted with lower alkyl, halogen, —OH, —O-lower alkyl, —O-halogeno lower alkyl or oxo. .

R ² : —H, —CN, lower alkyl, halogeno lower alkyl, lower alkylene —OR ⁰ , halogen, —OR ⁰ , —O-halogeno lower alkyl, —O-lower alkylene —OR ⁰ , —O-lower alkylene— NR ⁰ R ^0a , -O-lower alkylene-C (O) OR ⁰ , -O-lower alkylene-C (O) NR ⁰ R ^0a , -NR ⁰ R ^0a , -NR ⁰ C (O) -R ^0a , -C (O) R ⁰ , -C (O) OR ⁰ , -C (O) NR ⁰ R ^0a , -C (O) NR ⁰ -lower alkylene-NR ^0a R ^0b , -S-lower alkyl, -S (O) -lower alkyl, --S (O) ₂ -lower alkyl, cycloalkyl, --O-cycloalkyl, --O-lower alkylene-cycloalkyl, aryl, --O-aryl, --O-lower alkylene-aryl, -NR ⁰ -aryl, -C (O) NR ⁰ -aryl, -NR ⁰ C (O) -aryl, heterocycle, -O-heterocycle, -O-lower alkylene-heterocycle, -NR ⁰ -heterocycle , -C (O) NR ⁰ -heterocycle, -NR ⁰ C (O) -heterocycle or -C (O) NR ⁰ -lower alkylene-heterocycle.
Provided that aryl, -O-aryl, -O-lower alkylene-aryl, -NR ⁰ -aryl, -C (O) NR ⁰ -aryl and -NR ⁰ C (O) -aryl aryl moieties, and heterocycles , -O-heterocycle, -O-lower alkylene-heterocycle, -NR ⁰ -heterocycle, -C (O) NR ⁰ -heterocycle, -NR ⁰ C (O) -heterocycle and -C (O) The heterocycle part of NR ⁰ -lower alkylene-heterocycle is lower alkyl, halogen, —OH, —O-lower alkyl, —O-halogeno lower alkyl, oxo, —NR ⁰ R ^0a , —SR ⁰ , —SO ₂ R ^{0, -C (O) R 0} , -C (O) oR 0, -C (O) NR 0 R 0a, optionally substituted by -CN or ^{-NR 0 C (O) -R 0a} .

Or, R ¹ and R ² are combined into * -lower alkylene-, * -O-lower alkylene-, * -lower alkylene-O-, * -lower alkylene-O-lower alkylene-, * -O-lower. Alkylene-O-, * -N (R ⁶ ) -lower alkylene-, * -lower alkylene-N (R ⁶ )-, * -lower alkylene-N (R ⁶ ) -lower alkylene-, * -N (R ⁶ ) -CH = CH-, * -CH = CH-N (R ⁶ )-, * -N = CH-CH = CH-, * -CH = N-CH = CH-, * -CH = CH-N = CH-, * -CH = CH-CH = N-, * -N = CH-CH = N-, * -CH = NN = CH-, * -N (R ⁶ ) -N = CH-, * -CH = NN (R ⁶ )-, * -CH = CH-C (O) -O-, * -N (R ⁶ ) -C (R ⁰ ) = N-, * -N = C (R ⁰ ) -N (R ⁶ )-, * -N = C (halogeno lower alkyl) -N (R ⁶ )-or * -N (R ⁶ ) -C (halogeno lower alkyl) = N- , * Indicates a bond to the position indicated by R ¹ ). However, * -lower alkylene-, * -O-lower alkylene-, * -lower alkylene-O-, * -lower alkylene-O-lower alkylene-, * -O-lower alkylene-O-, * -N (R ⁶ ) -Lower alkylene, * -lower alkylene-N (R ⁶ )-and * -lower alkylene-N (R ⁶ ) -lower alkylene-lower alkylene part may be substituted by halogen, -OR ⁰ or oxo Good.

R ⁶ : -H, lower alkyl, -C (O) -lower alkyl, -C (O) -heterocycle, -C (O) O-lower alkyl, lower alkylene-OR ⁰ , lower alkylene-O-lower Alkylene-OR ⁰ , lower alkylene-C (O) OR ⁰ or lower alkylene-C (O) NR ⁰ R ^0a .

R ³ : —H, lower alkyl, halogen, —OR ⁰ , —NR ⁰ R ^0a , lower alkylene —OR ⁰ , lower alkylene —NR ⁰ R ^0a or —NR ⁰ C (O) —R ^0a .
R ⁴ : —H, —C (O) OR ⁰ or —C (O) NR ⁰ R ^0a .
R ⁵ : lower alkyl, aryl, lower alkylene-aryl or lower alkylene-heterocycle.
Provided that the aryl moiety of aryl and lower alkylene-aryl and the heterocyclic moiety of the lower alkylene-heterocycle are lower alkyl, halogen, -OH, -O-lower alkyl, -O-halogeno lower alkyl, -NR ⁰ R ^0a ,- SR ⁰ , -S (O) ₂ R ⁰ , -C (O) R ⁰ , -C (O) OR ⁰ , -C (O) NR ⁰ R ^0a , -CN or -NR ⁰ C (O) -R ^It may be substituted with ^0a . ]

The usefulness of the compound (I) of the present invention was confirmed by the following test.
Test Example 1 STAT6-dependent reporter activity measurement 1) Construction of STAT6-responsive reporter plasmid
STAT6 reporter plasmid pGL2-CI was prepared by the following method. Germline An annealed synthetic deoxyribonucleic acid (DNA) (SEQ ID NO: 1 and 2) containing C / EBP binding sequence and IL-4 reactive sequence in ε promoter sequence in tandem, and pGL2-Basic vector (Promega (Promega)) at the XhoI and BglII sites. Furthermore, TATA box sequence DNA (SEQ ID NOs: 3 and 4) present on the adenovirus major late promoter was synthesized, annealed, and inserted into the BglII and HindIII sites of the same vector. Furthermore, pGL2-CI / bs was constructed by inserting the blasticidin resistance gene of pUCSV-BSD (Funakoshi) into the BamHI site of the constructed pGL2-CI.
2) Construction of STAT6 reporter cells pGV in FW4 cells ("Molecular and Cellular Biology", (USA), Vol. 14, p.5433-5440), a human IL-4-responsive cell -CI / bs was transfected by electroporation (320V, 960μF / 0.4 cm cuvettes (Nippon Bio-Rad)), and after 40 hours, 6μg / ml blasticidin (Funakoshi) was added and resistant cells were added. Selected. Whether or not the reporter plasmid was constitutively introduced was determined by detecting luciferase induced by IL-4 stimulation. STAT6 reporter cell CI / FW4 was constructed by the above operation.
3) STAT6 reporter assay using CI / FW4 cells
CI / FW4 cells (1 x 10 ⁴ cells / 0.1 ml) in white 96-well plate (Nunc) 10 ng / ml human IL-4 (Genzyme Techne) Stimulation was performed. For compound evaluation, compound dilutions were added into the wells before the cells were seeded into 96-well plates. The compound was diluted with RPMI1640 medium containing 10% fetal bovine serum (FBS) so that the final concentration of dimethyl sulfoxide (DMSO) in which the compound was dissolved was 0.1% or less. 16 hours after IL-4 stimulation 50 μl of cell lysis buffer (10 mM Tris (hydroxymethyl) aminomethane-HCl buffer (Tris-HCl) pH 7.8, 0.5 mM magnesium chloride (MgCl ₂ ), 10 mM dithiothreitol (Ditiothreitol) and 0.1% (v / v) nonionic surfactant (registered trademark: Triton X-100) were added and stirred for 1 minute, followed by luciferase substrate solution (10 mM Tris-HCl pH 7.8, 5 Add 50 μl of mM luciferin, 2 mM coenzyme A, 2 mM adenosine triphosphate (ATP), 0.5 mM MgCl ₂ and 2 mM magnesium hydroxide (Mg (OH) ₂ ), and stir for 1 minute Later, the luciferase activity was measured using a luminescence measuring device (trade name: ML3000 luminometer, Dynatech Laboratories, Inc.) The relative value of the measured value in ML3000 when DMSO was added instead of the compound Emission intensity (Relative Light Unit: RLU) is 100% and IL-4 is stimulated The RLU when no 0%, was evaluated the inhibitory activity of the test compound.
The results are shown in Table 1 below. Ex represents an Example compound number described later, and Inh represents an inhibition rate when the test compound is 0.1 μM.

Test Example 2 Measurement of STAT6 tyrosine phosphorylation
H292 cells (ATCC) (2 x 10 ⁵ cells / 0.5 ml) were seeded in a 12-well plate (IWAKI), and after overnight culture, 1 ng / ml human IL-4 (Genzyme Techne) (Genzyme Techne)) Stimulation was performed. In the case of compound evaluation, the compound dilution was added into the well 1 hour before IL-4 stimulation. The compound was diluted with RPMI1640 containing 10% FBS so that the final concentration of DMSO in which the compound was dissolved was 0.1% or less. After 5 minutes of IL-4 stimulation, the culture supernatant was aspirated and discarded, and then cell lysate (TNE buffer: 10 mM Tris-HCl pH7.8, 1% surfactant NP-40, 0.15 M sodium chloride ( NaCl), 1 mM disodium ethylenediaminetetraacetate (EDTA), 10μg / ml aprotinin (aprotinin), a 1 mM sodium fluoride (NaF) and 1 mM orthovanadate (V) sodium _{(Na 3 VO 4) 100μl /} well The cell lysate was collected, and 15 μl was subjected to SDS electrophoresis and Western blotting with an anti-tyrosine phosphorylated STAT6 antibody (Santa Cruz), which is around 110 kDa detected depending on IL-4 stimulation. It was determined whether the tyrosine phosphorylated band disappeared, and the STAT6 protein was uniformly transcribed by Western blot using an anti-STAT6 antibody (Santa Cruz) using the same transcription membrane. It was confirmed.
As a result of the above test, it was confirmed that tyrosine phosphorylation was inhibited by the compound of the present invention.

Test Example 3 Th2 differentiation measurement
N-wool (Wako Pure Chemical Industries) adherent cells were removed from spleen cells of C57BL / 6 mice (Nippon Charles River) to prepare T cells. Anti-CD28 antibody (1 μg / ml) (Pharmingen), interleukin − using a 96-well plate preliminarily immobilized with anti-CD3ε antibody (10 μg / ml) (Sederlane) Seeding T cells (2 x 10 ⁵ cells / 0.2 ml) under stimulation with 2 (IL-2) (10 ng / ml) (Peprotech) and IL-4 (10 ng / ml) (Peprotech) did. After culturing for 2 days, the total cell suspension was diluted to 1 ml with a medium containing IL-2 (10 ng / ml) and IL-4 (10 ng / ml). Further, the cells were cultured for 3 days to induce differentiation. The cell concentration was counted, and the differentiated cells prepared to 1 × 10 ⁶ cells / ml were seeded on a 96-well plate on which an anti-CD3ε antibody was immobilized to induce IL-4 production. The supernatant after 24-hour stimulation was collected, and the amount of IL-4 produced was quantified by ELISA (enzyme-linked immunosorbent assay). The biotinylated antibody used for ELISA was purchased from Pharmingen. Further, horseradish peroxidase (HRPO) -labeled streptavidin (Amersham Pharmacia) was used for detection of biotinylated antibody, and peroxidase coloring reagent (Sumitomo Bakelite) was used for HRPO color development. In the case of compound evaluation, a compound dilution was added to the well before addition of T cells, and a compound equal to the initial concentration was added even at the time of dilution after 2 days. The compound was diluted with RPMI1640 medium containing 10% FBS so that the final concentration of dimethyl sulfoxide (DMSO) in which the compound was dissolved was 0.1% or less. IL-4 production when DMSO is added instead of compound is 100%, IL-4 production when anti-CD28 antibody and IL-4 are not added is 0%, and the concentration at which the test compound inhibits by 50% Was defined as IC ₅₀ of Th2 differentiation inhibitory activity of the compound.
As a result of the above test, it was confirmed that the compound of the present invention inhibits Th2 differentiation.

Test Example 4 Evaluation in mouse asthma model Active sensitization was performed by twice intraperitoneally administering ovalbumin (OA) and adjuvant aluminum hydroxide gel (Alum) to female Balb / c mice. Twelve days after the first sensitization, OA was exposed by inhalation. After 72 hours of exposure, the mice were exsanguinated and then alveolar lavage was performed. As a test compound and a control, 0.5% methylcellulose was orally administered for 3 days from the day of OA exposure. After measuring the total leukocyte count in the alveolar lavage fluid, the cell smear was stained, and the total number of eosinophils was calculated from the abundance ratio of eosinophils determined from the morphological characteristics. As a result, the compound of the present invention satisfactorily suppressed the number of eosinophils infiltrating into the respiratory tract and alveoli.

Inhibition of immune cell activation by stimulating antigen receptors is also due to inhibition of increased intracellular calcium concentration in B cell lines (RAMOS cells) by stimulation with IgM antibodies ("Advances in Immunology") (US), 2000, vol. 75, p.283-316) or inhibition of IL-2 production from mouse spleen-derived T cells by anti-CD3 antibody stimulation (“Japanese clinical”, 1999, vol. 57, p.273-277). As a result, it was confirmed that the compound of the present invention has a high inhibition of STAT6 activation compared with the immune cell activation inhibition action by antigen receptor stimulation, and selectively inhibits STAT6 activation.

Hereinafter, the present invention will be described in detail.
In the present specification, “alkyl” means a linear or branched saturated aliphatic hydrocarbon chain.
“Lower alkyl” means C _1-6 alkyl. For example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, tert-butyl and the like can be mentioned. Preferred are methyl, ethyl, propyl and isopropyl.
“Lower alkenyl” means C _2-6 alkenyl. For example, vinyl, 1-propenyl, allyl, butenyl, pentenyl, hexenyl, isopropenyl and the like can be mentioned. Of these, vinyl and allyl are preferable.
The “lower alkylene” means a divalent group obtained by removing one arbitrary hydrogen atom from the “lower alkyl”. Examples include methylene, ethylene, propylene, butylene, methylmethylene, dimethylmethylene and the like. Methylene, ethylene and propylene are preferred.

“Halogen” means F, Cl, Br and I.
“Halogeno lower alkyl” means a lower alkyl substituted with one or more halogens. Examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl. Difluoromethyl, trifluoromethyl and difluoroethyl are preferred.

The “cycloalkyl” is a C _3-12 cycloalkyl, which may form a bridged ring or a spiro ring. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl and the like. Cyclopropyl, cyclopentyl, cyclohexyl and adamantyl are preferred.

“Aryl” means C _6-14 mono- to tricyclic aryl. In addition, a C _5-8 cycloalkyl ring may be condensed with phenyl. For example, phenyl, naphthyl, indanyl, tetrahydronaphthyl and the like can be mentioned. Preferred are phenyl and naphthyl.

“Heterocycle” means a saturated, unsaturated or partially unsaturated 4 to 8 membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from O, S and N, 8 to 14 It means a membered bicyclic heterocycle, an 11-20 membered tricyclic heterocycle. The heterocycle may be condensed with a phenyl ring or a C _5-8 cycloalkyl ring. In addition, ring atoms S or N may be oxidized to form an oxide or a dioxide, or a bridged ring or a spiro ring may be formed. For example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl Quinoxalinyl, cinnolinyl, pyrrolidinyl, dihydropyridyl, dihydropyrrolyl, dihydrooxazolyl, dihydrothiazolyl, dihydroimidazolyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrazolidinyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, thiazolidinyl, thiazolidinyl Pyranyl, Tiger tetrahydrothiopyranyl, tetrahydropyrimidinyl, chromanyl, dioxolanyl, diazepanyl, homomorpholinyl, 1-azabicyclo [2.2.2] octyl, 2,5-diazabicyclo [2,2,1] heptyl, and the like. Preferred are pyridyl, pyrimidinyl, pyrazinyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, 1-azabicyclo [2.2.2] octyl.

  The term “which may be substituted” means “not substituted” or “substituted with 1 to 5 substituents which are the same or different”.

Preferred embodiments of the compound in the present invention are shown below.
A is preferably ═CH—.
R ¹ is preferably a heterocycle or ^a group represented by —L ^a —R ^1b . However, the hetero ring is -OH, oxo, -C (O) OR ⁰ , -C (O) NR ⁰ R ^0a , lower alkylene-OR ⁰ , lower alkylene-C (O) OR ⁰ , lower alkylene-C ( O) optionally substituted with NR ⁰ R ^0a or lower alkylene NR ⁰ R ^0a . Here, L ^a and R ^1b have the following meanings.
L ^a : * -O-, * -N (R ⁰ )-, * -C (O)-, * -N (R ⁰ ) C (O)-, * -N (R ⁰ ) -lower alkylene, * -C (O) N (R ⁰ ) -lower alkylene or * -N (R ⁰ ) C (O) -lower alkylene. However, * means the coupling ^| bonding to R1b.
R ^1b : lower alkyl, cycloalkyl, heterocycle or lower alkylene-heterocycle. However, lower alkyl and cycloalkyl are each substituted with -OH, halogen, -O-lower alkylene-OR ⁰ , -C (O) OR ⁰ , -C (O) NR ⁰ R ^0a or NR ⁰ R ^0a The heterocycle and the heterocycle part of the lower alkylene-heterocycle may be -OH, oxo, -C (O) OR ⁰ , -C (O) NR ⁰ R ^0a , lower alkylene-OR ⁰ , lower alkylene-C (O) OR ⁰ or lower alkylene-C (O) NR ⁰ R ^0a may be substituted.
R ¹ is more preferably -heterocycle, -C (O) NH-lower alkyl, -C (O) NH-cycloalkyl, -C (O) -heterocycle or -C (O) NH-lower alkylene- Heterocycle. Provided that the lower alkyl portion of -C (O) NH-lower alkyl and the cycloalkyl portion of -C (O) NH-cycloalkyl are -OH, -O-lower alkylene-OH, -C (O) OR ⁰ , ^Optionally substituted with -C (O) NR ⁰ R ^0a , wherein the heterocycle, -C (O) -heterocycle or -C (O) NH-lower alkylene-heterocycle is OH,- C (O) NR ⁰ R ^0a , lower alkylene-OR ⁰ or lower alkylene-C (O) NR ⁰ R ^0a may be substituted.

R ² is preferably -H, -O- (lower alkyl optionally substituted with halogen or -OH), -C (O) NH- (heterocycle optionally substituted with alkyl) or -C (O) NH- lower alkylene -NR ⁰ R ^0a, more preferably -H or -O- lower alkyl.

Another preferred embodiment of R ¹ and R ^2, R ¹ and R ² together ^{form, * - N (R 6)} - (CH 2) 2 -, * - (CH 2) 2 -N (R ⁶ )-, * -N (R ⁶ )-(CH ₂ ) ₃ -or *-(CH ₂ ) ₃ -N (R ⁶ )-. More preferably, it is * -N (R ⁶ ) — (CH ₂ ) ₂ — or * — (CH ₂ ) ₂ —N (R ⁶ ) —. Here, R ⁶ is preferably methyl or acetyl.

R ³ is preferably H.
R ⁴ is preferably H or halogen, and more preferably H.
R ⁵ is preferably -lower alkylene- (phenyl optionally substituted with halogen), more preferably -CH _2- (phenyl optionally substituted with F).

The compound of the present invention may have a geometric isomer or a tautomer depending on the kind of the substituent, but the present invention includes a mixture of these isomers or a mixture thereof.
In addition, the compound of the present invention may have an asymmetric carbon atom, and (R) -form and (S) -form optical isomers based on this may exist. The present invention includes all of these optical isomers and isolated ones.

Furthermore, the compounds of the present invention include pharmacologically acceptable prodrugs. A pharmacologically acceptable prodrug is a compound having a group that can be converted to NH ₂ , OH, CO ₂ H, etc. of the present invention by solvolysis or under physiological conditions. Prodrug-forming groups include "Progress in Medicine", Life Science Medica, 1985, Volume 5, p.2157-2161 and "Pharmaceutical Development (Volume 7) Molecule The group described in “Design”, Yodogawa Shoten, 1990, p.163-198.

The compound of the present invention may form a salt with a base depending on the type of acid addition salt or substituent. Such salts are pharmaceutically acceptable salts, specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid. Acid addition salts with organic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid, sodium, Examples thereof include inorganic bases such as potassium, magnesium, calcium and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, and ammonium salts.
Furthermore, the present invention also includes various hydrates and solvates of the compound (I) and salts thereof and crystalline polymorphic substances.

(Production method)
Compound (I) and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent. In this case, depending on the type of functional group, it is effective in terms of production technology to protect the functional group with a suitable protective group at the raw material or intermediate stage, or to replace it with a group that can be easily converted to the functional group. There are cases. Examples of such functional groups include amino groups, hydroxyl groups, and carboxyl groups. Examples of protective groups for these functional groups include Protective Groups in Organic Synthesis by TW Greene and PGM Wuts. (Protective Groups in Organic Synthesis) ”, (USA), 3rd edition, John Wiley & Sons, 1999. It may be appropriately selected and used accordingly. In such a method, after carrying out the reaction by introducing the protecting group, the desired compound can be obtained by removing the protecting group as necessary or converting it to a desired group. Further, the prodrug of compound (I) can be produced by introducing a specific group at the stage of a raw material or an intermediate, or reacting with the obtained compound (I) in the same manner as the above protecting group. The reaction can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, carbamate formation, dehydration and the like.

（式中、R¹、R²、R³、R⁴及びAは上述の基を示し、L¹は脱離基を示す。以下同様。）
本製法はピロロピリミジン化合物（II）とアミン化合物（III）とを反応させ、化合物（Ｉ）を得る方法である。ここで、L¹の脱離基としては、例えばハロゲン原子、メチルスルファニル、メチルスルフィニル、メチルスルホニル、トリフラート基等が挙げられる。
反応は無溶媒中若しくはベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（THF）、1,4-ジオキサン等のエーテル類、ジクロロメタン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、N,N-ジメチルホルムアミド（DMF）、N,N-ジメチルアセトアミド（DMA）、1-メチルピロリジン-2-オン（NMP）、酢酸エチル、アセトニトリル等反応に不活性な溶媒中、化合物（ＩＩ）と（III）を等モル乃至一方を過剰量用い、室温乃至加熱還流下に行うことができる。反応温度は化合物に応じて適宜設定できる。反応は、パラジウム、ホスフィンリガンド存在下、及び金属塩基共存下で行うことが出来る。パラジウムとしては、酢酸パラジウム等の２価パラジウムや、トリス（ジベンジリデンアセトン）ジパラジウム等の０価パラジウムを使用することができる。ホスフィンリガンドとしては、2,2'-ビス（ジフェニルホスフィノ)-1,1'-ビナフチル（BINAP）、1,1’-ビス(ジフェニルホスフィノ)フェロセン（DPPF）等の2座配位子、トリ（tert-ブチル）ホスフィン等の単座配位子、反応系中でカルベン型リガンドを発生する1,3-ビス(2,6-ジイソプロピルフェニル)イミダゾリウムクロリド等を使用することができる。金属塩基としては、炭酸セシウム、リン酸カリウム、ナトリウムtert-ブトキサイド等を使用することができる。
また、化合物によっては、上記のパラジウムやホスフィンを使用することなく、酸性条件下（4M 塩化水素/1,4-ジオキサン溶液、4M 塩化水素/酢酸エチル溶液等の存在下）に反応を行うことができる。
尚、化合物（Ｉ）が１級または２級のアミノ基を有する場合には、原料である化合物（II）や化合物（III）のアミノ基を予め保護基で保護しておき、当該置換反応を実施後、保護基を除去することにより製造できる。保護基としては前述の「プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）」に記載の保護基を適宜選択することができる。 Hereinafter, representative production methods of the compound (I) of the present invention will be described.
Process A Substitution reaction

(In the formula, R ¹ , R ² , R ³ , R ⁴ and A represent the above-mentioned groups, L ¹ represents a leaving group, and so on.)
This production method is a method for obtaining a compound (I) by reacting a pyrrolopyrimidine compound (II) with an amine compound (III). Here, examples of the leaving group for L ¹ include a halogen atom, methylsulfanyl, methylsulfinyl, methylsulfonyl, and a triflate group.
The reaction is carried out in the absence of a solvent or halogenated aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dichloromethane, 1,2-dichloroethane, chloroform, etc. Hydrocarbons, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), 1-methylpyrrolidin-2-one (NMP), ethyl acetate, acetonitrile, etc. (II) and (III) can be carried out using an equimolar amount or an excess amount of one, and from room temperature to heating under reflux. The reaction temperature can be appropriately set according to the compound. The reaction can be performed in the presence of palladium, a phosphine ligand, and in the presence of a metal base. As palladium, divalent palladium such as palladium acetate and zerovalent palladium such as tris (dibenzylideneacetone) dipalladium can be used. Examples of phosphine ligands include bidentate ligands such as 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) and 1,1'-bis (diphenylphosphino) ferrocene (DPPF). A monodentate ligand such as tri (tert-butyl) phosphine, 1,3-bis (2,6-diisopropylphenyl) imidazolium chloride that generates a carbene-type ligand in the reaction system, and the like can be used. As the metal base, cesium carbonate, potassium phosphate, sodium tert-butoxide and the like can be used.
Depending on the compound, the reaction may be carried out under acidic conditions (in the presence of 4M hydrogen chloride / 1,4-dioxane solution, 4M hydrogen chloride / ethyl acetate solution, etc.) without using the above palladium or phosphine. it can.
When the compound (I) has a primary or secondary amino group, the amino group of the starting compound (II) or compound (III) is protected with a protecting group in advance, and the substitution reaction is carried out. After implementation, it can be produced by removing the protecting group. As the protecting group, the protecting group described in the above-mentioned “Protective Groups in Organic Synthesis” can be appropriately selected.

（式中、L²は、脱離基を表す。）
本製法はピリミジン化合物（IV）を酸性条件化反応させ、化合物（Ｉ）を得る方法である。ここで、L²は、低級アルコキシ基が使用できる。酸性条件としては、塩酸/メタノールやトリフルオロ酢酸等が使用できる。 Production Method B Ring Closure Reaction (1)

(In the formula, L ² represents a leaving group.)
In this production method, the pyrimidine compound (IV) is reacted under an acidic condition to obtain the compound (I). Here, L ² can be a lower alkoxy group. As acidic conditions, hydrochloric acid / methanol, trifluoroacetic acid or the like can be used.

本製法はシアノピリミジン化合物（V）を塩基性条件化反応させ、化合物（Ｉ）を得る方法である。ここで、R³は、エステル基が使用できる。塩基としては、ナトリウムメトキシド/メタノール等が使用できる。 Production Method C Ring Closure Reaction (2)

This production method is a method for obtaining a compound (I) by subjecting a cyanopyrimidine compound (V) to a basic conditioning reaction. Here, R ³ can be an ester group. As the base, sodium methoxide / methanol or the like can be used.

Production method D Other production methods The compounds of the present invention having various functional groups such as amide group, alkylamino group, hydroxyl, etc. are prepared from the compounds of the present invention having the corresponding ester group, carboxyl group, amino group, etc. It can also be produced by applying a self-evident method, a known production method, or a modified method thereof. For example, the following reaction can be applied.
D-1: Amidation Various carboxylic acid compounds and reactive derivatives thereof are reacted with the present compound having an amino group, or various amino compounds are reacted with the present compound having a carboxyl group. Thus, various amide compounds can be produced. For the reaction, a free carboxylic acid or a reactive derivative thereof can be used. Examples of the reactive derivative include acid halides (acid chloride, acid bromide, etc.), acid anhydrides (ethyl chlorocarbonate, benzyl chlorocarbonate, phenyl chlorocarbonate). , Mixed acid anhydride obtained by reaction with p-toluenesulfonic acid, isovaleric acid, etc., or symmetric acid anhydride), active ester (phenol optionally substituted with an electron withdrawing group such as nitro group or fluorine atom) 1-hydroxybenzotriazole (HOBt), esters prepared using N-hydroxysuccinimide (HONSu), etc.), lower alkyl esters, acid azides and the like. These reactive derivatives can be produced by conventional methods.
When a free carboxylic acid is used, a condensing agent (N, N′-dicyclohexylcarbodiimide (DCC), PS-carbodiimide (Argonaut, USA), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide ( WSC), 1,1′-carbonylbisimidazole (CDI), N, N′-disuccinimidyl carbonate, Bop reagent (Aldrich, USA), 2- (1H-benzotriazol-1-yl) -1 , 1,3,3-Tetramethyluronium tetrafluoroborate (TBTU), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU ), Diphenylphosphoric acid azide (DPPA), phosphorus oxychloride, phosphorus trichloride, triphenylphosphine / N-bromosuccinimide, etc.), and in some cases, it is preferable to use additives (for example, HONSu, HOBt, etc.).
The reaction is carried out using an equimolar amount of carboxylic acid derivative (VI) and amine (VII) or an excess of one, aromatic hydrocarbons, halogenated hydrocarbons, ethers, DMF, DMA, NMP, ethyl acetate or acetonitrile. In an inert solvent such as under cooling to heating, preferably at -20 ° C to 60 ° C. Depending on the type of reactive derivative, the reaction may be facilitated by the reaction in the presence of a base (preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc.). In some cases, it may be advantageous to proceed. Pyridine can also serve as a solvent.

D-2: Alkylation (1)
An alkyl group can be introduced by reacting a compound having an amino group with various alkylating agents (for example, alkyl halides, alkylsulfonic acid esters, etc.) in a conventional manner. In the case of producing a secondary amine from a primary amine, a method in which it is once converted into a trifluoroacetylamino form, alkylated and then hydrolyzed (“Tetrahedron Letters” (Netherlands) 1978, p. .4987 etc.) are applicable.

D-3: Alkylation (2)
An alkylated product can be produced by subjecting a compound having an amino group to a reductive alkylation reaction with various carbonyl compounds. For the reaction, for example, the method described in “Chemical Experiment Course (Vol. 20) Organic Synthesis 2” edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992, p.

D-4: Alkylation (3)
According to the method of ARKatritzky et al. (“Heterocycles”, 1995, p.345, etc.), after reacting the compound having an amino group with 1-hydroxymethylbenziditriazole, sodium borohydride And a compound having an N-methylamino group can be produced.

D-5: Oxidation An oxide can be obtained by treating a compound having a nitrogen-containing aromatic ring such as a tertiary amino group or pyridine with various oxidizing agents. For the reaction, for example, the method described in the Chemical Society of Japan, “Experimental Chemistry Course (Volume 23) Organic Chemistry 5”, 4th edition, Maruzen, 1991, p.271 can be applied.

D-6: Reduction A compound having a hydroxyl group can be produced by subjecting a compound having an ester group or a formyl group to reductive treatment (for example, reaction with lithium aluminum hydride or the like).

(式中、L³は、脱離基を表す。)
本製法は、前記製法D-2と同様にして行うことができる。また、脱離基L³としては、前記脱離基L¹と同様の基を用いることができる。 Production Method E Production of Raw Material Compound The raw material compound used for the production of compound (I) can be produced by a conventional method using, for example, a known reaction shown in the following synthesis route diagram.
Production method E-1 Alkylation

(In the formula, L ³ represents a leaving group.)
This production method can be carried out in the same manner as the production method D-2. As the leaving group L ³ , the same group as the leaving group L ¹ can be used.

各工程は公知の反応を用いて常法により製造できる。例えば、以下の反応が適用できる。第一工程の置換反応はオゼキ（Ozeki）らの方法（「ケミカル・アンド・ファーマシューティカル・ブレチン（Chemical & Pharmaceutical Bulletin）」、1989年、第37巻、11号、p.1780-178７）に準じて行うことができる。第二工程のクロル化反応は、オキシ塩化リンとジエチルアニリン等の塩基を用いて行うことができる。第三工程の置換反応は、対応するアミノ体（XI）とジイソプロピルエチルアミン存在下で反応させることができる。第四工程の加水分解は前記の「プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）」、に記載のカルボキシル基の脱保護の条件が適用でき、エチルエステルに代わり、他のアルキルエステルやベンジルエステル等も使用できる。第五工程のアミド化は、前記製法Ｃと同様にして行うことができる。第六工程の還元は前記D-6と同様にして行うことができる。第七工程のウィッティッヒ（Wittig）反応は、例えばn-ブチルリチウムと（メトキシメチル）トリフェニルホスホニウム クロリドを用いて行うことができる。 Manufacturing method E-2

Each step can be produced by a conventional method using a known reaction. For example, the following reaction can be applied. The substitution reaction in the first step is based on the method of Ozeki et al. ("Chemical & Pharmaceutical Bulletin", 1989, Vol. 37, No. 11, p. 1780-1787). It can be done according to this. The chlorination reaction in the second step can be performed using a base such as phosphorus oxychloride and diethylaniline. The substitution reaction in the third step can be reacted with the corresponding amino compound (XI) in the presence of diisopropylethylamine. For the hydrolysis in the fourth step, the deprotection conditions for the carboxyl group described in “Protective Groups in Organic Synthesis” can be applied. Alkyl esters and benzyl esters can also be used. The amidation in the fifth step can be carried out in the same manner as in the above production method C. The reduction in the sixth step can be performed in the same manner as D-6. The Wittig reaction in the seventh step can be performed using, for example, n-butyllithium and (methoxymethyl) triphenylphosphonium chloride.

各工程は公知の反応を用いて常法により製造できる。例えば、以下の反応が適用できる。
第一工程の置換反応は、前記製法E-2の第一工程と同様にして行うことができる。第二工程のクロル化反応は、前記製法E-2の第二工程と同様にして行うことができる。第三工程の置換反応は、前記製法E-2の第三工程と同様にして行うことができる。 Manufacturing method E-3

Each step can be produced by a conventional method using a known reaction. For example, the following reaction can be applied.
The substitution reaction in the first step can be performed in the same manner as in the first step of the production method E-2. The chlorination reaction in the second step can be performed in the same manner as in the second step of production method E-2. The substitution reaction in the third step can be performed in the same manner as in the third step of the production method E-2.

The reaction product obtained by each of the above production methods can be isolated and purified as various solvates such as a free compound, a salt thereof or a hydrate. The salt can be produced by subjecting it to normal salt formation treatment.
Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.
Various isomers can be isolated by conventional methods utilizing physicochemical differences between isomers. For example, optical isomers can be separated by a general optical resolution method such as fractional crystallization or chromatography. Optical isomers can also be produced from appropriate optically active raw material compounds.

A preparation containing one or more of the compounds of the present invention or a salt thereof as an active ingredient is usually prepared using carriers, excipients and other additives used for formulation.
Administration is oral by tablets, pills, capsules, granules, powders, liquids, etc., or parenteral by injections such as intravenous injections, intramuscular injections, suppositories, transdermal agents, nasal agents or inhalants. Either form may be sufficient. The dosage is appropriately determined according to the individual case, taking into account the symptoms, age of the subject, sex, etc. In general, in the case of oral administration, it is about 0.001 mg / kg to 100 mg / kg per day for an adult. This is administered once, or divided into 2 to 4 times. When administered intravenously, it is usually administered once or multiple times per day in the range of 0.0001 mg / kg to 10 mg / kg per adult. In the case of nasal administration, it is usually administered once or multiple times in a range of 0.0001 mg / kg to 10 mg / kg per adult. In the case of inhalation, it is usually administered once or several times a day in the range of 0.0001 mg / kg to 1 mg / kg per adult.

  As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances are present in at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. Mixed with magnesium aluminate acid. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with sugar coating or gastric or enteric coating agent.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and include commonly used inert solvents such as purified water, ethanol, etc. . In addition to the inert solvent, the composition may contain adjuvants such as solubilizers, wetting agents, and suspending agents, sweeteners, corrigents, fragrances, and preservatives.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solvent include distilled water for injection and physiological saline. Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (Pharmacopeia name), and the like. Such a composition may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving and suspending it in sterile water or a sterile solvent for injection before use.
Transmucosal agents such as inhalants and nasal agents are used in the form of solids, liquids, and semisolids, and can be produced according to conventionally known methods. For example, excipients such as lactose and starch, and pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be added as appropriate. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable gas such as a suitable propellant such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.

EXAMPLES Hereinafter, the present invention will be specifically described by way of examples, but these do not limit the scope of the present invention. Moreover, the manufacturing method of a raw material compound is shown in a reference example.
The following abbreviations are used in Reference Examples, Examples and Tables below.
Rex: Reference example number, EX: Example number, Syn: Production method (the numbers indicate the example numbers produced in the same manner), R, R ¹ , R ² , R ³ , R ⁴ : Substituents in the general formula , N: number of repeats in general formula, DMF: N, N-dimethylformamide, DMA: N, N-dimethylacetamide, NMP: 1-methylpyrrolidin-2-one, DMSO: dimethylsulfoxide, Me: methyl , Et: ethyl, nPr: normal propyl, iPr: isopropyl, cPr: cyclopropyl, nBu: normal butyl, iBu: isobutyl, tBu: tert-butyl, cBu: cyclobutyl, nPen: normal pentyl, cPen: cyclopentyl, nHex: normal Ruhexyl, cHex: cyclohexyl, Ac: acetyl, Ph: phenyl, Bn: benzyl, Py: pyridyl, azet: azetidinyl, pyrr: pyrrolidinyl, pipe: piperidinyl, pipea: piperazinyl, mor: morpholinyl, THF: tetrahydrofuranyl, THP: Tetrahydropyranyl, THSP: Tetrahydrothiopyranyl, Boc: tert-butoxycarbonyl, di: di, tri: tri, cis: cis, trans: trans, WSC: 1- [3- (dimethylamino) propyl]- 3-ethylcarbodiimide, HOBt: 1-hydroxybenzotriazole, BINAP: 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, rac: racemic.
Dat: physicochemical data (F: FAB-MS (M + H) ⁺ ; FN: FAB-MS (MH) ⁻ ; EI: EI-MS (M + H) ⁺ ; ES: ESI-MS (M + H ^{) +; ESN: ESI-MS} (MH) -; AP: AP-MS (M + H) +; NMR1: characteristic peaks of δ at ¹ HNMR in _{DMSO-d 6 (ppm);} NMR2: CDCl 3 Δ (ppm) of the characteristic peak in ¹ HNMR in the above; Sal: salt (not shown: free form; HCl: hydrochloride; number indicates the ratio of the acid component, for example, 2HCl means dihydrochloride. )) Respectively.
In addition, the number before the substituent indicates the substitution position, and a plurality of numbers indicates a plurality of substitutions. For example, 3,4-diHO-1-pipe represents 3,4-dihydroxypiperidin-1-yl and 3-pyrr-CH ₂ —NH— represents pyrrolidin-3-ylmethylamino.

Reference Example 1-1 and Reference Example 1-2
4-amino-5-bromo-2-chloropyrimidine is reacted in DMF with tributyl [(Z) -2-ethoxyvinyl] tin in the presence of bis (triphenylphosphine) palladium dichloride and tetrabutylammonium chloride, and a silica gel column Purification by chromatography (hexane / ethyl acetate) gave 4-amino-2-chloro-5-[(Z) -2-ethoxyvinyl] pyrimidine (Reference Example 1-1: ES: 200) and 5-acetyl- 4-Amino-2-chloropyrimidine (Reference Example 1-2: ES: 172) was obtained.

Reference example 2
4-Amino-2-chloro-5-[(Z) -2-ethoxyvinyl] pyrimidine was treated with trifluoroacetic acid in dichloroethane to give 2-chloro-1H-pyrrolo [2,3-d] pyrimidine . ES: 154

Reference example 3
2-Chloro-1H-pyrrolo [2,3-d] pyrimidine is reacted with 3,5-difluorobenzyl bromide in DMSO in the presence of potassium carbonate to give 2-chloro-7- (3,5-difluorobenzyl) -7H -Pyrrolo [2,3-d] pyrimidine was obtained. ES: 280

Reference example 4
After reacting ethyl 2,4-dichloropyrimidine-5-carboxylate with 2,6-difluorobenzylbenzylamine in tetrahydrofuran at −70 ° C. in the presence of diisopropylethylamine, see International Patent Publication No. WO2004 / 002964 In accordance with the method of Example 16, 2-chloro-4-[(2,6-difluorobenzyl) amino] -N-methoxy-N-methylpyrimidine-5-carboxamide was synthesized (F: 343). It is then reacted with 4-[(1-methylpiperidin-3-yl) oxy] aniline dihydrochloride in NMP to give 4-[(2,6-difluorobenzyl) amino] -N-methoxy-N-methyl-2 -({4-[(1-methylpiperidin-3-yl) oxy] phenyl} aminopyrimidine-5-carboxamide (ES: 513) was obtained. The resulting pyrimidine-5-carboxamide was then added in tetrahydrofuran. Treated with lithium aluminum hydride and treated with 4-[(2,6-difluorobenzyl) amino] -2-({4-[(1-methylpiperidin-3-yl) oxy] phenyl} amino) pyrimidine-5-carbohydrate The aldehyde was obtained ES: 454

Reference Example 5
2- (Methylsulfanyl) -4-oxo-1 according to the method of “Chemical & Pharmaceutical Bulletin”, 1989, Vol. 37, No. 11, p.1780-1787 , 4-Dihydropyrimidine-5-carboxylate and 4-morpholin-4-ylaniline, then treated with phosphorus oxychloride to give 4-chloro-2-[(4-morpholin-4-ylphenyl) amino ] Methyl pyrimidine-5-carboxylate (ES: 349) was synthesized. It is then reacted with 2,3,6-trifluorobenzylamine in DMA in the presence of diisopropylethylamine to give 2-[(4-morpholin-4-ylphenyl) amino] -4-[(2,3,6-trifluoro [Benzyl) amino] pyrimidine-5-carboxylate (ES: 474) was synthesized. The obtained compound was hydrolyzed with 1M aqueous sodium hydroxide solution in methanol-tetrahydrofuran and then treated with N-methoxy-N-methylamine hydrochloride in the presence of WSC hydrochloride, HOBt and triethylamine in DMF to give a carboxamide. N-methoxy-N-methyl-2-[(4-morpholin-4-ylphenyl) amino] -4-[(2,3,6-trifluorobenzyl) amino] pyrimidine-5-carboxamide (ES: 503) Got. The resulting compound was treated with lithium aluminum hydride in tetrahydrofuran to give 2-[(4-morpholin-4-ylphenyl) amino] -4-[(2,3,6-trifluorobenzyl) amino] pyrimidine -5-carbaldehyde was obtained. ESN: 442

Reference Example 6
N-methoxy-N-methyl-2-chloro-4-[(2,6-difluorobenzyl) amino] pyrimidine-5-carboxamide was treated with lithium aluminum hydride in tetrahydrofuran to give 2-chloro-4-[( 2,6-Difluorobenzyl) amino] pyrimidine-5-carbaldehyde (ES: 284) was obtained. N-Butyllithium was added to a tetrahydrofuran solution of (methoxymethyl) triphenylphosphonium chloride at 0 ° C. and stirred for 10 minutes. Further, a tetrahydrofuran solution of 2-chloro-4-[(2,6-difluorobenzyl) amino] pyrimidine-5-carbaldehyde was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate) and 2-chloro-N-[(2,6-difluorobenzyl) -5- (2-methoxyvinyl) pyrimidin-4-amine (ES : 312) was synthesized as a mixture of E and Z forms. The obtained compound was dissolved in 15 ml of methanol, 3 ml of concentrated hydrochloric acid aqueous solution was added, and the mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate) to give 2-chloro-7- (2,6-difluoro (Benzyl) -7H-pyrrolo [2,3-d] pyrimidine was obtained. ES: 280

Reference Example 7
N-Butyllithium was added to a tetrahydrofuran solution of (methoxymethyl) triphenylphosphonium chloride at 0 ° C. and stirred for 30 minutes. Further, 5-acetyl-4-amino-2-chloropyrimidinetetrahydrofuran solution was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform: methanol), 5 ml of concentrated hydrochloric acid aqueous solution was added to 20 ml of solid methanol solution, and the mixture was stirred at 80 ° C. for 13 hours. The reaction mixture was cooled to room temperature, diluted with water, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol) to give 2-chloro-5-methyl-7H-pyrrolo [2,3 -d] pyrimidine (ES: 168) was obtained. The obtained pyrrolopyrimidine and benzyl bromide were reacted in the presence of potassium carbonate to obtain 7-benzyl-2-chloro-5-methyl-7H-pyrrolo [2,3-d] pyrimidine. ES: 258

Reference Example 8
{Methyl [1- (4-nitrophenyl) piperidin-4-nyl] amino} ethyl acetate was catalytically reduced in ethanol in the presence of 10% palladium / carbon to give {{1- (4-aminophenyl) piperidin- 4-Nyl] (methyl) amino} ethyl acetate was obtained. ES: 292

Reference Example 9-1 and Reference Example 9-2
After reacting 4-fluoronitrobenzene and ethyl 4-aminocyclohexanecarboxylate in DMF in the presence of diisopropylethylamine, the cis and trans isomers were separated and purified by silica gel column chromatography, each containing 10% palladium / carbon in ethanol. Under catalytic reduction, ethyl cis-4-[(4-aminophenyl) amino] cyclohexanecarboxylate (Reference Example 9-1: ES: 263) and trans-4-[(4-aminophenyl) amino] cyclohexane Ethyl carboxylate (Reference Example 9-2: ES: 263) was obtained.

Reference Example 10
A nitro compound obtained by reacting 4-fluoronitrobenzene and piperazin-2-ylethyl acetate in DMF in the presence of diisopropylethylamine was reacted with a formalin aqueous solution in formic acid to obtain an N-methyl compound. Furthermore, catalytic reduction was carried out in ethanol in the presence of 10% palladium / carbon to obtain [4- (4-aminophenyl) -1-methylpiperazin-2-yl] ethyl acetate. F: 278

Reference Example 11
4- (4-Nitrophenoxy) piperidine and ethyl bromoacetate were reacted in DMF in the presence of sodium carbonate, and the resulting compound was treated in the same manner as the catalytic reduction shown in Reference Example 8 to give [4- (4-amino Phenoxy) piperidin-1-yl] ethyl acetate was obtained. ES: 279

Reference Example 12
[4- (4-Aminophenoxy) piperidin-1-yl] acetic acid was treated with lithium aluminum hydride in tetrahydrofuran at room temperature in tetrahydrofuran to give 2- [4- (4-aminophenoxy) piperidin-1-yl] Ethanol was obtained. ES: 237

Reference Example 13
1- (4-Nitrophenyl) piperazine and 2-chloroethyldimethylamine hydrochloride were reacted in DMF in the presence of sodium carbonate at room temperature for 10 hours and further at 80 ° C. for 6 hours. The resulting compound is shown in Reference Example 8. Treatment as in catalytic reduction gave 2- (dimethylamino) ethyl 4- (4-aminophenylpiperazine-1-carboxylate NMR2: 2.31 (6H, s), 2.61 (2H, t, J = 5.8Hz), 2.94-3.02 (4H, m), 3.59-3.65 (4H, m), 4.22 (2H, t, J = 6.0Hz), 6.63-6.68 (2H, m), 6.78-6.83 (2H, m )

Reference Example 14
After treating quinuclidine-4-carboxylic acid hydrochloride with thionyl chloride, it was reacted with 4-nitroaniline in pyridine at 120 ° C. for 5 hours, and the resulting compound was treated in the same manner as the catalytic reduction shown in Reference Example 8. N- (4-aminophenyl) quinuclidine-4-carboxamide was obtained. ES: 245

Reference Example 15
1-Azabicyclo [2.2.2] oct-4-ylmethanol and 4-fluoronitrobenzene were reacted in tetrahydrofuran at 60 ° C. for 5 hours in the presence of sodium hydride, and the resulting compound was similar to the catalytic reduction shown in Reference Example 8. To give 4- (1-azabicyclo [2.2.2] oct-4-ylmethoxy) aniline. ES: 233

Reference Example 16
1- (4-Nitrophenyl) piperidin-4-ol and ethyl bromoacetate were reacted in the same manner as in Reference Example 15 to obtain ethyl {[1- (4-aminophenyl) piperidin-4-yl] oxy} acetate. . ES: 279

Reference Example 17
1- (4-Nitrophenyl) piperazine and ethyl acrylate were reacted in NMP in the presence of diisopropylethylamine at 60 ° C. for 5 hours, and the resulting compound was treated in the same manner as the catalytic reduction shown in Reference Example 8 to obtain 3 Ethyl-[4- (4-aminophenyl) piperazin-1-yl] propionate was obtained. ES: 278

Reference Example 18
1- (4-Nitrophenyl) piperazine and 4- (dimethylamino) butanoic acid hydrochloride were reacted in DMF in the presence of WSC hydrochloride, HOBt and triethylamine, and the resulting compound was subjected to catalytic reduction shown in Reference Example 8. The same treatment was performed to obtain 4- {4- [4- (dimethylamino) butanoyl] piperazin-1-yl} aniline. ES: 291

Reference Example 19
4-Nitrobenzoyl chloride and 1-Boc-4-aminopiperidine are reacted in the presence of triethylamine in DMF, and the resulting compound is treated in the same manner as the catalytic reduction shown in Reference Example 8 to give 4-[(4- Aminobenzoyl) amino] piperidine-1-carboxylate tert-butyl was obtained. F: 320

Reference Example 20
2-Fluoro-4-nitrobenzoic acid is treated with thionyl chloride in the presence of a catalytic amount of DMF, then reacted with 1-Boc-4-aminopiperidine in pyridine, and the resulting compound is subjected to catalytic reduction shown in Reference Example 8. To give tert-butyl 4-[(4-amino-3-fluorobenzoyl) amino] piperidine-1-carboxylate. F: 338

Reference Example 21
4-Nitro-N-piperidin-4-ylbenzamide and 2-fluoroethyl tosylate were reacted in DMF in the presence of potassium carbonate at 80 ° C. for 8 hours, and the resulting compound was treated in the same manner as the catalytic reduction shown in Reference Example 8. Treatment gave 4-amino-N- [1- (2-fluoroethyl) piperidin-4-yl] benzamide. ES: 266

Reference Example 22
1- (4-Nitrophenyl) piperazine and ethyl 2-bromo-2-methylpropionate are heated to reflux in 2-butanone for 18 hours, and the resulting compound is treated in the same manner as the catalytic reduction shown in Reference Example 8. , Ethyl 2- [4- (4-aminophenyl) piperazin-1-yl] -2-methylpropionate was obtained. ES: 292

Reference Example 23
4-{[7- (3,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} benzoic acid in DMF solution was added WSC hydrochloride and HOBt at room temperature. Stir overnight. After concentrating the reaction solution, the resulting residue was washed with water and further washed successively with methanol and ethyl acetate to give N- {4-[(1H-1,2,3-benzotriazol-1-yloxy) carbonyl]. Phenyl} -7- (3,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine was obtained. F: 498

Reference Example 24
To the DMF solution of 4- (aminomethyl) piperidine-1-carboxylic acid tert-butyl N- {4-[(1H-1,2,3-benzotriazol-1-yloxy) carbonyl] phenyl} -7- (3 , 5-Difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine was added and stirred at 50 ° C. overnight. The reaction mixture was diluted with saturated brine, and extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol) to give 4-{[(4-{[7- (3,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} benzoyl) amino] methyl} piperidine-1-carboxylate tert-butyl was obtained. F: 577

Reference Example 25
According to the method of Reference Example 5, 2- (methylsulfanyl) -4-oxo-1,4-dihydropyrimidine-5-carbonitrile was reacted with morpholinaniline, then treated with phosphorus oxychloride, Chloro-2-[(4-morpholin-4-ylphenyl) amino] pyrimidine-5-carbonitrile (FN: 314) was synthesized. Next, it is reacted with methyl benzylaminoacetate in the presence of diisopropylethylamine in DMF to obtain methyl (benzyl {5-cyano-2-[(4-morpholin-4-ylphenyl) amino] pyrimidin-4-yl} amino) acetate. It was. AP: 459

Reference Example 26
Chloroacetone, potassium carbonate, and potassium iodide were added to a DMF solution of 4-nitro-N-piperidin-4-ylbenzamide, stirred at 50 degrees for 4 hours, and 4-nitro-N- [1- (2-oxo Propyl) piperidin-4-yl] benzamide was obtained as colorless crystals (ES: 306). Diethylaminosulfur trifluoride was added to a dichloromethane solution of this compound, the temperature was raised from −70 ° C. to room temperature, and the mixture was stirred for 18 hours to give N- [1- (2,2-difluoropropyl) piperidin-4-yl] -4. -Nitrobenzamide was obtained as a reddish brown solid (ES: 328). 20% palladium hydroxide / carbon was added to a methanol / acetic acid mixed solvent of this compound, and the mixture was stirred at normal pressure under a hydrogen atmosphere for 1 day to give 4-amino-N- [1- (2,2-difluoropropyl) piperidine-4 -Il] benzamide was obtained. ES: 298

Reference Example 27
Sodium borohydride was added to a methanol solution of 4-nitro-N- [1- (2-oxopropyl) piperidin-4-yl] benzamide, stirred at room temperature for 30 minutes, and N- [1- (2-hydroxypropyl ) Piperidin-4-yl] -4-nitrobenzamide was obtained as a colorless solid (ES: 308). Diethylaminosulfur trifluoride was added to a dichloromethane solution of this compound, the temperature was raised from −70 ° C. to room temperature, and the mixture was stirred for 18 hours. N- [1- (2-fluoropropyl) piperidin-4-yl] -4-nitro Benzamide was obtained as a tan solid (ES: 310). 4-amino-N- [1- (2-fluoropropyl) piperidin-4-yl] benzamide was prepared by adding 10% palladium / carbon to an ethanol / tetrahydrofuran mixed solvent of this compound and stirring at normal pressure under a hydrogen atmosphere for 20 hours. Got. ES: 280

Reference Example 28
Sodium azide was added to a mixture of 1-acetyl-4- (4-fluorobenzoyl) piperidine and DMF and stirred at 100 ° C. to obtain 1-acetyl-4- (4-azidobenzoyl) piperidine (F: 273) . Next, 10% palladium / carbon was added to the mixture of the azide and ethanol, and catalytic reduction was performed in a hydrogen atmosphere to obtain 1-acetyl-4- (4-aminobenzoyl) piperidine. F: 247.

Reference Examples 29-1, 29-2
2-Bromoethylamine hydrobromide was reacted with di-tertbutyl dicarbonate in ethyl acetate-water in the presence of sodium bicarbonate to obtain tert-butyl (2-bromoethyl) carbamate. The obtained tert-butyl (2-bromoethyl) carbamate was reacted with ethyl 4-methyl-1H-imidazole-5-carboxylate in DMF in the presence of potassium carbonate to give 1- {2-[(tert-butoxy Carbonyl) amino] ethyl} -4-methyl-1H-imidazole-5-carboxylate and ethyl-{2-[(tert-butoxycarbonyl) amino] ethyl} -5-methyl-1H-imidazole-4-carboxylate Got. The obtained compounds were each treated with hydrogen chloride / ethyl acetate in ethanol to give ethyl 1- (2-aminoethyl) -4-methyl-1H-imidazole-5-carboxylate dihydrochloride (Reference Example 29-1). , ES: 198) and ethyl 1- (2-aminoethyl) -5-methyl-1H-imidazole-4-carboxylate dihydrochloride (Reference Example 29-2, ES: 198).

Reference Example 30
10% palladium / carbon was added to a mixture of 2-cyano-4-methoxypyrimidine, ethyl acetate and acetic acid, and catalytic reduction was performed in a hydrogen atmosphere to obtain 2-aminomethyl-4-methoxypyrimidine. ES: 140.

Reference Example 31
Add palladium acetate, BINAP, cesium carbonate to a mixture of 2-chloro-6-cyanopyridine, 2-aminoethanol and 1,4-dioxane, heat at 85 ° C, and then add 2- (2-hydroxyethyl) amino-6- Cyanopyridine was obtained (ES: 164). Raney nickel was added to a mixture of this cyano compound, ethanol and concentrated aqueous ammonia, and catalytic reduction was performed at 60 ° C. under a hydrogen pressure of 3 kgf / cm ² to obtain 2- (2-hydroxyethyl) amino-6-aminomethylpyridine. . ES: 168.

Reference Example 32
Trans-Aminocyclohexanol was added to a 1,4-dioxane solution of 5-amino-2-benzofuran-1 (3H) -one, and the mixture was stirred under heating under reflux for 2 days to give 4-amino-N- (trans-4- Hydroxycyclohexyl) -2- (hydroxymesyl) benzamide was obtained (ES: 265).

Example 33
Potassium carbonate and isopropyl iodide were added to a DMF solution of methyl 2-hydroxy-4-nitrobenzoate and stirred at 60 ° C. for 14 hours. Methyl 4-amino-2-isopropoxybenzoate was obtained. F: 210

Reference Example 34
1) 2-hydroxy-4-nitrobenzoic acid, HOBt, and PS-carbodiimide were sequentially added to a DMF solution of 2- (2-aminoethoxy) ethanol and stirred at room temperature for one day. The resin was removed by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol) to give 2-hydroxy-N- [2- (2-hydroxyethoxy) ethyl] -4- 2.06 g of nitrobenzamide was obtained. (FN 269)
2) To a DMF solution of 1.00 g of 2-hydroxy-N- [2- (2-hydroxyethoxy) ethyl] -4-nitrobenzamide, sequentially add potassium carbonate bromo, tert-butyl acetate and potassium iodide to 60 ° C. And stirred for 1 day. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M aqueous sodium hydroxide solution, then washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol) to obtain [2-({[2- (2-hydroxyethoxy) ethyl] amino} carbonyl) -5-nitrophenoxy. ] Tert-Butyl acetate was obtained. (F 385)
3) [2-({[2- (2-hydroxyethoxy) ethyl] amino} carbonyl) -5-nitrophenoxy] acetic acid tert-butyl was treated in the same manner as the catalytic reduction shown in Reference Example 8 to give [5- Amino-2-({[2- (2-hydroxyethoxy) ethyl] amino} carbonyl) phenoxy] acetic acid tert-butyl was obtained. F: 355

Reference Example 35
242 mg of sodium borohydride was added to 40 ml of methanol containing 506 mg of nickel chloride hexahydrate under ice cooling. After stirring at room temperature for 1 hour, the mixture was ice-cooled again, and ethyl 2- (cyclopropylmethoxy) -4-nitrobenzoate (1.13 g) in methanol (20 ml) and sodium borohydride (484 mg) were added. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure, 5% aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 959 mg of ethyl 4-amino-2- (cyclopropylmethoxy) benzoate. F: 236

Reference Example 36
Benzyl 2-bromoethyl ether and ethyl 2-hydroxy-4-nitrobenzoate were reacted in DMF in the presence of potassium carbonate, and then purified by silica gel column chromatography (hexane: ethyl acetate) to give 2- [2- (benzyloxy ) Ethoxy] -4-nitrobenzoate (ES: 346) was obtained. Subsequently, the obtained compound was treated in the same manner as the catalytic reduction shown in Reference Example 8 to synthesize ethyl 4-amino-2- (hydroxyethoxy) benzoate. ES: 226

Reference Example 37
Sodium chlorodifluoroacetate and ethyl 2-hydroxy-4-nitrobenzoate were reacted in DMF in the presence of diisopropylethylamine, and then purified by silica gel column chromatography (hexane: ethyl acetate) and 2- (difluoromethoxy) -4-nitro. Ethyl benzoate (ES: 262) was obtained. Subsequently, the obtained compound was treated in the same manner as the catalytic reduction shown in Reference Example 8 to obtain ethyl 4-amino-2- (difluoromethoxy) benzoate. ES: 232

In the same manner as in Reference Example 3, Reference Examples 38 to 43 shown in Table 2 were produced.

In the same manner as in Reference Example 5, Reference Examples 44 to 56 shown in Table 3 were produced.

Reference Example 57 was produced in the same manner as Reference Example 6.
Reference Example 57
2-Chloro-7- (2,3,6-trifluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidine
ES: 298

Reference Examples 58 to 62 shown in Table 4 were produced in the same manner as Reference Example 9-1.

In the same manner as in Reference Example 11, Reference Examples 63 to 65 shown in Table 5 were produced.

Reference Example 66 was produced in the same manner as Reference Example 18.
Reference Example 66
4-[(3-Aminobenzoyl) amino] piperidine-1-carboxylic acid tert-butyl
F: 320

Reference Example 67 was produced in the same manner as Reference Example 19.
Reference Example 67
4-[(4-Aminobenzoyl) (methyl) amino] piperidine-1-carboxylic acid tert-butyl
F: 334

Reference Example 68 was produced in the same manner as Reference Example 21.
Reference Example 68
4-Amino-N- [1- (2,2-difluoroethyl) piperidin-4-yl] benzamide
ES: 284

In the same manner as in Reference Example 24, Reference Examples 69 to 75 shown in Table 6 were produced.

Reference Example 77 was produced in the same manner as Reference Example 34.
Reference Example 77
(5-Amino-2-{[(trans-4-hydroxycyclohexyl) amino] carbonyl} phenoxy) tert-butyl acetate

Reference Examples 78 to 100 shown in Tables 7 to 8 were produced in the same manner as Example 1 described later.

Reference Examples 94 to 97 shown in Table 9 were produced in the same manner as Example 4 described later.

Reference Examples 113 to 116 shown in Table 10 were produced in the same manner as Example 5 described later.

Reference Examples 117 to 128 and Reference Example 129 shown in Table 11 were produced in the same manner as Example 7 described later.

Reference Example 129
Methyl {[(4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} phenyl) acetyl] amino} acetic acid
ES: 466

Reference Examples 130 to 133 and Reference Example 134 shown in Table 12 were produced in the same manner as Example 9 described later.

Reference Example 134
[3- (4-{[7- (3,5-Difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} phenoxy) piperidin-1-yl] acetic acid ethyl
ES: 522

Example 1
Under argon atmosphere, ethyl 4-aminobenzoate 383 mg, 2-chloro-7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidine 650 mg, palladium acetate 79 mg, rac-BINAP A solution of 328 mg and 915 mg of cesium carbonate in 15 ml of dioxane was stirred at 90 ° C. for 7 hours. The reaction solution was concentrated, 30 ml of chloroform was added, and insoluble matters were filtered off. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol) and recrystallized (hexane-ethyl acetate) to give 4-{[7- (2,5-difluorobenzyl) -7H. 351 mg of ethyl -pyrrolo [2,3-d] pyrimidin-2-yl] amino} benzoate was obtained as brown crystals.

Example 2
1-methyl-1,2,3,4-tetrahydroquinolin-7-amine dihydrochloride 183 mg of NMP in 5 ml solution, 4 M hydrogen chloride / 1,4-dioxane solution 0.50 ml, 2-chloro-7- A mixture of 150 mg of (2,3,6 trifluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidine and 3 drops of water was stirred in a sealed tube at 130 ° C. for 3 days. The reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the resulting solid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate), further washed with ethanol, and 1-methyl-N- [(2,3,6-trifluorobenzyl) -7H- (2-pyrrolo [2,3-d] pyrimidyl)]-1,2,3,4-tetrahydroquinolin-7-amine 23 mg ivory crystals Got as.

Example 3
To a solution of 490 mg of (methoxymethyl) triphenylphosphonium chloride in 5 ml of tetrahydrofuran was added 0.9 ml of n-butyllithium at 0 ° C., and the mixture was stirred for 30 minutes. Further at 260C 4-[(2,6-difluorobenzyl) amino] -2-({4-[(1-methylpiperidin-3-yl) oxy] phenyl} amino) pyrimidine-5-carbaldehyde 260 mg Tetrahydrofuran 5 ml solution was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform methanol), N ⁴ - (2,6-difluorobenzyl) -5- ^{[2-methoxy-vinyl] -N 2 - {4 - [} (1- methyl 221 mg of an E, Z geometric isomer mixture of piperidin-3-yl) oxy] phenyl} pyrimidine-2,4-diamine was obtained as a brown oil (ES: 482). Concentrated hydrochloric acid (5 ml) was added to the obtained vinyl compound in methanol (10 ml) and stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with water, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol) to obtain crude crystals. This was dissolved in a tetrahydrofuran-ethyl acetate mixture, 1 ml of 4 M hydrogen chloride / ethyl acetate solution was added, and the precipitated crystals were collected by filtration and recrystallized (tetrahydrofuran-ethyl acetate) to give 7- (2 , 6-Difluorobenzyl) -N- {4-[(1-methylpiperidin-3-yl) oxy] phenyl} -7H-pyrrolo [2,3-d] -2-pyrimidin-2-amine dihydrochloride 130 mg was obtained as yellow crystals.

Example 4
4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} ethyl benzoate 300 mg, ethanol 10 ml, tetrahydrofuran 3 ml, 1M hydroxylation A sodium aqueous solution (2.2 ml) was added, and the mixture was stirred at 70 ° C. for 3 hours. Further, 1.1 ml of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at 70 ° C. for 3 hours. The reaction mixture was cooled to room temperature, 3.3 ml of 1M hydrochloric acid was added, and the precipitate was collected by filtration. The solid collected by filtration was washed with water, and 306 mg of 4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} benzoic acid was colorless. Obtained as crystals.

Example 5
4- (4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} phenyl) piperazine-1-carboxylate tert-butyl 698 mg Ethanol 10 ml, chloroform 10 ml, 4M hydrogen chloride-ethyl acetate solution 1.5 ml were added, and the mixture was stirred at 60 ° C. for 3 hours. Further, 1.5 ml of 4M hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred at 60 ° C. for 4 hours. Diethyl ether (20 ml) was added, and the precipitate was collected by filtration. The filtered solid was washed with diethyl ether to give 7- (2,5-difluorobenzyl) -N- (4-piperidin-1-ylphenyl) -7H-pyrrolo [2,3-d] pyrimidine-2- 620 mg of amine trihydrochloride was obtained as colorless crystals.

Example 6
tert-butyl 3-[(4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} benzoyl) amino] azetidine-1-carboxylate To 100 mg, 10 ml of dichloroethane and 1.0 ml of trifluoroacetic acid were added and stirred at room temperature for 24 hours. After concentration, the obtained solid was dissolved in methanol, 20 ml of diethyl ether was added, and the precipitate was collected by filtration. The filtered solid was washed with diethyl ether to give N-azetidin-3-yl-4-{[7- (2,5-difluorobezyl) -7H-pyrrolo [2,3-d] pyrimidine-2- [Il] amino} benzamide 1.5 trifluoroacetate salt 95 mg was obtained as colorless crystals.

Example 7
4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pymirimidin-2-yl] amino} benzoic acid 80 mg in 1-methylpiperidin-4-amine DMF 10 ml The solution, 57 mg of HOBt, and 81 mg of WSC / hydrochloride were added and stirred at room temperature for 24 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol) and then recrystallized (hexane-ethyl acetate) to give 4-{[7- (2,5-difluorobenzyl)- 65 mg of 7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -N- (1-methylpiperidin-4-yl) benzamide was obtained as colorless crystals.

Example 8
4-{[7- (2,5-Difluorobezyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} benzoic acid 110 mg plus DMF 10 ml, 1,1'-carbonyldi 57 mg of imidazole was added and stirred at room temperature for 5 hours. Next, a solution of 57 mg of 3- (1H-imidazol-1-yl) propan-1-amine in 5 ml of DMF was added and stirred at room temperature for 15 hours. After concentration, water was added and extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol) and recrystallized (ethyl acetate-ethanol-hexane) to give 4-{[7- (2,5-difluorovegetable). ) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -N- [3- (1H-imidazol-1-yl) propyl] benzamide (42 mg) was obtained as colorless crystals.

Example 9
7- (2,5-difluorobenzyl) -N- (4-piperidin-1-ylphenyl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine trihydrochloride 300 mg in DMF 10 ml solution A solution of sodium carbonate 240 mg and ethyl bromoacetate 104 mg in DMF 5 ml was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol) and recrystallized (hexane-ethyl acetate) to give [4- (4-{[7- (2,5- 265 mg of ethyl difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} phenyl) piperazin-1-yl] acetate was obtained as colorless crystals.

Example 10
7- (3,5-difluorobenzyl) -N- [4- (piperidin-3-yloxy) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-2-amine 2 mg in 200 ml DMF solution -118 mg of fluoroethyl-4-methylbenzenesulfonate and 203 mg of potassium carbonate were added, and the mixture was stirred at 50 ° C. for 5 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, the solvent was evaporated, the obtained residue was purified by silica gel column chromatography (chloroform: methanol), recrystallized (2-propanol), and 7- (3, 5-difluorobenzyl) -N- (4-{[1- (2-fluoroethyl) piperidin-3-yl] oxy} phenyl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine 80 mg Obtained as a colorless solid.

Example 11
1- (4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} phenyl) piperidin-4-one 200 mg of 1,2- Ethanolamine 0.033 ml, acetic acid 0.1 ml, and triacetoxy sodium borohydride 147 mg were added to a dichloroethane 5 ml solution, and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with water, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with a chloroform-methanol mixture. The organic layer was washed with saturated brine, the solvent was evaporated, the obtained residue was purified by silica gel column chromatography (chloroform: methanol), recrystallized (2-propanol), and 2-{[1 -(4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} phenyl) piperidin-4-yl] amino} ethanol 140 mg colorless Obtained as a solid.

Example 12
200 mg of 7-benzyl-N- (4-morpholin-4-ylphenyl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine at 0 ° C in a solution of 0.24 ml phosphorus oxychloride in 3 ml DMF DMF 3 ml solution was added and stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform: methanol), and N- (7-benzyl-5-formyl-7H-pyrrolo [2,3-d] pyrimidin-2-yl-N- (4- 78 mg of morpholin-4-ylphenyl) formamide was obtained as a yellow oil (ES: 442) To a mixture of 5 ml of the obtained formyl tetrahydrofuran and 5 ml of methanol was added 3 ml of 1M aqueous sodium hydroxide solution, The mixture was stirred for 2 hours at 80 ° C. The reaction solution was cooled to room temperature, concentrated, diluted with water and extracted with chloroform, the organic layer was washed with saturated brine, and the solvent was evaporated to give 7-benzyl-2- 70 mg of [(4-morpholin-4-ylphenyl) amino] -7H-pyrrolo [2,3-d] pyrimidine-5-carbaldehyde was obtained as a yellow solid (ES: 414). To 5 ml of the solution, add 8 mg of lithium aluminum hydride at 0 ° C and stir for 30 minutes. The reaction mixture was diluted with 1M aqueous sodium hydroxide solution and water, the reaction mixture was filtered, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol). Recrystallize the crystals (methanol) to give 37 mg of {7-benzyl-N- (4-morpholin-4-ylphenyl) amino] -7H-pyrrolo [2,3-d] pyrimidin-5-yl} methanol. Obtained as light brown crystals.

Example 13
(Benzyl {5-cyano-2-[(4-morpholin-4-ylphenyl) amino] pyrimidin-4-yl} amino) methyl acetate 1.69 g methanol-tetrahydrofuran 1: 1 (15 ml) sodium methoxide 498 mg And heated to reflux for 2 hours. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with methanol and water, and 5-amino-7-benzyl-2-[(4-morpholin-4-ylphenyl) amino] -7H-pyrrolo [ 1.63 g of methyl 2,3-d] pyrimidine-6-carboxylate was obtained as yellow crystals.

Example 14
1- (5-{[7- (3,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} pyridin-2-yl) piperidin-4-ol 217 mg To a solution of chloroform 7 ml, m-chloroperbenzoic acid 107 mg was gradually added at 0 ° C. and stirred for 1 hour 30 minutes. After concentrating the reaction solution, the resulting residue was purified by silica gel column chromatography (chloroform: methanol) and further recrystallized (ethanol) to give 1- (5-{[7- (3,5-difluorobenzyl) 27 mg of -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} pyridin-2-yl) piperidin-4-ol 1-oxide was obtained as pale brown crystals.

Example 15
7- (2,5-difluorobenzyl) -N- (4-cyanophenyl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine 135 mg, methanol 10 ml, tetrahydrofuran 10 ml, hydroxylamine aqueous solution 0.25 ml solution was added and stirred at 70 ° C. for 24 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with chloroform. The solvent was distilled off, and 153 mg of 4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -N-hydroxybenzene carboximidamide was added. Obtained as a colorless solid (ES: 395). 4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -N-hydroxybenzenecarboxyimidamide 153 mg and triethyl orthoformate 10 ml, 5 mg of p-toluenesulfonic acid and 10 ml of dichloroethane were added and stirred at 90 ° C. for 5 hours. The reaction mixture was concentrated, 20 ml of saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol) and then recrystallized (hexane-ethyl acetate) to give 7- (2,5-difluorobenzyl) -N- [4 46 mg of-(1,2,4-oxadiazol-3-yl) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-2-amine was obtained as colorless crystals.

Example 16
7- (2,5-difluorobenzyl) -N- [4- (1,4-dioxa-8-azaspiro [4.5] dec-8-yl) phenyl] -7H-pyrrolo [2,3-d] pyrimidine- 10 ml of water was added to a 10 ml solution of 818 mg of 4-amine 4M hydrogen chloride / 1,4-dioxane, and the mixture was stirred at 70 ° C. for 2.5 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, the solvent was evaporated, and the obtained solid was recrystallized (2-propanol-ethanol) to give 1- (4-{[7- (2,5-difluorobenzyl) Obtained 617 mg of -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} phenyl) piperidin-4-one as a colorless solid.

Example 17
N- {4- [4- (3-Aminopropyl) piperazin-1-yl] phenyl} -7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine 4 To a mixture of 183 mg of hydrochloride, 0.23 ml of triethylamine and 15 ml of DMF, 0.03 ml of acetyl chloride was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, 1M aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol), and then N- {3- [4- (4-{[7- (2,5-difluorobenzyl) -7H- Pyrrolo [2,3-d] pyrimidin-2-yl] amino} phenyl) piperazin-1-yl] propyl} acetamide and N- (4- {4- [3- (acetylamino) propyl] piperazin-1-yl } Phenyl) -N- [7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] acetamide was obtained in an amount of 115 mg. Ethanol 10 ml and 1M sodium hydroxide aqueous solution 0.3 ml were added to the obtained mixture, and the mixture was stirred at 80 ° C. for 6 hours. Further, 0.2 ml of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature, 0.5 ml of 1M hydrochloric acid was added, concentrated, water was added, and the mixture was extracted with chloroform. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol) and recrystallized (hexane-ethyl acetate) to give N- {3- [4- (4-{[7- 80 mg of (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} phenyl) piperazin-1-yl] propyl} acetamide was obtained as colorless crystals.

Example 18
{[1- (4-{[7- (3,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} phenyl) piperidin-4-yl] oxy} ethyl acetate 200 48 mg of lithium aluminum hydride was added to a solution of mg of 6 ml of tetrahydrofuran at 0 ° C. and stirred for 30 minutes. The reaction solution was diluted with 1M aqueous sodium hydroxide solution and water, the reaction solution was filtered, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain crude crystals. This was dissolved in a tetrahydrofuran-ethyl acetate mixture, and 1 ml of 4 M hydrogen chloride / ethyl acetate solution was added. After concentrating the reaction solution, the obtained residue was washed with heating (tetrahydrofuran-ethyl acetate) to give 2-{[1- (4-{[7- (3,5-difluorobenzyl) -7H-pyrrolo [2, 94 mg of 3-d] pyrimidin-2-yl] amino} phenyl) piperidin-4-yl] oxy} ethanol hydrochloride was obtained as pale brown crystals.

Example 19
4-{[7- (3,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -N-piperidin-4-ylbenzamide hydrochloride 166 mg in DMF 8 ml in solution Sodium carbonate (106 mg) and (3-bromopropoxy) (tert-butyl) dimethylsilane (0.1 ml) were added, and the mixture was stirred at room temperature for 1 day. After concentrating the reaction solution, the resulting residue was purified by silica gel column chromatography (chloroform: methanol) and purified by N- [1- (3-{[tert-butyl (dimethyl) siloxy] oxy} propyl) piperidin-4-yl ] -4-{[7- (3,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} benzamide 156 mg was obtained (F: 635). N- [1- (3-{[tert-butyl (dimethyl) siloxy] oxy} propyl) piperidin-4-yl] -4-{[7- (3,5-difluorobenzyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl] amino} benzamide 1.15 ml of 1M tetra n-butylammonium fluoride / tetrahydrofuran solution was added to a solution of 146 mg of tetrahydrofuran in 15 ml, and the mixture was stirred at room temperature for 90 minutes. The mixture was further stirred at 50 ° C. for 100 minutes. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol). The obtained crude crystals were washed with ethyl acetate and washed with 4-{[7- (3,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -N- [1- 45 mg of (3-hydroxypropyl) piperidin-4-yl] benzamide was obtained as colorless crystals.

Example 20
4-{[7- (3,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -N-piperidin-4-ylbenzamide 299 mg, ethanol 15 ml, DMF20 To the mixture of ml, 76 mg of sodium carbonate and 107 mg of 1H-benzotriazole-1-methanol were added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution, 45 mg of sodium borohydride was added, and the mixture was further stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the resulting residue was diluted with saturated brine and extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol). The obtained crude crystals were washed with ethyl acetate, and 4-{[7- (3,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -N- (1 183 mg of -methylpiperidin-4-yl) benzamide were obtained as colorless crystals.

Example 21
3-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -N-piperidin-4-ylbenzamide in a solution of 155 mg of formic acid in 2 ml A 37% aqueous formaldehyde solution (0.1 ml) was added, and the mixture was stirred at 90 ° C. for 6 hours. The reaction mixture was diluted with water, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol: concentrated aqueous ammonia solution). Further, it was washed with heating (ethyl acetate-hexane mixed solvent) to give 3-{[7- (2,5-difluorobenzyl) -7H-pyrrolo2,3-d] pyrimidin-2-yl] amino} -N- ( 53 mg of 1-methylpiperidin-4-yl) benzamide was obtained as a colorless solid.

Example 22
4-{[7- (3,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -N-piperidin-4-ylbenzamide in a solution of 395 mg of NMP in 10 ml of NMP Sodium carbonate 234 mg, sodium iodide 166 mg, and chloroacetone 88 μl were added, and the mixture was stirred at 60 ° C. for one day. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform) to give 4-{[7- (3,5-difluorobenzyl) -7H-pyrrolo [2, 290 mg of 3-d] pyrimidin-2-yl] amino} -N- [1- (2-oxopropyl) piperidin-4-yl] benzamide was obtained (F: 519). The obtained ketone body was dissolved in 20 ml of methanol, 41 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, saturated brine was added to the resulting residue, and the mixture was extracted with chloroform. After drying with sodium sulfate, the solvent was distilled off under reduced pressure, and 4-{[7- (3,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -N- [ 296 mg of 1- (2-hydroxypropyl) piperidin-4-yl] benzamide was obtained.

Example 23
1- (4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} benzoyl) pyrrolidine-2-carboxylic acid 170 mg, 2 drops of DMF To a mixture of 5 ml of tetrahydrofuran was added 0.13 ml of thionyl chloride at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, 10 ml of tetrahydrofuran and 10 ml of a cold ammonia solution were added, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol). Further recrystallization (2-propanol), 1- (4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} benzoyl) pyrrolidine -2-carboxamide 31 mg was obtained as a colorless solid.

Example 24
N- [4- (aminomethyl) phenyl] -7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidine 2-amine 250 mg in DMF 5 ml solution, diisopropylethylamine 0.36 ml, 79 μl of methyl acrylate was added and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain methyl N- (4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidine 2 192 mg of -yl] amino} benzyl) -β-alanine were obtained as pale brown crystals.

Example 25
Under ice-cooling, 97 μl of diethylaminosulfur trifluoride was dissolved in 15 ml of dichloromethane and then dissolved in 15 ml of dichloromethane. ] Pyrimidin-2-yl] amino} -N- [1- (2-hydroxypropyl) piperidin-4-yl] benzamide (284 mg) was added, and the mixture was stirred at room temperature for 4 days. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform), and the resulting crude crystals were washed with diethyl ether to give 4-{[7- (3, 40 mg of 5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -N- [1- (2-fluoropropyl) piperidin-4-yl] benzamide was obtained.

Example 26
7- (3,5-difluorobenzyl) -N- (4-piperazin-1-ylphenyl) -7H-pyrrolo [2,3-d] pyrimidin 2-amine 150 mg in DMF 5 ml solution, triethylamine 85 μl, Sodium carbonate (49 mg) and methanesulfonyl chloride (36 μl) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) and recrystallized (methanol) to give 7- (3,5-difluorobenzyl) -N- {4- [4- (methylsulfonyl) 30 mg of piperazin-1-yl] phenyl} -7H-pyrrolo [2,3-d] pyrimidine-2-amine was obtained as light brown crystals.

Example 27
[5-{[7- (2,5-Difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -2-({[2- (2-hydroxyethoxy) ethyl] Amino} carbonyl) phenoxy] tert-butyl acetate 362 mg of methanol 15 ml solution was bubbled with hydrogen chloride gas at room temperature for 15 minutes. The mixture was further stirred for 1 hour, and the solvent was distilled off under reduced pressure. To the resulting residue were added saturated brine and 1M aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform), [5-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2 , 3-d] pyrimidin-2-yl] amino} -2-({[2- (2-hydroxyethoxy) ethyl] amino} carbonyl) phenoxy] acetic acid methyl (229 mg) was obtained (F: 556). The obtained methyl ester compound was dissolved in 10 ml of methanol, and then 4 ml of 1M aqueous sodium hydroxide solution was added. The mixture was stirred at 50 ° C. for 2 hours, the solvent was distilled off under reduced pressure, and 1M hydrochloric acid was added to the resulting residue. The precipitated crystals were washed with ethyl acetate, and [5-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -2- ( 188 mg of {[2- (2-hydroxyethoxy) ethyl] amino} carbonyl) phenoxy] acetic acid was obtained.

Example 28
(5-{[7- (2,5-Difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -2-{[(trans-4-hydroxycyclohexyl) amino] carbonyl } Phenoxy) Acetic acid 270 mg was dissolved in DMF 12 ml, O- (benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate 372 mg, ammonium chloride 471 mg In addition, the mixture was stirred at room temperature for one day. The solvent was distilled off under reduced pressure, saturated brine was added to the resulting residue, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform). The obtained crude crystals were washed with chloroform to give 2- (2-amino-2-oxoethoxy) -4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidine. 91 mg of -2-yl] amino}}-N- (trans-4-hydroxycyclohexyl) benzamide was obtained.

Example 29
4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} benzoic acid 2.00 g of DMF in 30 ml solution was added 2-bromoethylamine bromide Hydrogenate 1.08 g, triethylamine 0.734 ml and WSC hydrochloride 1.01 g were added and stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was distilled off. Ethyl acetate was added to the obtained residue, insoluble matters were removed by filtration, and the residue was purified by silica gel column chromatography (chloroform: methanol). Subsequently, 0.099 ml of piperidine and 63 mg of p-toluenesulfonic acid monohydrate were added to a 5 ml solution of the obtained solid toluene, and the mixture was stirred for 16 hours with heating under reflux. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol: concentrated aqueous ammonia solution). Further recrystallization (2-propanol) gave 4-{[7- (2,5-difluorobenzyl) -7H-pyrrolo [2,3-d] pyrimidin-2-yl] amino} -N- (2- 98 mg of piperidin-1-ylethyl) benzamide were obtained as a colorless solid.

  The structures and physicochemical data of the example compounds are shown in Tables 13 to 58 below.

また、表５９〜６２に本発明の別の化合物の構造を示す。これらは、上記の製造法や実施例に記載の方法及び当業者にとって自明である方法、またはこれらの変法を用いることにより、容易に合成することができる。

Tables 59 to 62 show the structures of other compounds of the present invention. These can be easily synthesized by using the above-described production methods, the methods described in the Examples and methods obvious to those skilled in the art, or variations thereof.

The compound of the present invention is excellent in STAT6 activation inhibitory activity and is useful as a preventive / therapeutic agent for respiratory diseases (such as asthma and COPD) and allergic diseases (such as rhinitis and dermatitis) involving STAT6.
In addition, the compound of the present invention has high STAT6 activation inhibitory activity compared to inhibition of immune cell activation by antigen receptor stimulation, and is therefore useful as the prophylactic / therapeutic agent having little effect on the immunosuppressive function.

  The numerical heading <223> in the sequence listing below describes the “Artificial Sequence”. Specifically, each base sequence represented by SEQ ID NO: 1 or 2 in the sequence listing is an artificially synthesized enhancer sequence. Moreover, each base sequence represented by the sequence number 3 and 4 in the sequence listing is an artificially synthesized TATA box sequence.

Claims (1)

A pyrrolopyrimidine derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof.

[The symbols in the formula have the following meanings.
A: = C (R ⁰ )-or = N-.
R ⁰ _, R ^0a _, R ^0b _, R ^0c : the same or different from each other, —H or lower alkyl.

R ¹ : a group represented by —H, —R ^x , halogen, —CN, heterocycle or —LR ^1a . However, the heterocycle may be substituted with a group selected from the P group.

L: * -O-, * -NR ^0- , * -S-, * -S (O) _2- , * -C (O)-, * -C (O) O-, * -OC (O) -, * -C (O) NR ^0- , * -NR ⁰ C (O)-, * -NR ⁰ -C (O) NR ^0a- , * -OC (O) NR ^0- , * -NR ^0- C (O) O-, * -O-lower alkylene, * -NR ⁰ -lower alkylene, * -S-lower alkylene, * -SO ₂ -lower alkylene, * -C (O) -lower alkylene, * -C (O) O-lower alkylene, * -OC (O) -lower alkylene, * -C (O) NR ⁰ -lower alkylene or * -NR ⁰ C (O) -lower alkylene. However, * shows the coupling ^| bonding to R1a.

R ^1a : —H, —R ^1b , cycloalkyl, lower alkylene-cycloalkyl, aryl, lower alkylene-aryl, heterocycle, lower alkylene-heterocycle or lower alkylene-NR ⁰ -heterocycle.
However, the cycloalkyl part of cycloalkyl and lower alkylene-cycloalkyl may be substituted with a group selected from group Q, the aryl part of aryl and lower alkylene-aryl, and the heterocycle, lower alkylene-heterocycle And the heterocyclic portion of the lower alkylene-NR ⁰ -heterocycle may be substituted with a group selected from the group P.

R ^1b : lower alkyl optionally substituted with a group selected from group G ¹ .
G ¹ group: halogen, —CN, —OR ⁰ , —O-lower alkylene —OR ⁰ , —S-lower alkyl, —S (O) -lower alkyl, —S (O) ₂ -lower alkyl, —NR ⁰ R ^0a , -NR ⁰ -lower alkylene-OR ^0a , -N (lower alkylene-OR ⁰ ) (lower alkylene-OR ^0a ), ^-Si (lower alkyl) ₃ , -C (O) OR ⁰ , -C (O ) NR ⁰ R ^0a , -C (O) NR ⁰ -halogeno lower alkyl, -C (O) NR ⁰ -lower alkylene-OR ^0a , -C (O) NR ⁰ -lower alkylene-NR ^0a R ^0b , -C (O) NR ⁰ -lower alkylene-C (O) OR ^0a , -OC (O) R ⁰ , -NR ⁰ C (O) -R ^0a , -NR ⁰ S (O) ₂ -lower alkyl and -NR ⁰ S (O) ₂ -aryl. However, the aryl part of —NR ⁰ S (O) ₂ -aryl may be substituted with lower alkyl, halogen, —OH, —O-lower alkyl, —O-halogeno lower alkyl or oxo.

Group P: —R ^X , lower alkenyl optionally substituted with halogen, —halogen, —OH, —OR ^X , oxo, —CN, —nitro, —NH ₂ , —NH—R ^X , —NR ^X R ^{xa, -C (O) H,} -C (O) -R X, -C (O) OH, -C (O) OR X, -C (O) NH 2, -C (O) NH-R X , -C (O) NR ^X R ^Xa , -NR ⁰ C (O) -R ^X , -NR ⁰ C (O) NR ^0a R ^0b , -NR ⁰ C (= NR ^0a ) NR ^0b R ^0c , -NR ⁰ S (O) ₂ -lower alkyl, -S-lower alkyl, -S (O) -lower alkyl, -S (O) ₂ -lower alkyl, cycloalkyl, aryl and heterocycle.
However, the aryl and heterocycle may be substituted with lower alkyl, halogeno lower alkyl, halogen, —OH, —O-lower alkyl, —O-halogeno lower alkyl or oxo.

Q group: lower alkyl, lower alkylene-OR ⁰ , lower alkylene-C (O) OR ⁰ , lower alkylene-C (O) NR ⁰ R ^0a , —OR ⁰ , oxo, —NR ⁰ R ^0a , —C (O ) OR ⁰ , —C (O) NR ⁰ R ^0a , —NHC (O) -lower alkyl, —C (O) -lower alkyl, aryl and heterocycle.
However, the aryl and heterocycle may be substituted with lower alkyl, halogeno lower alkyl, halogen, —OH, —O-lower alkyl, —O-halogeno lower alkyl or oxo.

R ^X , R ^Xa : lower alkyl which may be the same or different from each other and may be substituted with a group selected from Group G ² .
Group G ² : halogen, —CN, —OR ⁰ , —O-lower alkylene —OR ⁰ , —S-lower alkyl, —S (O) -lower alkyl, —S (O) ₂ -lower alkyl, —NR ⁰ R ^0a , -NR ⁰ -lower alkylene-OR ^0a , -N (lower alkylene-OR ⁰ ) (lower alkylene-OR ^0a ), ^-Si (lower alkyl) ₃ , -C (O) OR ⁰ , -C (O ) NR ⁰ R ^0a , -C (O) NR ⁰ -halogeno lower alkyl, -C (O) NR ⁰ -lower alkylene-OR ^0a , -C (O) NR ⁰ -lower alkylene-NR ^0a R ^0b , -C (O) NR ⁰ -lower alkylene-C (O) OR ^0a , -OC (O) R ⁰ , -NR ⁰ C (O) -R ^0a , -NR ⁰ S (O) ₂ -lower alkyl, -NR ⁰ S (O) ₂ -aryl, cycloalkyl, aryl and heterocycle.
Provided that the aryl moiety and the heterocycle of aryl, —NR ⁰ S (O) ₂ -aryl may be substituted with lower alkyl, halogen, —OH, —O-lower alkyl, —O-halogeno lower alkyl or oxo. .

R ² : —H, —CN, lower alkyl, halogeno lower alkyl, lower alkylene —OR ⁰ , halogen, —OR ⁰ , —O-halogeno lower alkyl, —O-lower alkylene —OR ⁰ , —O-lower alkylene— NR ⁰ R ^0a , -O-lower alkylene-C (O) OR ⁰ , -O-lower alkylene-C (O) NR ⁰ R ^0a , -NR ⁰ R ^0a , -NR ⁰ C (O) -R ^0a , -C (O) R ⁰ , -C (O) OR ⁰ , -C (O) NR ⁰ R ^0a , -C (O) NR ⁰ -lower alkylene-NR ^0a R ^0b , -S-lower alkyl, -S (O) -lower alkyl, --S (O) ₂ -lower alkyl, cycloalkyl, --O-cycloalkyl, --O-lower alkylene-cycloalkyl, aryl, --O-aryl, --O-lower alkylene-aryl, -NR ⁰ -aryl, -C (O) NR ⁰ -aryl, -NR ⁰ C (O) -aryl, heterocycle, -O-heterocycle, -O-lower alkylene-heterocycle, -NR ⁰ -heterocycle , -C (O) NR ⁰ -heterocycle, -NR ⁰ C (O) -heterocycle or -C (O) NR ⁰ -lower alkylene-heterocycle.
Provided that aryl, -O-aryl, -O-lower alkylene-aryl, -NR ⁰ -aryl, -C (O) NR ⁰ -aryl and -NR ⁰ C (O) -aryl aryl moieties, and heterocycles , -O-heterocycle, -O-lower alkylene-heterocycle, -NR ⁰ -heterocycle, -C (O) NR ⁰ -heterocycle, -NR ⁰ C (O) -heterocycle and -C (O) The heterocycle part of NR ⁰ -lower alkylene-heterocycle is lower alkyl, halogen, —OH, —O-lower alkyl, —O-halogeno lower alkyl, oxo, —NR ⁰ R ^0a , —SR ⁰ , —SO ₂ R ^{0, -C (O) R 0} , -C (O) oR 0, -C (O) NR 0 R 0a, optionally substituted by -CN or ^{-NR 0 C (O) -R 0a} .

Or, R ¹ and R ² are combined into * -lower alkylene-, * -O-lower alkylene-, * -lower alkylene-O-, * -lower alkylene-O-lower alkylene-, * -O-lower. Alkylene-O-, * -N (R ⁶ ) -lower alkylene-, * -lower alkylene-N (R ⁶ )-, * -lower alkylene-N (R ⁶ ) -lower alkylene-, * -N (R ⁶ ) -CH = CH-, * -CH = CH-N (R ⁶ )-, * -N = CH-CH = CH-, * -CH = N-CH = CH-, * -CH = CH-N = CH-, * -CH = CH-CH = N-, * -N = CH-CH = N-, * -CH = NN = CH-, * -N (R ⁶ ) -N = CH-, * -CH = NN (R ⁶ )-, * -CH = CH-C (O) -O-, * -N (R ⁶ ) -C (R ⁰ ) = N-, * -N = C (R ⁰ ) -N (R ⁶ )-, * -N = C (halogeno lower alkyl) -N (R ⁶ )-or * -N (R ⁶ ) -C (halogeno lower alkyl) = N- , * Indicates a bond to the position indicated by R ¹ ). However, * -lower alkylene-, * -O-lower alkylene-, * -lower alkylene-O-, * -lower alkylene-O-lower alkylene-, * -O-lower alkylene-O-, * -N (R ⁶ ) -Lower alkylene, * -lower alkylene-N (R ⁶ )-and * -lower alkylene-N (R ⁶ ) -lower alkylene-lower alkylene part may be substituted by halogen, -OR ⁰ or oxo Good.

R ⁶ : -H, lower alkyl, -C (O) -lower alkyl, -C (O) -heterocycle, -C (O) O-lower alkyl, lower alkylene-OR ⁰ , lower alkylene-O-lower Alkylene-OR ⁰ , lower alkylene-C (O) OR ⁰ or lower alkylene-C (O) NR ⁰ R ^0a .

R ³ : —H, lower alkyl, halogen, —OR ⁰ , —NR ⁰ R ^0a , lower alkylene —OR ⁰ , lower alkylene —NR ⁰ R ^0a or —NR ⁰ C (O) —R ^0a .
R ⁴ : —H, —C (O) OR ⁰ or —C (O) NR ⁰ R ^0a .
R ⁵ : lower alkyl, aryl, lower alkylene-aryl or lower alkylene-heterocycle.
Provided that the aryl moiety of aryl and lower alkylene-aryl and the heterocyclic moiety of the lower alkylene-heterocycle are lower alkyl, halogen, -OH, -O-lower alkyl, -O-halogeno lower alkyl, -NR ⁰ R ^0a ,- SR ⁰ , -S (O) ₂ R ⁰ , -C (O) R ⁰ , -C (O) OR ⁰ , -C (O) NR ⁰ R ^0a , -CN or -NR ⁰ C (O) -R ^It may be substituted with ^0a . ]