JP2006045119A - Pyrazine derivative and nephritis-treating agent using the same as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new pyrazine derivative having a treating effect of nephritis. <P>SOLUTION: This pyrazine derivative expressed by formula (I) [wherein, (n) is an integer of 0-2; R<SB>1</SB>is H or a 1-3C straight chain alkyl; A is a specific heterocyclic ring group; and E is a direct bond or NH, when the E is NH, D is thiazolyl or phenyl which may be substituted with a specific substituent and when the E is a direct bond, the D is a specific aromatic group] or its pharmaceutically acceptable salts and a medicine containing these compounds as active ingredients, especially nephritis-treating agent are provided. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a therapeutic agent for nephritis containing a pyrazine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

  The kidneys are urinary organs that are paired on the back side of the body cavity. By generating urine, 1) excretion of water, 2) excretion of metabolites, particularly nitrogenous components, 3) excretion of electrolytes, 4) excretion of foreign substances, 5) Maintains homeostasis such as blood osmotic pressure, body fluid volume and acid / base balance adjustment. The kidney further regulates blood pressure through the production and secretion of renin and prostaglandins, regulates the differentiation and maturation of erythrocytes in the bone marrow through the production of erythropoietin, and is the precursor of vitamin D 25- It is an organ that has important physiological functions such as the function of activating hydroxyvitamin D (Blood, 68 (Suppl), 170a, 1986; Proc Natl Acad Sci USA, 28, 1199, 1981). The kidney is a collection of about 1 million functional units called nephrons, which are composed of glomeruli, Bowman's sac, proximal tubules, Helen snares, and distal tubules. The nephrons join the collecting duct, which opens to the renal pelvis. The glomeruli produce raw urine by filtering blood through a spherical capillary mass. The raw urine undergoes reabsorption and secretion in the tubule, producing the final urine. Normally, glomeruli are controlled so that necessary substances in the blood, especially serum proteins, do not leak into the urine during the filtration process, but when the glomerulus is damaged, mesangial cells, one of the constituent cells, Proliferation and increase of surrounding substrates occur, increasing the amount of protein excreted in the urine. When the amount of urinary protein excretion increases, this protein itself damages the tubule, which further deteriorates glomerular damage, leading to rapid decline in renal function.

  In clinical forms of WHO glomerular disease (clinical syndrome), nephritis can be acute nephritis (syndrome), rapidly progressive nephritis (syndrome), recurrent or persistent hematuria, chronic nephritis (syndrome), nephrosis (syndrome). being classified. In addition, in the tissue classification (morphological classification), microvariable type, focal segmental lesion, membranous nephropathy (membranous nephritis), mesangial proliferative glomerulonephritis, endoproliferative glomerulonephritis, membranous proliferative Examples include glomerulonephritis, crescent-forming glomerulonephritis, and sclerosing nephritis.

  Primary glomerulonephritis includes acute glomerulonephritis (AGN), post-streptococcal glomerulonephritis, rapidly progressive glomerulonephritis (RPGN), Goodpasture syndrome, chronic glomerulonephritis, mesangial proliferative glomerulonephritis, IgA nephritis There are symptoms. Nephrotic syndrome includes minimal change group nephrotic syndrome (MCNS), lipoid nephrosis, membranoproliferative glomerulonephritis (MPGN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), Examples include focal glomerulosclerosis, secondary nephrotic syndrome, and secondary nephrotic syndrome. Systematic diseases include collagen disease kidney (scleroderma kidney, scleroderma kidney crisis, lupus nephritis and the like.

  Steroids are mainly used for drug treatment of nephritis, and immunosuppressants, antiplatelets, antihypertensives, diuretics, etc. are used depending on the etiology and pathology. However, it is difficult to sufficiently treat nephritis with these nephritis therapeutic drugs, and there is no drug that can still be fully satisfied as a therapeutic drug for renal diseases. In addition, side effects due to long-term administration of steroids are also a problem. Basically, prevention and treatment based on patient rest and diet therapy are performed. From such a background, development of an effective drug for nephritis is desired.

  On the other hand, a large number of pyrazine derivatives have been reported so far, but there is no report of pyrazine derivatives as therapeutic agents for nephritis (for example, pyrazine derivatives exhibiting hematopoietic regulation, see Patent Document 1).

  As the nephritis model, anti-glomerular basement membrane (GBM) antibody nephritis model, Thy-1 nephritis model using Thy-1 monoclonal antibody and anti-thymic antibody, Heymann nephritis model, hub venom nephritis model, rat and mouse were used. There are many hereditary lupus nephritis models, IgA nephropathy models, and PAN nephropathy models induced by aminonucleosides. Among them, the anti-GBM antibody nephritis model is an animal model that induces nephritis by administering an antibody against GBM to the animal. GBM includes laminin, fibronectin, collagen, and the like, and nephritis is induced by administering antibodies against these to experimental animals (rats, mice, etc.). More specifically, when an antiserum prepared by administering rat GBM to a rabbit together with Freund's band is administered to a rat, the administered antibody reacts with GBM and linear deposition begins. Simultaneously, complement is activated, various mediators are released, leukocyte accumulation in glomerular snares, activation of blood coagulation system, etc. are added, and tissue damage occurs in GBM. Excretion of protein into the urine (proteinuria) is also observed, and leakage of alkaline phosphatase, N-acetyl-β-glucosaminidase, etc. occurs in the urine. This is referred to as a heterogeneous phase because it is based on antibodies from the first phase or heterologous animals. The first phase reaction decreases after a few days. Rabbit antibodies (γ-globulin) anchored to GBM are considered antigens and autoantibodies against them are produced in rats. When this binds to the rabbit γ-globulin on GBM, the complement is added and the renal lesion is exacerbated. This extreme phase of tissue injury is seen 7 to 14 days after antibody administration. In the pathological model of renal histology, glomerular cell proliferation is mild, but GBM thickening is prominent. Glomerular hemorrhoids, lobulation, adhesion, etc. are observed, and meniscus formation may be observed. In this nephritis model, nephritis can be induced by administration of only one antibody, and the induced nephritis progresses to renal failure, so the pathophysiology and treatment in nephritis as an optimal model for examining the effect of therapeutic agents on nephritis Widely used in research on the effects of drug administration (see, for example, Non-Patent Document 1).

  The anti-Thy-1 antibody nephritis model is an animal model that induces nephritis by administering an antibody against a membrane surface antigen of mesangial cells to the animal. Thy-1.1 antigen is present on the cell membrane surface of mesangial cells such as rats, and administration of these antibodies to experimental animals (rats, etc.) damages mesangial cells and subsequently induces mesangial proliferative nephritis . This lesion can be caused not only by polyclonal antibodies against rat thymocytes but also by monoclonal antibodies. More specifically, when an antibody (antiserum) against rat thymocytes is prepared, it contains an anti-Thy-1.1 antibody. When this anti-Thy-1.1 antibody is administered to a rat, the antibody is immediately It binds to the glomerular mesangial cell surface and activates complement. As a result, about 1 hour after administration, mesangial cells are degenerated and necrotic, and finally the mesangial region is dissociated from GBM, resulting in marked mesangial melting. Mesangial melting becomes prominent 1-2 days after antibody administration, the vascular lumen is enlarged, and a typical example is recognized as ballooning of glomerular snare walls. During this period, inflammatory cell infiltration such as macrophages and polymorphonuclear leukocytes, and platelet accumulation are observed, while the number of mesangial cells is decreasing. From day 3-4, mesangial cells begin to grow and mesangial matrix also increases. Excretion of protein into the urine (proteinuria) is also observed, and leakage of alkaline phosphatase, N-acetyl-β-glucosaminidase, etc. occurs in the urine. Many macrophages are initially observed, but gradually decrease. The proliferation of mesangial cells and the increase in the substrate peak at 1-2 weeks after antibody administration, and present an image of mesangial proliferative nephritis. Although there are differences in the timing of mesangial proliferation and some quantitative differences in proteinuria due to species differences and sex differences in rats, and the antibodies used, this nephritis model is a Thy-1.1 antigen, which is a polyclonal antibody against rat thymus. The same pathological changes can be reproducibly induced by the administration of monoclonal antibodies against, and the induced nephritis is very similar to clinical mesangial proliferative nephritis and IgA nephropathy. As an optimal model, it is widely used for research on the pathological condition in nephritis and the effect of therapeutic drug administration (Non-patent Document 2). An anti-Thy-1 antibody nephritis model that causes chronic growth of proliferative changes and progression to glomerulosclerosis by modifying the lesion using frequent administration of antibodies and various other methods in addition to single antibody administration Is also known.

Using these models, glomerular filtration rate (GFR), renal blood flow
Physiological renal function tests such as reral blood flow (RBF), renal plasma flow (RPF), tubular reabsorption rate (TRR), blood urea nitrogen level, blood creatinine level, endogenous The effect of therapeutic drugs on nephritis is tested by conducting biochemical renal function tests and renal histological tests such as creatinine clearance, urinary electrolyte excretion, protein excretion (urine protein), and enzyme leakage. be able to.

  As described above, many models are known as nephritis models, but the onset process is often common. There are two primary episodes. One is when an animal actively makes antibodies against its own antigen (such as GBM), and the other is when antibodies against passively made antigens in other animals are administered. . In either case, autologous GBM or mesangial cell Thy-1.1 serves as an antigen and binds to antibodies in the blood. In the second onset process, if the antibody bound to the antigen is from a heterologous animal, a new antibody is produced, and the antibody further binds to the heteroantibody previously bound to the antigen, resulting in nephritis. cause. The third onset process is a case where a conjugate of an antigen and an antibody unrelated to GBM or Thy-1.1 of mesangial cells is first formed in the blood and adheres to GBM or the like. In any case, the place where the onset process is triggered is GBM or mesangial cells, and antibodies play an important role. Substantial activation of complement and growth of cells such as mesangial cells and substrate production are also involved. These are in common with human nephritis. Therefore, the recognition of the therapeutic effect in the anti-GBM antibody nephritis model and the anti-Thy-1 nephritis model indicates that it is effective in various nephritis including human lupus nephritis and IgA nephropathy.

WO96 / 19457 Oseto, S., Moriyama, T., Kawada, N., Nagatoya, K., Takeji, M., Ando, A., Yamamoto, T., Imai, E., Hori, M., Therapeutic effect of all- trans retinoic acid on rats with anti-GBM antibody glomerulonephritis, Kidney Int. 64, 1241-1252 (2003) Bagchus W.M., Hoedemaeker P.J., Rozing J., Bakker W.W., Lab Invest. 1986 Dec; 55 (6): 680-687

  Conventional therapeutic agents for nephritis do not have sufficient therapeutic effects on nephritis, and problems of side effects due to long-term administration have been pointed out, and the development of effective therapeutic agents is desired.

  As a result of intensive studies, the present inventors have found that a specific pyrazine derivative or a pharmaceutically acceptable salt thereof is effective for the treatment of nephritis, leading to the present invention.

[式中、nは、0-2の整数を表し、R₁は、水素又はC1-C3の直鎖アルキル基を表し、Aは、インドールジイル基、ピロールジイル基、フランジイル基、チオフェンジイル基、ピラゾールジイル基、イソオキサゾールジイル基、イソチアゾールジイル基、イミダゾールジイル基、オキサゾールジイル基、チアゾールジイル基又はトリアゾールジイル基を表し、Eは、直接結合又は-NH-を表し、Eが-NH-の場合、Dは、チアゾリル基、又はメトキシ基、ハロゲン、シアノ基、アミノ基、水酸基及びトリフルオロメチル基から選ばれる1又は2個の置
換基で置換されていてもよいフェニル基であり、Eが直接結合の場合、Dは、フェニル基、2-フェノキシフェニル基、ナフチル基、キノリル基、イソキノリル基、インドリル基、ベンゾフラニル基、ベンゾチエニル基、ピロリル基、チアゾリル基、イソチアゾリル基、インダゾリル基、ベンゾイミダゾリル基、７−アザインドリル基、 That is, the present invention includes the following inventions.
(1) Formula I

[Wherein, n represents an integer of 0-2, R ₁ represents hydrogen or a C1-C3 linear alkyl group, A represents an indolediyl group, a pyrrolediyl group, a furandiyl group, a thiophenediyl group, Pyrazole diyl group, isoxazole diyl group, isothiazole diyl group, imidazole diyl group, oxazole diyl group, thiazole diyl group or triazole diyl group, E represents a direct bond or -NH-, and E represents -NH- In this case, D is a thiazolyl group, or a phenyl group optionally substituted with one or two substituents selected from a methoxy group, a halogen, a cyano group, an amino group, a hydroxyl group, and a trifluoromethyl group, and E is In the case of a direct bond, D is a phenyl group, 2-phenoxyphenyl group, naphthyl group, quinolyl group, isoquinolyl group, indolyl group, benzofuranyl group, benzothienyl group, Lyl group, thiazolyl group, isothiazolyl group, indazolyl group, benzimidazolyl group, 7-azaindolyl group,

（式中、R₂は、水素、C1-C3の直鎖アルキル基、C3-C5の分岐アルキル基、-C(O)R_3、-SO₂R₃を表し、R₃は、水素、C1-C3の直鎖アルキル基、C3-C5の分岐アルキル基、又はハロゲン、ニトロ基、シアノ基、アミノ基、水酸基、トリフルオロメチル基、C1-C3の直鎖アルキル基、C3-C5の分岐アルキル基、C1-C3の直鎖アルコキシ基及びC3-C5の分岐アルコキシ基から選ばれる1又は2個の置換基で置換されていてもよいフェニル基を表す。）
で表される基、又は、式III Formula II

(Wherein R ₂ represents hydrogen, a C1-C3 linear alkyl group, a C3-C5 branched alkyl group, —C (O) R _3, —SO ₂ R ₃ , R ₃ represents hydrogen, C1 -C3 linear alkyl group, C3-C5 branched alkyl group, or halogen, nitro group, cyano group, amino group, hydroxyl group, trifluoromethyl group, C1-C3 linear alkyl group, C3-C5 branched alkyl And a phenyl group which may be substituted with one or two substituents selected from a group, a C1-C3 linear alkoxy group and a C3-C5 branched alkoxy group.)
Or a group represented by formula III

（式中、Xは、N又はCHであり、R₄は、水素、メチル基、ハロゲン、水酸基、メトキシ基、トリフルオロメチル基、-OCH₂CH₂OH、-OCH₂CH₂OMe、アミノ基、-C(O)NHMe、シアノ基、-COOR₁、-CH₂COOR₁、-CH₂CH₂COOR₁(但し、R₁は、前記定義と同じ)、又は、-(CH₂)_m-Y-(CH₂)_o-R₇で表され、Yは、直接結合、-O-、-NH-、-NHC(O)-、-C(O)NH-(但し、R₇がピペリジル基、ピロリジニル基、又は、R₈で置換されていてもよいピペラジニル基である場合を除く)又は-C(O)-であり、R₇は、C1-C3の直鎖アルキル基、C3-C5の分岐アルキル基、フェニル基、ピペリジル基、ピロリジニル基、モルホリニル基、又は、R₈で置換されていてもよいピペラジニル基であり、R₈は、C1-C3の直鎖アルキル基、C3-C5の分岐アルキル基、-C(O)R₃(但し、R₃は、前記定義と同じ)、-SO₂R₃(但し、R₃は、前記定義と同じ)を表し、m、oはそれぞれ0-3の整数であり（但し、Yが-O-又は-NH-であり、R₇がピペリジル基、ピロリジニル基、モルホリニル基、又はR₈で置換されていてもよいピペラジニル基の場合、oは、2又は3）、R₅及びR₆は、独立して水素、ハロゲン、ニトロ基、シアノ基、アミノ基、水酸基、トリフルオロメチル基、C1-C3の直鎖アルキル基、C3-C5の分岐アルキル基、C1-C3の直鎖アルコキシ基、C3-C5の分岐アルコキシ基、又は、-(CH₂)_m-Y-(CH₂)_o-R₇（但し、m、o、Y、R₇は、前記定義と同じ）で表され、式IIIの4、5、6及び7位のいずれの位置に結合してもよい。）
で表される基である。]
で表されるピラジン誘導体又はその薬学的に許容される塩。

(Wherein, X is N or CH, R ₄ is hydrogen, methyl group, halogen, hydroxyl group, methoxy group, trifluoromethyl group, —OCH ₂ CH ₂ OH, —OCH ₂ CH ₂ OMe, amino group , -C (O) NHMe, cyano group, -COOR ₁ , -CH ₂ COOR ₁ , -CH ₂ CH ₂ COOR ₁ (where R ₁ is as defined above), or-(CH ₂ ) _m- Y- (CH ₂ ) _o -R ₇ where Y is a direct bond, -O-, -NH-, -NHC (O)-, -C (O) NH- (where R ₇ is a piperidyl group , A pyrrolidinyl group, or a piperazinyl group optionally substituted by R ₈ ) or -C (O)-, and R ₇ is a C1-C3 linear alkyl group, C3-C5 branched alkyl group, a phenyl group, piperidyl group, pyrrolidinyl group, morpholinyl group, or substituted with R ₈ is also good piperazinyl group, R ₈ is a linear alkyl group of C1-C3, branched C3-C5 alkyl, -C (O) R ₃ (where, R ₃ is defined as the same), - SO ₂ R ₃ (where, R ₃ is the Represents the same) justified, m, o are each an integer of 0 to 3 (provided that, Y is -O- or -NH-, R ₇ is piperidyl group, pyrrolidinyl group, morpholinyl group, or R ₈ In the case of an optionally substituted piperazinyl group, o is 2 or 3), R ₅ and R ₆ are independently hydrogen, halogen, nitro group, cyano group, amino group, hydroxyl group, trifluoromethyl group, C 1 linear alkyl group -C3, branched alkyl groups of C3-C5, C1-C3 straight chain alkoxy group, a C3-C5 branched alkoxy group, _{or, - (CH 2) m -Y-} (CH 2) o - R ₇ (where m, o, Y and R ₇ are the same as defined above) may be bonded to any of the 4, 5, 6 and 7 positions of formula III.)
It is group represented by these. ]
Or a pharmaceutically acceptable salt thereof.

(2) The pyrazine derivative or the pharmaceutically acceptable salt thereof according to (1), wherein n is 0 or 1 in formula I.
(3) In formula I, E is a direct bond, and D is represented by indolyl group, benzofuranyl group, benzothienyl group, pyrrolyl group, isothiazolyl group, indazolyl group, benzimidazolyl group, 7-azaindolyl group, or formula III The pyrazine derivative or the pharmaceutically acceptable salt thereof according to (2), which is a group.

(4) The pyrazine derivative or the pharmaceutically acceptable salt thereof according to (3), wherein in formula I, D is an indolyl group, an indazolyl group, or a group represented by formula III.
(5) A medicament comprising the pyrazine derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (4) as an active ingredient.
(6) A therapeutic agent for nephritis comprising the pyrazine derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (4) as an active ingredient.

(7) The above described (6), wherein the nephritis is acute glomerulonephritis, chronic glomerulonephritis, mesangial proliferative glomerulonephritis, IgA nephropathy, minimal change group nephrotic syndrome, membranoproliferative glomerulonephritis, or lupus nephritis. For the treatment of nephritis.

  ADVANTAGE OF THE INVENTION According to this invention, the novel pyrazine derivative which shows sufficient therapeutic effect with respect to nephritis can be provided.

The pyrazine derivative of the present invention is represented by the above formula I.
In the formula I, n represents an integer of 0-2.

R ₁ represents hydrogen or a C1-C3 linear alkyl group, preferably represents hydrogen, a methyl group or an ethyl group, and more preferably represents hydrogen or a methyl group.

  A represents an indole diyl group, a pyrrole diyl group, a furandiyl group, a thiophene diyl group, a pyrazole diyl group, an isoxazole diyl group, an isothiazole diyl group, an imidazole diyl group, an oxazole diyl group, a thiazole diyl group or a triazole diyl group; Preferably, it represents an indole diyl group, a pyrrole diyl group, a thiophene diyl group, a pyrazole diyl group, an isoxazole diyl group, an isothiazole diyl group, an imidazole diyl group, an oxazole diyl group, a thiazole diyl group or a triazole diyl group, more preferably Indole diyl group, pyrrole diyl group, pyrazole diyl group, isoxazole diyl group, isothiazole diyl group, imidazole diyl group, oxazole diyl group, thiazole diyl group or Represents a triazolediyl group.

  E represents a direct bond or —NH—, and when E is —NH—, D is a thiazolyl group, or 1 or 2 selected from a methoxy group, a halogen, a cyano group, an amino group, a hydroxyl group, and a trifluoromethyl group A phenyl group optionally substituted by one substituent, preferably a thiazolyl group, or one or two substituents selected from a methoxy group, a halogen, a cyano group, an amino group, a hydroxyl group and a trifluoromethyl group And more preferably a thiazolyl group or a phenyl group substituted with one or two substituents selected from chlorine, fluorine, cyano group, amino group and trifluoromethyl group.

  When E is a bond, D is a phenyl group, 2-phenoxyphenyl group, naphthyl group, quinolyl group, isoquinolyl group, indolyl group, benzofuranyl group, benzothienyl group, pyrrolyl group, thiazolyl group, isothiazolyl group, indazolyl group, benzimidazolyl Represents a group, 7-azaindolyl group, or a group represented by Formula II or Formula III, preferably indolyl group, benzofuranyl group, benzothienyl group, pyrrolyl group, thiazolyl group, isothiazolyl group, indazolyl group, benzimidazolyl group , 7-azaindolyl group, or a group represented by Formula II or Formula III, and more preferably an indolyl group, indazolyl group, benzimidazolyl group, 7-azaindolyl group, or Formula II or Formula III. Represents a group.

In the formula II, R ₂ represents hydrogen, a C1-C3 linear alkyl group, a C3-C5 branched alkyl group, —C (O) R _3, —SO ₂ R ₃ , preferably hydrogen, methyl group, an ethyl group, an isopropyl group, an isobutyl _group, -C (O) R _3, represents -SO ₂ R _3, more preferably hydrogen, methyl, isopropyl, _isobutyl, -C (O) R _3, -SO ₂ R _{3 is} represented.

R ₃ is hydrogen, C1-C3 linear alkyl group, C3-C5 branched alkyl group, or halogen, nitro group, cyano group, amino group, hydroxyl group, trifluoromethyl group, C1-C3 linear alkyl group , C3-
Represents a phenyl group which may be substituted with one or two substituents selected from a C5 branched alkyl group, a C1-C3 linear alkoxy group and a C3-C5 branched alkoxy group, preferably hydrogen, methyl Group, ethyl group, isopropyl group, isobutyl group, or halogen, nitro group, cyano group, amino group, hydroxyl group, trifluoromethyl group, methyl group, ethyl group, isopropyl group, isobutyl group, methoxy group, ethoxy group, isopropyloxy Represents a phenyl group substituted with one or two substituents selected from a group and an isobutyloxy group, more preferably hydrogen, methyl group, isopropyl group, isobutyl group, or chlorine, fluorine, cyano group, amino group, Trifluoromethyl, methyl, isopropyl, isobutyl, methoxy, isopropyloxy and isobutyloxy Represents a phenyl group substituted with 1 or 2 substituents selected from

In the formula III, X represents N or CH.
R ₄ is hydrogen, methyl group, halogen, hydroxyl group, methoxy group, trifluoromethyl group, -OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ OMe, amino group, -C (O) NHMe, cyano group, -COOR _{1, -CH 2 COOR 1, -CH} 2 CH 2 COOR 1 ( where, R ₁ is defined as the same), _{or, - (CH 2) m -Y-} (CH 2) represents an _o -R _7, preferably hydrogen, methyl, chlorine, fluorine, methoxy group, trifluoromethyl _{group, -OCH 2 CH 2 OH, -OCH} 2 CH 2 OMe, amino group, -C (O) NHMe, cyano group, -COOH, -CH ₂ COOH or-(CH ₂ ) _m -Y- (CH ₂ ) _o -R ₇ , more preferably hydrogen, chlorine, fluorine, trifluoromethyl group, amino group, -C (O) NHMe, a cyano group, or — (CH ₂ ) _m —Y— (CH ₂ ) _o —R ₇ is represented.

Y is a direct bond, -O-, -NH-, -NHC (O)-, -C (O) NH- (in which R ₇ is substituted with a piperidyl group, pyrrolidinyl group, or R ₈ Represents a good piperazinyl group) or -C (O)-.

R ₇ represents a C1-C3 linear alkyl group, a C3-C5 branched alkyl group, a phenyl group, a piperidyl group, a pyrrolidinyl group, a morpholinyl group, or a piperazinyl group optionally substituted by R ₈ , preferably Represents a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a phenyl group, a piperidyl group, a pyrrolidinyl group, a morpholinyl group, or a piperazinyl group optionally substituted by R ₈ , more preferably a methyl group, isopropyl A group, an isobutyl group, a piperidyl group, a pyrrolidinyl group, a morpholinyl group, or a piperazinyl group optionally substituted by R ₈ ;

R ₈ is a C1-C3 linear alkyl group, a C3-C5 branched alkyl group, -C (O) R ₃ (where R ₃ is as defined above), -SO ₂ R ₃ (where R _{3 3} represents the same as defined above), preferably a methyl group, an ethyl group, an isopropyl group, an isobutyl group, —C (O) R ₃ (where R ₃ is as defined above), —SO ₂ R ₃ (wherein R ₃ is the same as defined above), and more preferably a methyl group, an ethyl group, —C (O) R ₃ (where R ₃ is as defined above), —SO ₂ R ₃ (wherein R ₃ is the same as defined above).

m and o are each an integer of 0 to 3 (provided that Y is —O— or —NH—, and R ₇ is a piperidinyl group, a pyrrolidinyl group, a morpholinyl group, or a piperazinyl group substituted with R ₈ ; Represents 2,3). Preferably, m and o are each an integer of 0-2 (provided that Y is —O— or —NH— and R ₇ is substituted with a piperidyl group, pyrrolidinyl group, morpholinyl group, or R _8. In the case of a good piperazinyl group, o represents 2 or 3).

R ₅ and R ₆ are independently hydrogen, halogen, nitro group, cyano group, amino group, hydroxyl group, trifluoromethyl group, C1-C3 linear alkyl group, C3-C5 branched alkyl group, C1-C3 A straight-chain alkoxy group, a C3-C5 branched alkoxy group, or — (CH ₂ ) _m —Y— (CH ₂ ) _o —R ₇ (where m, o, Y, and R ₇ are as defined above) And may be bonded to any of the 4, 5, 6 and 7 positions of formula III, preferably independently hydrogen, chlorine, fluorine, nitro group, cyano group, amino group, trifluoromethyl group, a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a methoxy group, an ethoxy group, isopropyloxy group, isobutyl group, _{or, - (CH 2) m -Y-} (CH 2) o -R 7 ( where m, o, Y, and R ₇ are the same as defined above, and more preferably, independently hydrogen, chlorine, fluorine, nitro group, cyano group, amino group, trif Fluoromethyl group, methyl group, isopropyl group, methoxy group, ethoxy group, isopropyloxy group, or — (CH ₂ ) _m —Y— (CH ₂ ) _o —R ₇ (where m, o, Y, R ₇ are Represents the same as defined above.

  Preferable specific examples of the compounds of the present invention include the compounds described in the following Tables 1 to 13, their pharmaceutically acceptable salts, and the compounds described in the Examples. It is not limited.

  The production method of the compound represented by Formula I (hereinafter, for example, “the compound represented by Formula I” may be simply represented as “I”) is shown below. It is not limited to. In various production methods, reaction conditions are appropriately selected from those described below.

Among the compounds represented by Formula I, IV in which R ₁ is hydrogen and E is a direct bond is VII in an alcoholic solvent such as methanol, tetrahydrofuran, dimethoxyethane, 1,4-dioxane, It can be produced by hydrolysis with a base such as an aqueous sodium hydroxide solution, an aqueous lithium hydroxide solution or an aqueous barium hydroxide solution. Although reaction temperature is not specifically limited, Usually, it is about 0 degreeC-room temperature, and reaction time is about 1 hour-48 hours. The amount of base added is usually about 1 to 5 equivalents relative to VII.

（式中、A、D及びnは、前記定義と同じ）
VIIは、下記の工程によって製造することができる（なお、本明細書において、化学反応中、「工程」は、「step」と記載する）。

(Wherein A, D and n are the same as defined above)
VII can be produced by the following steps (in the present specification, “step” is described as “step” during the chemical reaction).

（式中、R₉は、塩素、臭素又はヨウ素を表し、A、R₁、D及びnは、前記定義と同じ）

(Wherein R ₉ represents chlorine, bromine or iodine, and A, R ₁ , D and n are as defined above)

  When the 2-position of the pyrazine ring is bonded to the carbon atom of A, Step 1 can be performed by the method described in “Palladium in Heterocyclic Chemistry vol. 20, 2000, PERGAMON” and its cited references. That is, in a solvent such as dimethylformamide, dioxane, tetrahydrofuran, dimethoxyethane, V and VIII in the presence of 3 mol% to 20 mol% palladium catalyst with respect to V and 1 to 4 equivalents of tertiary amine or inorganic base with respect to V. Can be carried out by reacting. Palladium catalysts include tetrakis (triphenylphosphine) palladium, palladium acetate, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, bis (methyldiphenylphosphine) palladium (II) dichloride, bis (2,4-pentanedionate) palladium (II), bis (triphenylphosphine) palladium (II) dichloride, and the like are used, but not limited thereto. Further, triphenylphosphine, tri-o-tolylphosphine, tetrabutylammonium chloride and the like may be added as appropriate. Examples of the tertiary amine include, but are not limited to, triethylamine and diisopropylethylamine. Examples of the inorganic base include potassium carbonate, potassium phosphate, sodium carbonate, cesium carbonate, but are not limited thereto. Although reaction temperature is not specifically limited, It is about 60 to 140 degreeC, and reaction time is about 2 to 12 hours.

Further, it can also be produced by “Palladium in Heterocyclic Chemistry vol. 20, 2000, PERGAMON” and the following method (Suzuki coupling) described in the cited reference. That is, in a solvent such as dimethylformamide, dioxane, tetrahydrofuran, dimethoxyethane, V and R in the presence of 3 to 20 mol% palladium catalyst with respect to V and 1 to 4 equivalents of tertiary amine or inorganic base with respect to V. ₁ OOC- (CH ₂₎ a _n -AB (OH) ₂ can be prepared by reacting. Palladium catalysts include tetrakis (triphenylphosphine) palladium, palladium acetate, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex, bis (methyldiphenylphosphine) palladium (II) dichloride, bis (
2,4-pentanedionate) palladium (II), bis (triphenylphosphine) palladium (II) dichloride and the like are used, but not limited thereto. Examples of tertiary amines and inorganic bases include triethylamine, diisopropylethylamine, potassium carbonate, potassium phosphate, sodium carbonate, and cesium carbonate, but are not limited thereto. Although reaction temperature is not specifically limited, Usually, it is about 60 to 140 degreeC, and reaction time is about 2 to 12 hours.

When the 2-position of the pyrazine ring is bonded to the nitrogen atom of A, step 1 can be performed by the method described in “Angew. Chem. Int. Ed. 2003, 42, 5400-5449” and the cited references. . That is, it can be carried out by reacting V and VIII in the presence of a catalytic amount of copper, an organic amine and a base in a solvent such as toluene, benzene, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran or dioxane. Examples of copper include, but are not limited to, Cu, CuI, CuCl, CuSCN, Cu ₂ O, CuCl ₂ , CuSO ₄ , Cu (OAc) ₂ , and Cu (acac) ₂ . Organic amines include ethylenediamine, N, N'-dimethylethylenediamine, N-methyl-N'-dimethylethylenediamine, N, N-dimethylethylenediamine, Nn-butylethylenediamine, N-methylethylenediamine, cyclohexane 1,2-diamine, N, N′-dimethylcyclohexane-1,2-diamine and the like are used, but not limited thereto. Further, as the base, potassium phosphate, potassium carbonate, cesium carbonate, sodium t-butoxide and the like are used, but not limited thereto. The amount of copper used is about 5 mol% to 20 mol% with respect to V, and the amount of organic amine is about 5 mol% to 40 mol% with respect to V. The base is used in an amount of about 1 to 4 equivalents with respect to V. Although reaction temperature is not specifically limited, Usually, it is about 70 to 140 degreeC, and reaction time is about 12 to 48 hours.

Steps 2, 3 and 4 can be performed in the same manner as in step 1.
In I, XI wherein R ₁ is hydrogen and E is —NH— can be produced from XII using a method similar to the step of producing IV from VII.

（式中、A、D及びnは、前記定義と同じ）

(Wherein A, D and n are the same as defined above)

（式中、R₉は、塩素、臭素又はヨウ素を表し、A、R₁、D及びnは、前記定義と同じ） XII can be produced by the following steps.

(Wherein R ₉ represents chlorine, bromine or iodine, and A, R ₁ , D and n are as defined above)

Steps 2 and 3 of the XII production can be carried out in the same manner as in the case where the 2-position of the pyrazine ring and the nitrogen atom of A in the VII production step 1 are bonded.
Steps 1 and 4 of the XII production can be performed in the same manner as the step 1 of the VII production.

  In VIII, XV in which A is pyrrole, n is 1 and the substitution position is 3-position can be produced by the following steps.

Step 1 is a step of protecting the nitrogen atom of pyrrole with a triisopropylsilyl group (TIPS). In a solvent such as dimethylformamide, tetrahydrofuran, or dimethoxyethane, XVI is reacted with a base such as sodium hydride or potassium t-butoxide for XVI and then 1 equivalent of triisopropylsilyl chloride for XVI. It can be carried out by reacting. The amount of the base and triisopropylsilyl chloride can be appropriately increased. The reaction temperature is not particularly limited, but is about 0 ° C. to 50 ° C., and the reaction time is about 1 hour to 5 hours. In addition to triisopropylsilyl chloride, t-butyldiphenylsilyl chloride can also be used to protect with a bulky protecting group.

  In step 2, in a solvent such as dichloromethane or chloroform, about 1 to 3 equivalents of alkyloxyoxalyl chloride and XVII are added in the presence of about 1 to 3 equivalents of a tertiary amine such as pyridine, triethylamine or diisopropylethylamine. It can be carried out by reacting. The reaction temperature is not particularly limited, but is about -20 ° C to 50 ° C, and the reaction time is about 2 hours to 48 hours.

  Step 3 is a step of deprotecting the triisopropylsilyl group. It can be carried out by reacting XVIII with 1 to 3 equivalents of tetra-n-butylammonium fluoride with respect to XVIII in a solvent such as tetrahydrofuran or dimethoxyethane. The reaction temperature is not particularly limited, but is about 0 ° C. to 50 ° C., and the reaction time is about 1 hour to 5 hours.

  In step 4, in the presence of a catalytic amount of an acid catalyst such as p-toluenesulfonic acid in an alcoholic solvent such as methanol or ethanol, 1 to 3 equivalents of p-toluenesulfonyl hydrazide and XIX are reacted. Under acidic conditions by reduction with 1 to 3 equivalents of sodium cyanoborohydride relative to XIX. In order to make it acidic, dilute hydrochloric acid or dilute sulfuric acid is usually used, but it is not limited thereto. The reaction temperature of p-toluenesulfonyl hydrazide and XIX is not particularly limited, but is about 50 ° C to 100 ° C, and the reaction time is about 1 to 6 hours. The reduction reaction temperature with sodium cyanoborohydride is not particularly limited, but is about room temperature to about 100 ° C., and the reaction time is about 2 hours to 6 hours.

  In VIII, XX in which A is pyrrole, n is 1 and the substitution position is position 2 can be produced by the following steps.

Step 1 can be performed in the same manner as Step 2 of the XV manufacturing process.
Step 2 can be performed in the same manner as step 4 of the XV manufacturing process.

  In VIII, XXII in which A is pyrrole, n is 0, and the substitution position is position 3 can be produced by the following steps.

Step 1 can be performed in the same manner as Step 1 of the XV manufacturing process.
Step 2 can be carried out by reacting XVII with 1 equivalent of trifluoroacetic anhydride relative to XVII in a solvent such as chloroform or dichloromethane. Although reaction temperature is not specifically limited, Usually, it is about room temperature-about 50 degreeC, and reaction time is about 1 hour-about 6 hours.

Step 3 can be performed in the same manner as step 3 of the XV manufacturing process.
Step 4 can be performed by hydrolyzing XXIV with a 6N aqueous sodium hydroxide solution in a solvent such as methanol, ethanol, tetrahydrofuran, or dioxane. Sodium hydroxide (solid) may be added to the reaction solution in a mixed solvent such as methanol / water, ethanol / water, tetrahydrofuran / water, dioxane / water and the like. The reaction temperature is not particularly limited, but is usually 50 ° C. to reflux temperature, and the reaction time is about 2 to 8 hours.

  Step 5 can be performed by dissolving XXV in a solvent such as methanol or ethanol and heating under acidic conditions. In order to make it acidic, hydrochloric acid or sulfuric acid is usually used, but it is not limited thereto. Although reaction temperature is not specifically limited, Usually, it is 40 degreeC-recirculation | reflux temperature, and reaction time is about 2 hours-about 10 hours.

  The reaction products obtained by the respective production methods are isolated and purified as various solvates such as a free compound, a salt or a hydrate thereof. The salt can be produced by subjecting it to a normal salt formation treatment. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.

  Pharmaceutically acceptable salts of the compounds of formula I include ammonium salts, alkali metal salts (eg, sodium salts and potassium salts), alkaline earth metal salts (eg, calcium salts, and magnesium salts). Or inorganic base salts such as dicyclohexylamine salt, N-methyl-D-glucamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, diisopropanolamine salt, tris (hydroxymethyl) aminomethane salt And amino acid salts such as lysine salt and arginine salt.

  The compound of the present invention is used to treat various types of nephritis such as acute glomerulonephritis, chronic glomerulonephritis, mesangial proliferative glomerulonephritis, IgA nephropathy, minimal change group nephrotic syndrome, membranoproliferative glomerulonephritis, lupus nephritis and the like. It can be used as a medicine.

  When the compound of the present invention is used as a therapeutic agent for the above-mentioned diseases, the compound represented by Formula I and its base addition salt are orally administered to mammals as a powder or as a pharmaceutical composition in an appropriate dosage form. Alternatively, it can be administered parenterally (for example, transdermal administration, intravenous administration, rectal administration, inhalation administration, nasal administration, ophthalmic administration, etc.).

  Specific examples of the dosage form for administration include tablets, powders, pills, capsules, granules, syrups, solutions, injections, emulsions, suspensions, suppositories and the like. Such dosage forms are produced by a method known per se and contain various carriers usually used in the pharmaceutical field. Examples include excipients, lubricants, binders, disintegrants in solid preparations; solvents, solubilizers, suspending agents, soothing agents, etc. in liquid preparations. If necessary, additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can also be used.

Examples of the excipient include lactose, D-mannitol, starch, sucrose, corn starch, crystalline cellulose, and light anhydrous silicic acid. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like. Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate, or polyvinyl alcohol, polyvinylpyrrolidone, and methylcellulose. , Hydrophilic polymers such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like. Examples of isotonic agents include glucose, sodium chloride, D-sorbitol, D-mannitol and the like. Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Examples of soothing agents include benzyl alcohol. Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite and ascorbic acid.

  The effective dose and frequency of administration of the compound represented by Formula I or a pharmaceutically acceptable salt thereof varies depending on the dosage form, patient age, body weight, nature or severity of the symptom to be treated, but is usually an adult. 1 to 1000 mg per day, preferably 1 to 300 mg can be administered once or divided into several times.

  The compound of the present invention is a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an antiobesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, an antithrombotic agent, cachexia It can be used in combination with a drug such as an improving drug (hereinafter abbreviated as a concomitant drug). In this case, the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. The concomitant drug may be a low molecular compound, a high molecular protein, a polypeptide, an antibody, or a vaccine. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, a concomitant drug may be used in an amount of 0.01 to 100 for the compound 1 of the present invention.

  Antidiabetic drugs include animal insulin preparations extracted from bovine and porcine pancreas, Escherichia coli, human insulin preparations genetically engineered using yeast, insulin preparations such as insulin zinc, protamine insulin zinc, insulin fragments or derivatives , Insulin resistance improvers such as pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, α-glucosidase inhibitors such as voglibose, acarbose, miglitol, emiglitate, biguanides such as phenformin, metformin, buformin, tolbutamide, glibenclamide , Gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybsol, repaglinide, nateglinide, miti Insulin secretion promoters such as linide or its calcium salt hydrate, amylin agonists such as pramlintide, phosphotyrosine phosphatase inhibitors such as vanadic acid, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, SGLUT inhibitors, etc. Is mentioned.

  As therapeutic agents for diabetic complications, aldose reductase inhibitors such as tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, neurotrophic factors such as NGF, NT-3, BDNF, neurotrophic factor production Examples include secretagogues, PKC inhibitors, AGE inhibitors, active oxygen scavengers such as thioctic acid, and cerebral vasodilators such as thioprid and mexiletine.

Antihyperlipidemic drugs include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, ripanple, cerivastatin, itavastatin, and other HMG-CoA reductase inhibitors, bezafibrate, beclobrate, vinifibrate, ciprofibrate, clinofibrate, clofibrate Fibrates, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pilifibrate, lonfibrate, fibrate compounds such as simfibrate, theofibrate, squalene synthase inhibitors, ACAT inhibitors such as avasimib, eflucimate, and choles Anion exchange resins such as tyramine, nicotinic acid drugs such as probucol, nicomol and niceritrol), ico Ethyl pent acid, soysterol and a plant sterol, such as gamma oryzanol.

  Antihypertensive agents include angiotensin converting enzyme inhibitors such as captopril, enalapril, delapril, angiotensin II antagonists such as candesartan cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan, and tasosartan, manidipine, nifedipine, nicardipine, amlodipine, Calcium antagonists such as efonidipine, potassium channel openers such as lebucromakalim, and clonidine.

  Anti-obesity agents include central anti-obesity drugs such as dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex, pancreatic lipase inhibitors such as orlistat , Β3 agonists, leptin, peptidic appetite suppressants such as CNTF (ciliary neurotrophic factor), and cholecystokinin agonists such as lynchtrypto.

  Diuretics include xanthine derivatives such as sodium theobromine salicylate and calcium theobromine, ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, thiazinolactones such as thiazide lactones such as pentylhydrochlorothiazide, penflutide, polythiazide, and meticlotiazide. Anti-aldosterone preparations such as triamterene, carbonic anhydrase inhibitors such as acetazolamide, chlorbenzenesulfonamide preparations such as chlorthalidone, mefluside, and indapamide, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

  Chemotherapeutic agents include alkylating agents such as cyclophosphamide and ifosfamide, antimetabolites such as methotrexate and 5-fluorouracil, anticancer antibiotics such as mitomycin and adriamycin, and plant-derived anticancer agents such as vincristine, vindesine and taxol. , Cisplatin, carboplatin, etopoxide and the like.

  Examples of the immunotherapeutic agent include muramyl dipeptide derivatives, picibanil, lentinan, schizophyllan, krestin, interferon, interleukin (IL), granulocyte colony stimulating factor, erythropoietin and the like.

  Antithrombotic agents include heparin such as heparin sodium, heparin calcium and sodium dalteparin, warfarin such as warfarin potassium, antithrombin drugs such as argatroban, thrombolytic agents such as urokinase, tisokinase, alteplase, nateplase, monteplase and pamiteplase, hydrochloric acid Examples thereof include platelet aggregation inhibitors such as ticlopidine, cilostazol, ethyl icosapentate, beraprost sodium, and sarpogrelate hydrochloride.

  As cachexia-improving drugs, cyclooxygenase inhibitors such as indomethacin and diclofenac, progesterone derivatives such as megesterol acetate, carbohydrate steroids such as dexamethasone, metoclopramide drugs, tetrahydrocannabinol drugs, and fat metabolism improvement such as eicosapentaenoic acid And antibodies against growth agents, growth hormones, IGF-1, or cachexia-inducing factors TNF-α, LIF, IL-6, and oncostatin M.

  EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to the following examples.

Example 1
Ethyl 2- [1- (6- {3-[(ethoxycarbonyl) methyl] indolyl} pyrazin-2-yl) indol-3-yl] acetate (1)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 26 mg, copper iodide 9 mg, indole-3-ethyl acetate 367 mg, tripotassium phosphate n-hydrate 506 mg, 2,6-di 300 mg of iodopyrazine was suspended in 1.8 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/2) and 234 mg of ethyl 2- [1- (6- {3-[(ethoxycarbonyl) methyl] indolyl} pyrazin-2-yl ) Indol-3-yl] acetate was obtained (56% yield).
MS (ESI): 483 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (6H, t, J = 7.1), 3.86 (4H, s), 4.22 (4H, q, J = 7.1), 7.28-7.35 (4H, m) , 7.68 (2H, d, J = 8.1), 7.83 (2H, s), 8.34 (2H, d, J = 8.1), 8.69 (2H, s)

Example 2
2- (1- {6- [3- (carboxymethyl) indolyl] pyrazin-2-yl} indol-3-yl) acetic acid (2)

Ethyl 2- [1- (6- {3-[(ethoxycarbonyl) methyl] indolyl} pyrazin-2-yl) indol-3-yl] acetate (230 mg) was dissolved in methanol (5 mL) and 1,4-dioxane (3 mL). A sodium hydroxide aqueous solution (2.5 mL) was added, and the mixture was stirred overnight at room temperature. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 133 mg of 2- (1- {6- [3- (carboxymethyl) indolyl] pyrazin-2-yl} indole- 3-yl) acetic acid was obtained (yield 66%).
MS (ESI): 427 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.80 (4H, s), 7.25-7.31 (4H, m), 7.66 (2H, d, J = 7.8), 8.15 (2H, s), 8.38 (2H, d, J = 7.8), 8.94 (2H, s)

Example 3
Ethyl 2- [1- (6-chloropyrazin-2-yl) indol-3-yl] acetate (3)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 28 mg, copper iodide 9 mg, indole-3-ethyl acetate 237 mg, tripotassium phosphate n-hydrate 543 mg, 2,6-dichloro 145 mg of pyrazine was suspended in 1.0 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/2) to obtain 112 mg of ethyl 2- [1- (6-chloropyrazin-2-yl) indol-3-yl] acetate (Yield 36%).
MS (ESI): 316 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.29 (3H, t, J = 7.1), 3.81 (2H, s), 4.20 (2H, q, J = 7.1), 7.30 (1H, t, J = 7.6), 7.39 (1H, t, J = 7.8), 7.63 (1H, d, J = 7.8), 7.76 (1H, s), 8.33 (1H, d, J = 8.3), 8.38 (1H, s), 8.78 (1H, s)

Example 4
Ethyl 2- (1- {6-[(3-chlorophenyl) amino] pyrazin-2-yl} indol-3-yl) acetate (4)

アルゴン雰囲気下、3-クロロアニリン57mg、エチル 2-[1-(6-クロロピラジン-2-イル)インドール-3-イル]アセテート100mg、トリス（ジベンジリデンアセトン）ジパラジウム7mg、1,1'-ビス（ジフェニルホスフィノ）フェロセン14mg、炭酸セシウム206mgを1,4-ジオキサン1.5mLに溶解し、110℃で18時間攪拌した。反応混合物をセライト(酢酸エチル)で濾過後、濃縮した。残渣をシリカゲルカラムクロマトグラフィー(n-ヘキサン/酢酸エチル=10/4)で精製し、99mgのエチル 2-(1-{6-[(3-クロロフェニル)アミノ]ピラジン-2-イル}インドール-3-イル)アセテートを得た(収率77％)。
MS(ESI)：407(M+H)^+
1H-NMR(300 MHz,CDCl₃)δ:1.30(3H,t,J=7.1),3.83(2H,s),4.21(2H,q,J=7.1),6.78(1H,s),7.08(1H,d,J=7.8),7.25-7.31(3H,m),7.63(2H,d,J=7.8),7.70(1H,s),7.99(1H,s),8.20(1H,d,J=7.6),8.28(1H,s)

Under an argon atmosphere, 57 mg of 3-chloroaniline, 100 mg of ethyl 2- [1- (6-chloropyrazin-2-yl) indol-3-yl] acetate, 7 mg of tris (dibenzylideneacetone) dipalladium, 1,1'- Bis (diphenylphosphino) ferrocene 14 mg and cesium carbonate 206 mg were dissolved in 1,4-dioxane 1.5 mL and stirred at 110 ° C. for 18 hours. The reaction mixture was filtered through celite (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/4), and 99 mg of ethyl 2- (1- {6-[(3-chlorophenyl) amino] pyrazin-2-yl} indole-3 -Yl) acetate was obtained (yield 77%).
MS (ESI): 407 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1), 3.83 (2H, s), 4.21 (2H, q, J = 7.1), 6.78 (1H, s), 7.08 (1H, d, J = 7.8), 7.25-7.31 (3H, m), 7.63 (2H, d, J = 7.8), 7.70 (1H, s), 7.99 (1H, s), 8.20 (1H, d, J = 7.6), 8.28 (1H, s)

Example 5
2- (1- {6-[(3-Chlorophenyl) amino] pyrazin-2-yl} indol-3-yl) acetic acid (5)

Dissolve 74 mg of ethyl 2- (1- {6-[(3-chlorophenyl) amino] pyrazin-2-yl} indol-3-yl) acetate in 2 mL of methanol and 1 mL of 1,4-dioxane, and add 1M aqueous sodium hydroxide solution 0.5 mL was added and stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 45 mg of 2- (1- {6-[(3-chlorophenyl) amino] pyrazin-2-yl} indole-3 -Yl) Acetic acid was obtained (yield 65%).
MS (ESI): 379 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.73 (2H, s), 7.05 (1H, d, J = 7.8), 7.19-7.24 (2H, m), 7.35 (1H, t, J = 8.3), 7.47 (1H, d, J = 9.5), 7.61 (1H, d, J = 8.8), 7.95 (1H, s), 8.01 (1H, s), 8.09 (1H, s), 8.27 (1H, d, J = 8.1), 8.37 (1H, s), 9.94 (1H, s)

Example 6
Ethyl 2- [1- (6-indolylpyrazin-2-yl) indol-3-yl] acetate (6)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 9 mg, copper iodide 3 mg, indole 67 mg, tripotassium phosphate n-hydrate 177 mg, ethyl 2- [1- (6-chloro 100 mg of pyrazin-2-yl) indol-3-yl] acetate was suspended in 1.5 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1) to obtain 52 mg of ethyl 2- [1- (6-indolylpyrazin-2-yl) indol-3-yl] acetate. (Yield 41%).
MS (ESI): 397 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3), 3.86 (2H, s), 4.23 (2H, q, J = 7.3), 6.84 (1H, d, J = 3.7), 7.25-7.36 (4H, m), 7.70 (2H, t, J = 7.8), 7.83 (2H, d, J = 6.1), 8.33 (1H, d, J = 8.3), 8.37 (1H, d , J = 8.3), 8.71 (2H, d, J = 2.4)

Example 7
2- [1- (6-Indolylpyrazin-2-yl) indol-3-yl] acetic acid (7)

48 mg of ethyl 2- [1- (6-indolylpyrazin-2-yl) indol-3-yl] acetate was dissolved in 2 mL of methanol, 0.5 mL of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 29 mg of 2- [1- (6-indolylpyrazin-2-yl) indol-3-yl] acetic acid. (Yield 66%).
MS (ESI): 369 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.80 (2H, s), 6.90 (2H, d, J = 3.4), 7.21-7.32 (4H, m), 7.66 (1H, d, J = 7.1), 7.71 (1H, d, J = 6.8), 8.16 (1H, s), 8.23 (1H, d, J = 3.4), 8.39 (1H, t, J = 6.8), 8.96 (1H, s), 8.99 (1H, s)

Example 8
Ethyl 2- [1- (6-pyrrolylpyrazin-2-yl) indol-3-yl] acetate (8)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 9 mg, copper iodide 6 mg, pyrrole 170 mg, tripotassium phosphate n-hydrate 177 mg, ethyl 2- [1- (6-chloro 100 mg of pyrazin-2-yl) indol-3-yl] acetate was suspended in 0.9 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1) to obtain 26 mg of ethyl 2- [1- (6-pyrrolylpyrazin-2-yl) indol-3-yl] acetate. (24% yield).
MS (ESI): 347 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.29 (3H, t, J = 7.1), 3.83 (2H, s), 4.21 (2H, q, J = 7.1), 6.46 (2H, t, J = 2.4), 7.30 (1H, t, J = 8.1), 7.39 (1H, t, J = 8.1), 7.60 (2H, t, J = 2.0), 7.66 (1H, d, J = 7.8), 7.78 (1H , s), 8.35 (1H, d, J = 8.5), 8.52 (1H, s), 8.64 (1H, s)

Example 9
2- [1- (6-Pyrrolylpyrazin-2-yl) indol-3-yl] acetic acid (9)

26 mg of ethyl 2- [1- (6-pyrrolylpyrazin-2-yl) indol-3-yl] acetate is dissolved in 2 mL of methanol and 2 mL of 1,4-dioxane, and 0.38 mL of 1M aqueous sodium hydroxide solution is added, Stir at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 24 mg of 2- [1- (6-pyrrolylpyrazin-2-yl) indol-3-yl] acetic acid. (Yield 100%).
MS (ESI): 319 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.76 (2H, s), 6.44 (2H, s), 7.26 (1H, t, J = 7.8), 7.39 (1H, t, J = 7.1) , 7.64 (1H, d, J = 7.8), 7.82 (2H, s), 8.16 (1H, s), 8.44 (1H, d, J = 8.3), 8.92 (1H, s), 8.93 (1H, s)

Example 10
Ethyl 2- {1- [6- (1,3-thiazol-2-ylamino) pyrazin-2-yl] indol-3-yl} acetate (10)

Under argon atmosphere, 2-aminothiazole 40 mg, ethyl 2- [1- (6-chloropyrazin-2-yl) indol-3-yl] acetate 90 mg, tris (dibenzylideneacetone) dipalladium 11 mg, 9,9-dimethyl -4,5-bis (diphenylphosphino) xanthene 10 mg and sodium carbonate 42 mg were dissolved in 1.5 mL of 1,4-dioxane and stirred at 110 ° C. for 18 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/7), and 33 mg of ethyl 2- {1- [6- (1,3-thiazol-2-ylamino) pyrazin-2-yl] Indol-3-yl} acetate was obtained (yield 31%).
MS (ESI): 380 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1), 3.87 (2H, s), 4.22 (2H, q, J = 7.1), 6.98 (1H, d, J = 3.4), 7.25-7.36 (2H, m), 7.52-7.55 (1H, m), 7.69 (1H, d, J = 8.3) 7.96 (1H, s), 8.04 (1H, d, J = 8.1), 8.22 (1H, s), 8.50 (1H, s)

Example 11
2- {1- [6- (1,3-thiazol-2-ylamino) pyrazin-2-yl] indol-3-yl} acetic acid (11)

Dissolve 32 mg of ethyl 2- {1- [6- (1,3-thiazol-2-ylamino) pyrazin-2-yl] indol-3-yl} acetate in 2 mL of methanol and 2 mL of 1,4-dioxane, and add 1M water. A sodium oxide aqueous solution (0.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 12 mg of 2- {1- [6- (1,3-thiazol-2-ylamino) pyrazin-2-yl] Indol-3-yl} acetic acid was obtained (41% yield).
MS (ESI): 352 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.51 (2H, s), 7.13-7.20 (2H, m), 7.24 (1H, t, J = 7.8), 7.46 (1H, d, J = 3.4), 7.66 (1H, d, J = 7.8), 7.93 (2H, s), 8.11 (1H, d, J = 8.3), 8.34 (1H, s), 8.44 (1H, s)

Example 12
Ethyl 2- [1- (6-iodopyrazin-2-yl) pyrrol-3-yl] acetate (12)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 780 mg, copper iodide 260 mg, ethyl 2-pyrrol-3-yl acetate 4.2 g, tripotassium phosphate n-hydrate 15.3 g, 10 g of diiodopyrazine was suspended in 30 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/2) to obtain 5.9 g of ethyl 2- [1- (6-iodopyrazin-2-yl) pyrrol-3-yl] acetate. (Yield 49%).
MS (ESI): 358 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1), 3.53 (2H, s), 4.18 (2H, q, J = 7.1), 6.37 (1H, s), 7.40 -7.46 (2H, m), 8.34 (1H, s), 8.57 (1H, s)

Example 13
Ethyl 2- [1- (6- {3-[(ethoxycarbonyl) methyl] pyrrolyl} pyrazin-2-yl) pyrrol-3-yl] acetate (13)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 43 mg, copper iodide 14 mg, ethyl 2-pyrrol-3-yl acetate 254 g, tripotassium phosphate n-hydrate 843 mg, diiodo Pyrazine 500 mg was suspended in 2 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/2), and 105 mg of ethyl 2- [1- (6- {3-[(ethoxycarbonyl) methyl] pyrrolyl} pyrazin-2-yl ) Pyrrol-3-yl] acetate was obtained (yield 18%).
MS (ESI): 383 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.32 (6H, t, J = 7.1), 3.58 (4H, s), 4.21 (4H, q, J = 7.1), 6.40 (2H, s), 7.50 (4H, d, J = 2.0), 8.45 (2H, s)

Example 14
2- (1- {6- [3- (carboxymethyl) pyrrolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid (14)

エチル 2-[1-(6-{3-[(エトキシカルボニル)メチル]ピロリル}ピラジン-2-イル)ピロール-3-イル]アセテート90mgをメタノール3mL、1,4-ジオキサン2mLに溶解し、1M水酸化ナトリウム水溶液1.2mLを加えて、室温で2時間攪拌した。反応溶液に1M塩酸を加え酢酸エチルで抽出した。有機層を合わせて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、濃縮し、76mgの2-(1-{6-[3-(カルボキシメチル)ピロリル]ピラジン-2-イル}ピロール-3-イル)酢酸を得た(収率100％)。
MS(ESI)：327(M+H)^+
1H-NMR(300 MHz,DMSO-d₆)δ:3.44(4H,s),6.31(2H,s),7.71(2H,s),7.75(2H,t,J=2.4),8.83(2H,s)

90 mg of ethyl 2- [1- (6- {3-[(ethoxycarbonyl) methyl] pyrrolyl} pyrazin-2-yl) pyrrol-3-yl] acetate was dissolved in 3 mL of methanol and 2 mL of 1,4-dioxane, and 1M Sodium hydroxide aqueous solution 1.2mL was added and it stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 76 mg of 2- (1- {6- [3- (carboxymethyl) pyrrolyl] pyrazin-2-yl} pyrrole- 3-yl) acetic acid was obtained (yield 100%).
MS (ESI): 327 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.44 (4H, s), 6.31 (2H, s), 7.71 (2H, s), 7.75 (2H, t, J = 2.4), 8.83 (2H , s)

Example 15
Ethyl 2- [1- (6- {3-[(ethoxycarbonyl) methyl] indolyl} pyrazin-2-yl) pyrrol-3-yl] acetate (15)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 10 mg, copper iodide 4 mg, ethyl 2-pyrrol-3-yl acetate 68 mg, tripotassium phosphate n-hydrate 206 mg, ethyl 2 150 mg of-[1- (6-iodopyrazin-2-yl) indol-3-yl] acetate was suspended in 1 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/3), and 24 mg of ethyl 2- [1- (6- {3-[(ethoxycarbonyl) methyl] indolyl} pyrazin-2-yl ) Pyrrol-3-yl] acetate was obtained (yield 15%).
MS (ESI): 433 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.29 (3H, t, J = 7.1), 1.30 (3H, t, J = 7.1), 3.58 (2H, s), 3.82 (2H, s), 4.20 (2H, q, J = 7.1), 4.21 (2H, q, J = 7.1), 6.42 (1H, s), 7.29 (1H, t, J = 7.8), 7.38 (1H, t, J = 7.1), 7.51 (1H, s), 7.55 (1H, t, J = 2.4), 7.65 (1H, d, J = 7.8), 7.78 (1H, s), 8.31 (1H, d, J = 8.3), 8.48 (1H , s), 8.62 (1H, s)

Example 16
2- (1- {6- [3- (Carboxymethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid (16)

Ethyl 2- [1- (6- {3-[(ethoxycarbonyl) methyl] indolyl} pyrazin-2-yl) pyrrol-3-yl] acetate 24 mg was dissolved in 1 mL of methanol and 1 mL of 1,4-dioxane, and 1 M Sodium hydroxide aqueous solution 0.3mL was added and it stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 14 mg of 2- (1- {6- [3- (carboxymethyl) indolyl] pyrazin-2-yl} pyrrole- 3-yl) acetic acid was obtained (yield 67%).
MS (ESI): 377 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.48 (2H, s), 3.76 (2H, s), 6.37 (1H, brs), 7.25 (1H, t, J = 7.8), 7.38 (1H , t, J = 7.1), 7.64 (1H, d, J = 7.8), 7.71 (1H, s), 7.74 (1H, t, J = 2.9), 8.15 (1H, s), 8.42 (1H, d, J = 8.3), 8.88 (1H, s), 8.90 (1H, s)

Example 17
Ethyl 2- [1- (6-indolylpyrazin-2-yl) pyrrol-3-yl] acetate (17)

Under an argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 2 mg, copper iodide 1 mg, indole 40 mg, tripotassium phosphate n-hydrate 45 mg, ethyl 2- [1- (6-iodo 30 mg of pyrazin-2-yl) pyrrol-3-yl] acetate was suspended in 0.5 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/3) to obtain 24 mg of ethyl 2- [1- (6-indolylpyrazin-2-yl) pyrrol-3-yl] acetate. (Yield 83%).
MS (ESI): 347 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3), 3.58 (2H, s), 4.20 (2H, q, J = 7.3), 6.42 (1H, brs), 6.79 (1H, d, J = 3.4), 7.28 (1H, t, J = 7.1), 7.37 (1H, t, J = 7.1), 7.52 (1H, brs), 7.57 (1H, t, J = 2.4), 7.68 (1H, d, J = 7.8), 7.75 (1H, d, J = 3.4), 8.31 (1H, d, J = 8.3), 8.50 (1H, s), 8.64 (1H, s)

Example 18
2- [1- (6-Indolylpyrazin-2-yl) pyrrol-3-yl] acetic acid (18)

24 mg of ethyl 2- [1- (6-indolylpyrazin-2-yl) pyrrol-3-yl] acetate is dissolved in 1 mL of methanol and 1 mL of 1,4-dioxane, 0.3 mL of 1M aqueous sodium hydroxide solution is added, Stir at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 6 mg of 2- [1- (6-indolylpyrazin-2-yl) pyrrol-3-yl] acetic acid. (Yield 27%).
MS (ESI): 319 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.48 (2H, s), 6.37 (1H, s), 6.86 (1H, d, J = 3.4), 7.24 (1H, t, J = 7.6) 7.36 (1H, t, J = 8.3), 7.68 (1H, d, J = 7.8), 7.71 (1H, s), 7.75 (1H, s), 8.22 (1H, d, J = 3.4), 8.44 ( 1H, d, J = 8.3), 8.90 (1H, s), 8.95 (1H, s)

Example 19
Ethyl 2- [1- (6- (1,3-thiazol-2-yl) pyrazin-2-yl) indol-3-yl] acetate (19)

Under argon atmosphere, thiazole 61mg, ethyl 2- [1- (6-chloropyrazin-2-yl) indol-3-yl] acetate 150mg, tetrakistriphenylphosphine palladium 27mg, potassium acetate 70mg N, N'-dimethylacetamide It melt | dissolved in 1.5 mL and stirred at 150 degreeC for 18 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/3) and 59 mg of ethyl 2- [1- (6- (1,3-thiazol-2-yl) pyrazin-2-yl) Indol-3-yl] acetate was obtained (yield 34%).
MS (ESI): 365 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1), 3.84 (2H, s), 4.21 (2H, q, J = 7.1), 7.31 (1H, t, J = 7.1), 7.41 (1H, t, J = 7.3), 7.66 (1H, d, J = 7.3), 7.79 (1H, s), 8.43 (1H, d, J = 8.3), 8.54 (1H, s), 8.76 (1H, s), 8.78 (1H, s), 8.90 (1H, s)

Example 20
2- [1- (6- (1,3-Thiazol-2-yl) pyrazin-2-yl) indol-3-yl] acetic acid (20)

Dissolve 24 mg of ethyl 2- [1- (6- (1,3-thiazol-2-yl) pyrazin-2-yl) pyrrol-3-yl] acetate in 1 mL of methanol and 1 mL of 1,4-dioxane, and add 1M water. A sodium oxide aqueous solution (0.3 mL) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and 17 mg of 2- [1- (6- (1,3-thiazol-2-yl) pyrazin-2-yl) [Pyrrole-3-yl] acetic acid was obtained (yield 77%).
MS (ESI): 337 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.77 (2H, s), 7.26 (1H, t, J = 8.3), 7.37 (1H, t, J = 7.3), 7.64 (1H, d, J = 7.8), 8.16 (1H, s), 8.54 (1H, d, J = 8.3), 8.85 (1H, s), 9.04 (1H, s), 9.14 (1H, s), 9.31 (1H, s)

Example 21
Ethyl 2- (1- {6- [3- (2-morpholin-4-ylethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetate (21)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 8 mg, copper iodide 3 mg, 4- (2-indol-3-ylethyl) morpholine 116 mg, tripotassium phosphate n-hydrate 157 mg 100 mg of ethyl 2- [1- (6-iodopyrazin-2-yl) pyrrol-3-yl] acetate was suspended in 0.5 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/9), and 82 mg of ethyl 2- (1- {6- [3- (2-morpholin-4-ylethyl) indolyl] pyrazine-2 -Il} pyrrol-3-yl) acetate was obtained (yield 63%).
MS (ESI): 460 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1), 2.54-2.64 (4H, m), 2.77 (2H, t, J = 8.5), 3.02 (2H, t, J = 7.6), 3.59 (2H, s), 3.79 (4H, t, J = 4.6), 4.20 (2H, q, J = 7.1), 6.42 (1H, s), 7.29 (1H, t, J = 7.6 ), 7.38 (1H, t, J = 7.3), 7.51 (1H, s), 7.56 (1H, s), 7.62 (1H, s), 7.65 (1H, d, J = 7.8), 8.33 (1H, d , J = 8.3), 8.47 (1H, s), 8.61 (1H, s)

Example 22
2- (1- {6- [3- (2-morpholin-4-ylethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid (22)

Ethyl 2- (1- {6- [3- (2-morpholin-4-ylethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetate 81 mg was dissolved in 2 mL of methanol and 2 mL of 1,4-dioxane. Then, 1 mL of 1 M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 7 by adding 1 M hydrochloric acid, and then purified by C18 octadecyl column chromatography (methanol / water = 1/1) to obtain 65 mg of 2- (1- {6- [3- (2-morpholine-4 -Ylethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid was obtained (yield 86%).
MS (ESI): 460 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.42-2.50 (4H, m), 2.68 (2H, t, J = 8.3), 2.92 (2H, t, J = 7.3), 3.38 (2H, s), 3.60 (4H, t, J = 4.4), 6.36 (1H, s), 7.25 (1H, t, J = 7.6), 7.36 (1H, t, J = 8.3), 7.67 (1H, d, J = 7.6), 7.70 (1H, s), 7.74 (1H, s), 8.08 (1H, s), 8.44 (1H, d, J = 8.3), 8.84 (1H, s), 8.89 (1H, s)

Example 23
2- [1- (6-Iodopyrazin-2-yl) indol-3-yl] -1-morpholin-4-ylethane-1-one (23)

Under an argon atmosphere, trans-N, N′-dimethyl-1,2-cyclohexanediamine 26 mg, copper iodide 9 mg, 2-indol-3-yl-1-morpholin-4-ylethane-1-one 243 mg, triphosphate 500 mg of potassium n hydrate and 300 mg of 2,6-diiodopyrazine were suspended in 1.5 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/7), and 158 mg of 2- [1- (6-iodopyrazin-2-yl) indol-3-yl] -1-morpholine- 4-Iletan-1-one was obtained (39% yield).
MS (ESI): 449 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 3.52-3.62 (4H, m), 3.69 (4H, s), 3.86 (2H, s), 7.29 (1H, t, J = 7.1), 7.39 (1H , t, J = 7.1), 7.63 (1H, d, J = 7.8), 7.67 (1H, d, J = 12.7), 8.28 (1H, dd, J = 8.3,22.2), 8.62 (1H, s), 8.76 (1H, s)

Example 24
Ethyl 2- (1- {6- [3- (2-morpholin-4-yl-2-oxoethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetate (24)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 10 mg, copper iodide 3 mg, ethyl 2-pyrrol-3-yl acetate 65 mg, tripotassium phosphate n-hydrate 188 mg, 2- [1- (6-Iodopyrazin-2-yl) indol-3-yl] -1-morpholin-4-ylethane-1-one (158 mg) was suspended in 1 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) and 45 mg of ethyl 2- (1- {6- [3- (2-morpholin-4-yl-2-oxoethyl) indolyl] pyrazin-2-yl} pyrrole -3-yl) acetate was obtained (yield 27%).
MS (ESI): 474 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, dt, J = 1.2, 7.1), 3.54-3.64 (6H, m), 3.66-3.72 (4H, m), 3.89 (2H, s) , 4.20 (2H, q, J = 7.1), 6.42 (1H, s), 7.30 (1H, t, J = 7.3), 7.40 (1H, t, J = 7.3), 7.52 (1H, s), 7.55 ( 1H, brs), 7.67 (1H, d, J = 8.1), 7.71 (1H, s), 8.31 (1H, d, J = 8.1), 8.50 (1H, s), 8.62 (1H, s)

Example 25
2- (1- {6- [3- (2-morpholin-4-yl-2-oxoethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid (25)

Ethyl 2- (1- {6- [3- (2-morpholin-4-yl-2-oxoethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetate 45 mg, methanol 1 mL, 1,4-dioxane It melt | dissolved in 1 mL, 0.5 mL of 1M sodium hydroxide aqueous solution was added, and it stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 27 mg of 2- (1- {6- [3- (2-morpholin-4-yl-2-oxoethyl) indolyl ] Pyrazin-2-yl} pyrrol-3-yl) acetic acid was obtained (42% yield).
MS (ESI): 446 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.45-3.62 (10H, m), 3.89 (2H, s), 6.37 (1H, s), 7.24 (1H, t, J = 7.6), 7.37 (1H, t, J = 7.1), 7.67 (1H, d, J = 7.6), 7.70 (1H, s), 7.74 (1H, s), 8.01 (1H, s), 8.41 (1H, d, J = 8.1), 8.87 (1H, s), 8.89 (1H, s)

Example 26
Ethyl 2- (1- {6- [3- (2-morpholin-4-yl-2-oxoethyl) indolyl] pyrazin-2-yl} indol-3-yl) acetate (26)

Under argon atmosphere, trans-N, N′-dimethyl-1,2-cyclohexanediamine 7 mg, copper iodide 2 mg, 2-indol-3-yl-1-morpholin-4-ylethane-1-one 90 mg, triphosphate 131 mg of potassium n hydrate and 100 mg of ethyl 2- [1- (6-iodopyrazin-2-yl) indol-3-yl] acetate were suspended in 1 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) and 31 mg of ethyl 2- (1- {6- [3- (2-morpholin-4-yl-2-oxoethyl) indolyl] pyrazin-2-yl} indole -3-yl) acetate was obtained (yield 24%).
MS (ESI): 524 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3), 3.55-3.66 (4H, m), 3.71 (4H, s), 3.86 (2H, s), 3.92 (2H , s), 4.23 (2H, q, J = 7.3), 7.27-7.39 (4H, m), 7.65-7.70 (2H, m), 7.76 (1H, s), 7.82 (1H, s), 8.33 (2H , d, J = 8.1), 8.68 (1H, s), 8.69 (1H, s)

Example 27
2- (1- {6- [3- (2-morpholin-4-yl-2-oxoethyl) indolyl] pyrazin-2-yl} indol-3-yl) acetic acid (27)

Ethyl 2- (1- {6- [3- (2-morpholin-4-yl-2-oxoethyl) indolyl] pyrazin-2-yl} indol-3-yl) acetate 30 mg, methanol 1 mL, 1,4-dioxane Dissolved in 1 mL, added 0.3 mL of 1 M aqueous sodium hydroxide solution, and stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 8 mg of 2- (1- {6- [3- (2-morpholin-4-yl-2-oxoethyl) indolyl ] Pyrazin-2-yl} indol-3-yl) acetic acid was obtained (yield 28%).
MS (ESI): 496 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.47-3.65 (8H, m), 3.80 (2H, s), 3.91 (2H, s), 7.23-7.30 (4H, m), 7.66 (1H , d, J = 7.6), 7.70 (1H, d, J = 7.8), 8.09 (1H, s), 8.15 (1H, s), 8.38 (2H, t, J = 6.1), 8.94 (2H, s)

Example 28
Ethyl 3- [1- (6- {3- [2- (ethoxycarbonyl) ethyl] indolyl} pyrazin-2-yl) indol-3-yl] propanoate (28)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 13 mg, copper iodide 4 mg, ethyl 3-indolepropanoate 216 mg, tripotassium phosphate n-hydrate 241 mg, 2,6- 100 mg of diiodopyrazine was suspended in 1 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/7) and 90 mg of ethyl 3- [1- (6- {3- [2- (ethoxycarbonyl) ethyl] indolyl} pyrazine-2 -Yl) Indol-3-yl] propanoate was obtained (39% yield).
MS (ESI): 511 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.26 (6H, t, J = 7.3), 2.80 (4H, t, J = 7.6), 3.18 (4H, t, J = 7.6), 4.17 (4H, q, J = 7.3), 7.29 (2H, t, J = 7.3), 7.35 (2H, t, J = 8.1), 7.63 (2H, s), 7.67 (2H, d, J = 7.8), 8.34 (2H , d, J = 8.1), 8.63 (2H, s)

Example 29
3- (1- {6- [3- (2-carboxyethyl) indolyl] pyrazin-2-yl} indol-3-yl) propanoic acid (29)

Dissolve 90 mg of ethyl 3- [1- (6- {3- [2- (ethoxycarbonyl) ethyl] indolyl} pyrazin-2-yl) indol-3-yl] propanoate in 1 mL of methanol and 1 mL of 1,4-dioxane. Then, 0.8 mL of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 8 mg of 3- (1- {6- [3- (2-carboxyethyl) indolyl] pyrazin-2-yl} Indol-3-yl) propanoic acid was obtained (yield 100%).
MS (ESI): 455 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.73 (4H, t, J = 7.8), 3.02 (4H, t, J = 7.8), 7.22-7.30 (4H, m), 7.70 (2H, d, J = 7.6), 8.04 (2H, s), 8.38 (2H, d, J = 7.6), 8.91 (2H, s)

Example 30
Ethyl 2- (1- {6- [4- (2-morpholin-4-ylethoxy) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetate (30)

Under an argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 4 mg, copper iodide 1 mg, 4- (2-morpholin-4-ylethoxy) indole 69 mg, tripotassium phosphate n-hydrate 78 mg 50 mg of ethyl 2- [1- (6-iodopyrazin-2-yl) pyrrol-3-yl] acetate was suspended in 0.5 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 2/8), and 27 mg of ethyl 2- (1- {6- [4- (2-morpholin-4-ylethoxy) indolyl] pyrazine-2 -Il} pyrrol-3-yl) acetate was obtained (41% yield).
MS (ESI): 476 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3), 2.60-2.70 (4H, m), 2.94 (2H, t, J = 5.6), 3.58 (2H, s) , 3.76 (4H, t, J = 4.4), 4.21 (2H, q, J = 7.3), 4.32 (2H, t, J = 5.6), 6.42 (1H, s), 6.69 (1H, d, J = 8.1 ), 6.89 (1H, d, J = 3.4), 7.27 (1H, t, J = 8.1), 7.51 (1H, s), 7.55 (1H, s), 7.66 (1H, d, J = 3.4), 7.89 (1H, d, J = 8.3), 8.51 (1H, s), 8.64 (1H, s)

Example 31
2- (1- {6- [4- (2-morpholin-4-ylethoxy) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid (31)

Dissolve 27 mg of ethyl 2- (1- {6- [3- (2-morpholin-4-ylethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetate in 1 mL of methanol and 1 mL of 1,4-dioxane. Then, 0.3 mL of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 7 by adding 1M hydrochloric acid, and then purified by C18 octadecyl column chromatography (methanol / water = 1/1) to obtain 16 mg of 2- (1- {6- [4- (2-morpholine-4 -Ilethoxy) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid was obtained (yield 63%).
MS (ESI): 448 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.54-2.58 (4H, m), 2.80 (2H, t, J = 5.9), 3.48 (2H, s), 3.59 (4H, t, J = 4.4), 4.25 (2H, t, J = 5.9), 6.37 (1H, s), 6.79-6.83 (2H, m), 7.27 (1H, t, J = 8.3), 7.70 (1H, s), 7.74 ( 1H, s), 8.01 (1H, d, J = 8.5), 8.10 (1H, d, J = 2.7), 8.13 (1H, s), 8.90 (1H, s), 8.93 (1H, s)

Example 32
Ethyl 2- (1- {6- [5- (phenylmethoxy) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetate (32)

Under an argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 4 mg, copper iodide 1 mg, 5-benzyloxyindole 63 mg, tripotassium phosphate n-hydrate 78 mg, ethyl 2- [1- 50 mg of (6-iodopyrazin-2-yl) pyrrol-3-yl] acetate was suspended in 0.5 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 7/3), and 22 mg of ethyl 2- (1- {6- [5- (phenylmethoxy) indolyl] pyrazin-2-yl} pyrrole- 3-yl) acetate was obtained (35% yield).
MS (ESI): 453 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1), 3.59 (2H, s), 4.21 (2H, q, J = 7.1), 5.16 (2H, s), 6.43 (1H, s), 6.72 (1H, d, J = 3.6), 7.09 (1H, dd, J = 2.4,9.0), 7.21 (1H, d, J = 2.4), 7.34-7.43 (3H, m), 7.48-7.58 (4H, m), 7.74 (1H, d, J = 3.6), 8.27 (1H, d, J = 9.0), 8.48 (1H, s), 8.61 (1H, s)

Example 33
2- (1- {6- [5- (Phenylmethoxy) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid (33)

Dissolve 22 mg of ethyl 2- (1- {6- [5- (phenylmethoxy) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetate in 1 mL of methanol and 1 mL of 1,4-dioxane, and add 1M sodium hydroxide. 0.3 mL of an aqueous solution was added and stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 20 mg of 2- (1- {6- [5- (phenylmethoxy) indolyl] pyrazin-2-yl} pyrrole- 3-yl) acetic acid was obtained (yield 100%).
MS (ESI): 425 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.48 (2H, s), 5.16 (2H, s), 6.37 (1H, s), 6.77 (1H, s), 7.07 (1H, d, J = 9.0), 7.27-7.49 (6H, m), 7.70-7.73 (2H, m), 8.20 (1H, s), 8.37 (1H, d, J = 9.0), 8.85 (1H, s), 8.93 (1H , s)

Example 34
Ethyl 2- (1- {6- [3- (2- {4-[(tert-butyl) oxycarbonyl] piperazinyl} ethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetate (34)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 4 mg, copper iodide 1 mg, tert-butyl 4- (2-indol-3-ylethyl) piperazinecarboxylate 92 mg, tripotassium phosphate nhydrate 78 mg and ethyl 2- [1- (6-iodopyrazin-2-yl) pyrrol-3-yl] acetate 50 mg were suspended in 0.5 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/7) and 39 mg of ethyl 2- (1- {6- [3- (2- {4-[(tert-butyl) oxycarbonyl] ] Piperazinyl} ethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetate was obtained (yield 50%).
MS (ESI): 559 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1), 1.48 (9H, s), 2.48-2.54 (4H, brs), 2.79 (2H, t, J = 8.3) , 3.01 (2H, t, J = 8.3), 3.40-3.52 (4H, brs), 3.60 (2H, s), 4.22 (2H, q, J = 7.1), 6.43 (1H, s), 7.30 (1H, t, J = 7.8), 7.39 (1H, d, J = 7.8), 7.53-7.67 (4H, m), 8.34 (1H, s), 8.48 (1H, s), 8.62 (1H, s)

Example 35
2- (1- {6- [3- (2- {4-[(tert-butyl) oxycarbonyl] piperazinyl} ethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid (35)

Ethyl 2- (1- {6- [3- (2- {4-[(tert-butyl) oxycarbonyl] piperazinyl} ethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetate 39 mg is added to 1 mL of methanol. , Dissolved in 1 mL of 1,4-dioxane, 0.5 mL of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 33 mg of 2- (1- {6- [3- (2- {4-[(tert-butyl) oxycarbonyl] ] Piperazinyl} ethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid was obtained (89% yield).
MS (ESI): 531 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 2.64-2.76 (4H, m), 2.82-2.88 (2H, m), 2.95-3.04 (2H, m), 3.52-3.64 (6H, m), 6.41 (1H, s), 7.15-7.30 (3H, m), 7.45-7.54 (3H, m), 8.12 (1H, d, J = 8.3), 8.29 (1H, s), 8.45 (1H, s)

Example 36
2- (1- {6- [3- (2-Piperazinylethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid (36)

2- (1- {6- [3- (2- {4-[(tert-Butyl) oxycarbonyl] piperazinyl} ethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid 28 mg to trifluoroacetic acid 1.5 mL was added and stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to adjust the pH to 7, followed by purification by C18 octadecyl column chromatography (methanol / water = 1/1), and 12 mg of 2- (1- {6- [3- (2- Piperazinylethyl) indolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid was obtained (56% yield).
MS (ESI): 431 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 2.62-2.75 (6H, m), 2.87-2.95 (2H, m), 3.01-3.05 (4H, m), 3.47 (2H, s), 6.37 (1H , s), 7.26 (1H, t, J = 7.4), 7.37 (1H, t, J = 7.2), 7.64-7.75 (3H, m), 8.09 (1H, s), 8.43 (1H, d, J = 8.3), 8.53 (1H, s), 8.90 (1H, s)

Example 37
Ethyl 2- [1- (6-pyrrolo [2,3-b] pyridinylpyrazin-2-yl) pyrrol-3-yl] acetate (37)

Under argon atmosphere, trans-N, N′-dimethyl-1,2-cyclohexanediamine 10 mg, copper iodide 3 mg, 1H-pyrrolo [2,3-b] pyridine 67 mg, tripotassium phosphate · n hydrate 188 mg, 120 mg of ethyl 2- [1- (6-iodopyrazin-2-yl) pyrrol-3-yl] acetate was suspended in 0.8 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 7/3), and 87 mg of ethyl 2- [1- (6-pyrrolo [2,3-b] pyridinylpyrazin-2-yl) [Pyrrol-3-yl] acetate was obtained (yield 75%).
MS (ESI): 348 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1), 3.58 (2H, s), 4.21 (2H, q, J = 7.1), 6.40 (1H, t, J = 2.4), 6.72 (1H, d, J = 7.1), 7.23 (2H, dd, J = 4.6, 7.8), 7.54 (2H, d, J = 2.4), 7.98 (1H, dd, J = 1.7, 7.8) , 8.33 (1H, d, J = 3.9), 8.46 (1H, d, J = 3.2), 8.55 (1H, s)

Example 38
2- [1- (6-Pyrrolo [2,3-b] pyridinylpyrazin-2-yl) pyrrol-3-yl] acetic acid (38)

Dissolve 87 mg of ethyl 2- [1- (6-pyrrolo [2,3-b] pyridinylpyrazin-2-yl) pyrrol-3-yl] acetate in 2 mL of methanol and 2 mL of 1,4-dioxane, and add 1M water. A sodium oxide aqueous solution (0.75 mL) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 78 mg of 2- [1- (6-pyrrolo [2,3-b] pyridinylpyrazin-2-yl) [Pyrrole-3-yl] acetic acid was obtained (yield 98%).
MS (ESI): 320 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.45 (2H, s), 6.34 (1H, s), 6.89 (1H, d, J = 3.9), 7.33 (1H, dd, J = 4.6, 7.8), 7.79 (1H, s), 7.84 (1H, s), 8.15 (1H, d, J = 7.8), 8.46 (1H, d, J = 4.6), 8.54 (1H, d, J = 3.9), 8.93 (1H, s), 9.97 (1H, s)

Example 39
Ethyl 2- [1- (6- (1H-indazolyl) pyrazin-2-yl) pyrrol-3-yl] acetate (39)

Under an argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 10 mg, copper iodide 3 mg, indazole 67 mg, tripotassium phosphate n-hydrate 188 mg, ethyl 2- [1- (6-iodo 120 mg of pyrazin-2-yl) pyrrol-3-yl] acetate was suspended in 0.8 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 7/3) and 42 mg of ethyl 2- [1- (6- (1H-indazolyl) pyrazin-2-yl) pyrrol-3-yl] Acetate was obtained (yield 36%).
MS (ESI): 348 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.32 (3H, t, J = 7.1), 3.61 (2H, s), 4.22 (2H, q, J = 7.1), 6.45 (1H, s), 7.35 (1H, t, J = 7.3), 7.51 (1H, s), 7.57-7.62 (2H, m), 7.81 (1H, d, J = 8.1), 8.27 (1H, s), 8.51 (1H, s) , 8.67 (1H, d, J = 8.1), 9.18 (1H, s)

Example 40
2- [1- (6- (1H-indazolyl) pyrazin-2-yl) pyrrol-3-yl] acetic acid (40)

Dissolve 42 mg of ethyl 2- [1- (6- (1H-indazolyl) pyrazin-2-yl) pyrrol-3-yl] acetate in 1 mL of methanol and 1 mL of 1,4-dioxane, and add 0.5 mL of 1M aqueous sodium hydroxide solution. In addition, the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 27 mg of 2- [1- (6- (1H-indazolyl) pyrazin-2-yl) pyrrol-3-yl] Acetic acid was obtained (yield 70%).
MS (ESI): 320 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.51 (2H, s), 6.39 (1H, s), 7.41 (1H, t, J = 7.8), 7.69 (1H, t, J = 8.1) , 7.74 (1H, s), 7.78 (1H, s), 7.95 (1H, d, J = 7.8), 8.58 (1H, s), 8.63 (1H, d, J = 8.1), 8.92 (1H, s) , 9.06 (1H, s)

Example 41
Ethyl 2- [1- (6-Benzimidazolylpyrazin-2-yl) pyrrol-3-yl] acetate (41)

Under an argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 10 mg, copper iodide 3 mg, benzimidazole 67 mg, tripotassium phosphate n-hydrate 188 mg, ethyl 2- [1- (6- 120 mg of iodopyrazin-2-yl) pyrrol-3-yl] acetate was suspended in 0.8 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/7) to obtain 59 mg of ethyl 2- [1- (6-benzoimidazolylpyrazin-2-yl) pyrrol-3-yl] acetate. (Yield 51%).
MS (ESI): 348 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1), 3.59 (2H, s), 4.21 (2H, q, J = 7.1), 6.44 (1H, s), 7.40 -7.48 (2H, m), 7.52 (1H, s), 7.56 (1H, t, J = 2.4), 7.91 (1H, d, J = 7.3), 8.11 (1H, d, J = 7.3), 8.63 ( 1H, s), 8.66 (1H, s), 8.75 (1H, s)

Example 42
2- [1- (6-Benzimidazolylpyrazin-2-yl) pyrrol-3-yl] acetic acid (42)

Dissolve 59 mg of ethyl 2- [1- (6-benzimidazolylpyrazin-2-yl) pyrrol-3-yl] acetate in 2 mL of methanol and 2 mL of 1,4-dioxane, add 0.75 mL of 1M aqueous sodium hydroxide, For 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to obtain 38 mg of 2- [1- (6-benzoimidazolylpyrazin-2-yl) pyrrol-3-yl] acetic acid. (Yield 69%).
MS (ESI): 320 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.44 (2H, s), 6.38 (1H, s), 7.39 (1H, t, J = 7.6), 7.47 (1H, t, J = 7.1) , 7.72 (1H, s), 7.77 (1H, s), 7.81 (1H, d, J = 7.6), 8.32 (1H, d, J = 8.3), 9.03 (1H, s), 9.09 (1H, s) , 9.15 (1H, s)

Example 43
Ethyl 2- {1- [6- (3-chloro-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetate (43)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 16 mg, copper iodide 5 mg, 3-chloro-1H-indazole 128 mg, tripotassium phosphate n-hydrate 313 mg, ethyl 2- [ 200 mg of 1- (6-iodopyrazin-2-yl) pyrrol-3-yl] acetate was suspended in 1 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 8/2), and 28 mg of ethyl 2- {1- [6- (3-chloro-1H-indazolyl) pyrazin-2-yl] pyrrole- 3-yl} acetate was obtained (yield 13%).
MS (ESI): 382 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.31 (3H, t, J = 7.3), 3.61 (2H, s), 4.22 (2H, q, J = 7.3), 6.44 (1H, s), 7.41 (1H, t, J = 7.8), 7.48 (1H, s), 7.53 (1H, s), 7.65 (1H, t, J = 8.1), 7.76 (1H, d, J = 8.1), 8.51 (1H, s), 8.63 (1H, d, J = 8.5), 9.09 (1H, s)

Example 44
2- {1- [6- (3-Chloro-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetic acid (44)

Ethyl 2- {1- [6- (3-chloro-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetate 28 mg is dissolved in 1 mL of methanol and 1 mL of 1,4-dioxane, and 1M sodium hydroxide 0.5 mL of an aqueous solution was added and stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 18 mg of 2- {1- [6- (3-chloro-1H-indazolyl) pyrazin-2-yl] pyrrole- 3-yl} acetic acid was obtained (yield 67%).
MS (ESI): 354 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.50 (2H, s), 6.39 (1H, s), 7.52 (1H, t, J = 7.8), 7.73 (1H, s), 7.76-7.84 (2H, m), 7.87 (1H, d, J = 8.1), 8.65 (1H, d, J = 8.1), 8.96 (1H, s), 8.97 (1H, s)

Example 45
Ethyl 2- {1- [6- (6-nitro-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetate (45)

Under an argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 16 mg, copper iodide 5 mg, 6-nitroindazole 128 mg, tripotassium phosphate n-hydrate 313 mg, ethyl 2- [1- ( 200 mg of 6-iodopyrazin-2-yl) pyrrol-3-yl] acetate was suspended in 1 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 7/3) and 59 mg of ethyl 2- {1- [6- (6-nitro-1H-indazolyl) pyrazin-2-yl] pyrrole- 3-yl} acetate was obtained (yield 13%).
MS (ESI): 393 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1), 3.63 (2H, s), 4.22 (2H, q, J = 7.1), 6.50 (1H, s), 7.58 (1H, s), 7.61 (1H, s), 7.95 (1H, d, J = 8.8), 8.23 (1H, d, J = 8.8), 8.40 (1H, s), 8.63 (1H, s), 9.19 (1H, s), 9.69 (1H, s)

Example 46
2- {1- [6- (6-Nitro-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetic acid (46)

Dissolve 28 mg of 2- {1- [6- (6-nitro-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetate in 1 mL of methanol and 1 mL of 1,4-dioxane, and add 1M aqueous sodium hydroxide solution. 0.5 mL was added and stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 16 mg of 2- {1- [6- (6-nitro-1H-indazolyl) pyrazin-2-yl] pyrrole- 3-yl} acetic acid was obtained (62% yield).
MS (ESI): 365 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.48 (2H, s), 6.43 (1H, s), 7.73 (1H, s), 7.77 (1H, s), 8.20 (2H, s), 8.79 (1H, s), 9.01 (1H, s), 9.07 (1H, s), 9.49 (1H, s)

Example 47
1- (6-Iodopyrazin-2-yl) -2-phenoxybenzene (47)

Under an argon atmosphere, 130 mg of 2,6-diiodopyrazine, 23 mg of tetrakis (triphenylphosphine) palladium, 84 mg of (2-phenoxy) phenylboronic acid, 82 μL of triethylamine were dissolved in 5 mL of N, N-dimethylformamide, Stir for hours. After concentrating the reaction solution, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 200/1) to obtain 40 mg of 1- (6-iodopyrazin-2-yl) -2-phenoxybenzene. (Yield 27%).
MS (ESI): 375 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 6.98-7.01 (3H, m), 7.09-7.12 (1H, m), 7.25-7.43 (4H, m), 7.98-8.02 (1H, m), 8.47 ( 0.3H, s), 8.71 (0.7H, s), 9.14 (1H, s)

Example 48
Ethyl 2- {1- [6- (2-phenoxyphenyl) pyrazin-2-yl] pyrrol-3-yl} acetate (48)

Under an argon atmosphere, (1R, 2R) -N, N'-dimethylcyclohexane-1,2-diamine 3 mg, copper iodide 1 mg, pyrrole-3-ethyl acetate 20 mg, potassium phosphate n-hydrate 60 mg, 1- 40 mg of (6-iodopyrazin-2-yl) -2-phenoxybenzene was suspended in 2 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1), and 16 mg of ethyl 2- {1- [6- (2-phenoxyphenyl) pyrazin-2-yl] pyrrol-3-yl } Acetate was obtained (yield 36%).
MS (ESI): 400 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.29 (3H, t, J = 6.0), 3.54 (2H, s), 4.19 (2H, q, J = 6.0), 6.35-6.36 (1H, m) , 6.99-7.11 (4H, m), 7.29-7.34 (3H, m), 7.41-7.49 (3H, m), 8.03 (1H, dd, J = 3.0,6.0), 8.57 (1H, s), 8.98 ( 1H, s)

Example 49
2- {1- [6- (2-phenoxyphenyl) pyrazin-2-yl] pyrrol-3-yl} acetic acid (49)

14 mg of ethyl 2- {1- [6- (2-phenoxyphenyl) pyrazin-2-yl] pyrrol-3-yl} acetate is dissolved in 3 mL of methanol and 1 mL of 1,4-dioxane, and 1 M aqueous sodium hydroxide solution 0.4 mL was added and stirred at room temperature overnight. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 11 mg of 2- {1- [6- (2-phenoxyphenyl) pyrazin-2-yl] pyrrol-3-yl } Acetic acid was obtained (yield 88%). MS (ESI): 372 (M + H) ^+
1 H-NMR (300 MHz, CD ₃ OD) δ: 3.48 (2H, s), 6.31-6.33 (1H, m), 6.96 (2H, d, J = 6.0), 7.06-7.10 (2H, m), 7.30-7.38 (3H, m), 7.49-7.52 (2H, m), 7.56 (1H, dd, J = 1.8,2.1), 8.03 (1H, dd, J = 1.8,6.0), 8.72 (1H, s) , 8.84 (1H, s)

Example 50
Ethyl 2- [1- (6-phenylpyrazin-2-yl) pyrrol-3-yl] acetate (50)

Under an argon atmosphere, 98 mg of ethyl 2- [1- (6-iodopyrazin-2-yl) pyrrol-3-yl] acetate, 16 mg of tetrakis (triphenylphosphine) palladium, 33 mg of phenylboronic acid, 57 μL of triethylamine were added to N, N- Dissolved in 2 mL of dimethylformamide and stirred at 110 ° C. for 2 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/1), and 29 mg of ethyl 2- [1- (6-phenylpyrazin-2-yl) pyrrole-3 -Yl] acetate was obtained (34% yield).
MS (ESI): 308 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 5.4), 3.58 (2H, s), 4.20 (2H, q, J = 5.4), 6.39 (1H, dd, J = 1.5,1.5), 7.49-7.56 (3H, m), 7.59 (2H, d, J = 1.5), 8.08-8.10 (2H, m), 8.62 (1H, s), 8.83 (1H, s)

Example 51
2- [1- (6-Phenylpyrazin-2-yl) pyrrol-3-yl] acetic acid (51)

Ethyl 2- [1- (6-phenylpyrazin-2-yl) pyrrol-3-yl] acetate 29 mg is dissolved in 3 mL of methanol and 1 mL of 1,4-dioxane, 0.4 mL of 1M aqueous sodium hydroxide solution is added, Stir overnight at room temperature. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 22 mg of 2- [1- (6-phenylpyrazin-2-yl) pyrrol-3-yl] acetic acid. (Yield 85%).
MS (ESI): 280 (M + H) ^+
1 H-NMR (300 MHz, CD ₃ OD) δ: 3.54 (2H, s), 6.36-6.38 (1H, m), 7.50-7.54 (3H, m), 7.69-7.71 (2H, m), 8.15- 8.18 (2H, m), 8.80 (1H, s), 8.90 (1H, s)

Example 52
2- (6-Chloropyrazin-2-yl) benzo [b] thiophene (52)

Under an argon atmosphere, 300 mg of 2,6-dichloropyrazine, 116 mg of tetrakis (triphenylphosphine) palladium, 359 mg of benzo [b] thiophene-2-boronic acid and 420 μL of triethylamine were dissolved in 3 mL of N, N-dimethylformamide at 110 ° C. Stir for 2 hours. After concentration of the reaction solution, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/1) to obtain 168 mg of 2- (6-chloropyrazin-2-yl) benzo [b] thiophene. (Yield 34%).
MS (ESI): 248 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 7.39-7.44 (2H, m), 7.84-7.90 (2H, m), 8.01 (1H, s), 8.47 (1H, s), 8.94 (1H, s )

Example 53
Ethyl 2- [1- (6-benzo [b] thiophen-2-ylpyrazin-2-yl) pyrrol-3-yl] acetate (53)

Under an argon atmosphere, (1R, 2R) -N, N'-dimethylcyclohexane-1,2-diamine 19 mg, copper iodide 7 mg, pyrrole-3-ethyl acetate 208 mg, potassium phosphate n-hydrate 380 mg, 2- 168 mg of (6-chloropyrazin-2-yl) benzo [b] thiophene was suspended in 2 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1), and 25 mg of ethyl 2- [1- (6-benzo [b] thiophen-2-ylpyrazin-2-yl) pyrrole-3 -Yl] acetate was obtained (yield 21%).
MS (ESI): 364 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.31 (3H, t, J = 6.0), 3.58 (2H, s), 4.21 (2H, q, J = 6.0), 6.40 (1H, brs), 7.38 -7.42 (2H, m), 7.56-7.57 (2H, m), 7.84-7.89 (2H, m), 7.98 (1H, s), 8.55 (1H, s), 8.82 (1H, s)

Example 54
2- [1- (6-Benzo [b] thiophen-2-ylpyrazin-2-yl) pyrrol-3-yl] acetic acid (54)

Dissolve 25 mg of ethyl 2- [1- (6-benzo [b] thiophen-2-ylpyrazin-2-yl) pyrrol-3-yl] acetate in 3 mL of methanol and 2 mL of 1,4-dioxane, and add 1M sodium hydroxide 0.4 mL of an aqueous solution was added and stirred at room temperature for 6 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 20 mg
2- [1- (6-Benzo [b] thiophen-2-ylpyrazin-2-yl) pyrrol-3-yl] acetic acid was obtained (90% yield).
MS (ESI): 336 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 3.55 (2H, s), 6.38 (1H, dd, J = 1.1, 1.7), 7.38-7.42 (2H, m), 7.66-7.687 (2H, m) , 7.89-7.94 (2H, m), 8.19 (1H, s), 8.75 (1H, s), 8.97 (1H, s)

Example 55
2- (6-Chloropyrazin-2-yl) naphthalene (55)

Under an argon atmosphere, 300 mg of 2,6-dichloropyrazine, 116 mg of tetrakis (triphenylphosphine) palladium, 346 mg of naphthalene-2-boronic acid, and 420 μL of triethylamine were dissolved in 3 mL of N, N-dimethylformamide and stirred at 110 ° C. for 2 hours. . After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/1) to obtain 79 mg of 2- (6-chloropyrazin-2-yl) naphthalene (yield 16%).
MS (ESI): 242 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 7.55-7.59 (2H, m), 7.88-7.91 (1H, m), 7.97-7.99 (2H, m), 8.12 (1H, brd, J = 7.8) , 8.55 (2H, s), 9.08 (1H, s)

Example 56
Ethyl 2- [1- (6- (2-naphthyl) pyrazin-2-yl) pyrrol-3-yl] acetate (56)

Under argon atmosphere, (1R, 2R) -N, N'-dimethylcyclohexane-1,2-diamine 9 mg, copper iodide 3 mg, pyrrole-3-ethyl acetate 100 mg, potassium phosphate n-hydrate 183 mg, 2- 79 mg of (6-chloropyrazin-2-yl) naphthalene was suspended in 2 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1), and 12 mg of ethyl 2- [1- (6- (2-naphthyl) pyrazin-2-yl) pyrrol-3-yl] Acetate was obtained (6% yield).
MS (ESI): 358 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1), 3.60 (2H, s), 4.21 (2H, q, J = 7.1), 6.41-6.43 (1H, m) 7.55-7.59 (2H, m), 7.63 (2H, d, J = 2.4), 7.90-7.92 (1H, m), 7.99 (2H, d, J = 7.8), 8.20 (1H, dd, J = 1.7) , 8.8), 8.58 (1H, brs), 8.65 (1H, s), 8.97 (1H, s)

Example 57
2- [1- (6- (2-Naphtyl) pyrazin-2-yl) pyrrol-3-yl] acetic acid (57)

Dissolve 12 mg of ethyl 2- [1- (6- (2-naphthyl) pyrazin-2-yl) pyrrol-3-yl] acetate in 3 mL of methanol, add 0.4 mL of 1M aqueous sodium hydroxide solution, and add 6 mL at room temperature. Stir for hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 10 mg of 2- [1- (6- (2-naphthyl) pyrazin-2-yl) pyrrol-3-yl] Acetic acid was obtained (yield 85%).
MS (ESI): 330 (M + H) ^+
1 H-NMR (300 MHz, CD ₃ OD) δ: 3.47 (2H, s), 6.30-6.31 (1H, m), 7.46-7.48 (2H, m), 7.65-7.66 (2H, m), 7.82 7.84 (1H, m), 7.92-7.96 (2H, m), 8.19 (1H, dd, J = 1.7,8.6), 8.60 (1H, brs), 8.71 (1H, s), 8.96 (1H, s)

Example 58
1- (6-Chloropyrazin-2-yl) naphthalene (58)

Under an argon atmosphere, 300 mg of 2,6-dichloropyrazine, 116 mg of tetrakis (triphenylphosphine) palladium, 346 mg of naphthalene-1-boronic acid, and 420 μL of triethylamine were dissolved in 3 mL of N, N-dimethylformamide and stirred at 110 ° C. for 2 hours. . After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/1) to obtain 183 mg of 1- (6-chloropyrazin-2-yl) naphthalene (yield 38%).
MS (ESI): 242 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 7.53-7.61 (3H, m), 7.66 (1H, d, J = 5.4), 7.93-7.96 (1H, m), 7.99 (1H, d, J = 6.3), 8.08-8.10 (1H, m), 8.65 (1H, d, J = 0.6), 8.80 (1H, d, J = 0.6)

Example 59
Ethyl 2- [1- (6- (1-naphthyl) pyrazin-2-yl) pyrrol-3-yl] acetate (59)

Under an argon atmosphere, (1R, 2R) -N, N'-dimethylcyclohexane-1,2-diamine 22 mg, copper iodide 7 mg, pyrrole-3-ethyl acetate 233 mg, potassium phosphate n-hydrate 426 mg, 1- 183 mg of (6-chloropyrazin-2-yl) naphthalene was suspended in 2 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1), and 14 mg of ethyl 2- [1- (6- (1-naphthyl) pyrazin-2-yl) pyrrol-3-yl] Acetate was obtained (6% yield).
MS (ESI): 358 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 6.0), 3.55 (2H, s), 4.19 (2H, q, J = 6.0), 6.39 (1H, brs), 7.52 -7.62 (5H, m), 7.70 (1H, d, J = 3.0), 7.95-7.96 (1H, m), 8.00 (1H, d, J = 6.0), 8.21 (1H, d, J = 6.0), 8.66 (1H, s), 8.74 (1H, s)

Example 60
2- [1- (6- (1-Naphtyl) pyrazin-2-yl) pyrrol-3-yl] acetic acid (60)

14 mg of ethyl 2- [1- (6- (1-naphthyl) pyrazin-2-yl) pyrrol-3-yl] acetate is dissolved in 3 mL of methanol, 0.4 mL of 1M aqueous sodium hydroxide solution is added, and Stir for hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 11 mg of 2- [1- (6- (1-naphthyl) pyrazin-2-yl) pyrrol-3-yl] Acetic acid was obtained (yield 83%).
MS (ESI): 330 (M + H) ^+
1 H-NMR (300 MHz, CD ₃ OD) δ: 3.43 (2H, s), 6.27 (1H, dd, J = 1.7, 3.2), 7.44-7.58 (5H, m), 7.63 (1H, dd, J = 1.2,7.0), 7.88-7.90 (1H, m), 7.94 (1H, d, J = 8.3), 8.07-8.09 (1H, m), 8.55 (1H, s), 8.82 (
1H, s)

Example 61
Ethyl 2- [1- (6-benzo [b] thiophen-3-ylpyrazin-2-yl) pyrrol-3-yl] acetate (61)

Under an argon atmosphere, ethyl 2- [1- (6-iodopyrazin-2-yl) pyrrol-3-yl] acetate 80 mg, tetrakis (triphenylphosphine) palladium 13 mg, benzo [b] thiophene-3-boronic acid 40 mg, 47 μL of triethylamine was dissolved in 1 mL of N, N-dimethylformamide and stirred at 110 ° C. for 8 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/1), and 42 mg of ethyl 2- [1- (6-benzo [b] thiophen-3-ylpyrazine- 2-yl) pyrrol-3-yl] acetate was obtained (52% yield).
MS (ESI): 364 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 6.0), 3.58 (2H, s), 4.20 (2H, q, J = 6.0), 6.42 (1H, dd, J = 1.7,2.9), 7.44-7.54 (2H, m), 7.56 (1H, brs), 7.61 (1H, dd, J = 2.7,2.7), 7.95 (1H, d, J = 7.8), 8.01 (1H, s ), 8.58 (1H, d, J = 7.8), 8.65 (1H, s), 8.80 (1H, s)

Example 62
2- [1- (6-Benzo [b] thiophen-3-ylpyrazin-2-yl) pyrrol-3-yl] acetic acid (62)

Dissolve 42 mg of ethyl 2- [1- (6-benzo [b] thiophen-3-ylpyrazin-2-yl) pyrrol-3-yl] acetate in 4 mL of methanol and 4 mL of 1,4-dioxane, and add 1M aqueous sodium hydroxide solution. 0.8 mL was added and stirred overnight at room temperature. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 100/1), and 31 mg of 2- [1- (6-benzo [b] thiophen-3-ylpyrazin-2-yl) pyrrol-3-yl] acetic acid (Yield 80%).
MS (ESI): 336 (M + H) ^+
1 H-NMR (300 MHz, CD ₃ OD) δ: 3.55 (2H, s), 6.40 (1H, brs), 7.43-7.54 (2H, m), 7.67-7.69 (2H, m), 7.99 (1H, d, J = 8.2), 8.32 (1H, s), 8.66 (1H, d, J = 8.2), 8.79 (1H, s), 8.87 (1H, s)

Example 63
Ethyl 2- [1- (6-benzo [b] furan-3-ylpyrazin-2-yl) pyrrol-3-yl] acetate (63)

Under an argon atmosphere, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium / dichloromethane complex 42 mg, potassium phosphate / n hydrate 1.4 g, ethyl 2- [1- (6-iodopyrazine-2- Yl) pyrrol-3-yl] acetate (616 mg) was mixed with 2-benzo [b] furan-3-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 421 mg of 1,4- Dioxane (9 mL) solution was added and stirred at 80 ° C. for 27 hours. Water was added to the reaction solution and extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1), and 424 mg of ethyl 2- [1- (6-benzo [b] furan-3-ylpyrazin-2-yl) pyrrole-3 -Yl] acetate was obtained (yield 71%).
MS (ESI): 348 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.31 (3H, t, J = 5.5), 3.59 (2H, s), 4.21 (2H, q, J = 5.5), 6.42 (1H, brs), 7.39 -7.43 (2H, m), 7.55-7.60 (3H, m), 8.28-8.30 (2H, m), 8.58 (1H, s), 8.77 (1H, m)

Example 64
2- [1- (6-Benzo [b] furan-3-ylpyrazin-2-yl) pyrrol-3-yl] acetic acid (64)

Dissolve 424 mg of ethyl 2- [1- (6-benzo [b] furan-3-ylpyrazin-2-yl) pyrrol-3-yl] acetate in 15 mL of methanol and 5 mL of 1,4-dioxane, and add 1M aqueous sodium hydroxide solution. 20 mL was added and stirred at room temperature for 1 hour. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Methanol was added to the residue and the resulting precipitate was collected by filtration to obtain 147 mg of 2- [1- (6-benzo [b] furan-3-ylpyrazin-2-yl) pyrrol-3-yl] acetic acid (yield). Rate 38%).
MS (ESI): 320 (M + H) ^+
1 H-NMR (300 MHz, CD ₃ OD) δ: 3.57 (2H, m), 6.40 (1H, brs), 7.41-7.44 (2H, m), 7.60-7.62 (1H, m), 7.69-7.71 ( 2H, m), 8.37-8.39 (1H, m), 8.63-8.64 (1H, m), 8.74-8.75 (1H, m), 8.88-8.89 (1H, m)

Example 65
Methyl 5- (6-indolylpyrazin-2-yl) furan-2-carboxylate (65)

Under an argon atmosphere, methyl (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) furan-2-carboxylate (3.86 mmol), [1,1'-bis (Diphenylphosphino) ferrocene] dichloropalladium / dichloromethane complex 107.7 mg (0.131 mmol), 2-chloro-6-indolylpyrazine 394.5 mg (1.71 mmol), cesium carbonate 967.3 mg (9.12 mmol) were suspended in DMSO 10 mL. The reaction mixture was filtered through Hyflo Supercel and washed with ethyl acetate, and the filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by chromatography (n-hexane / ethyl acetate = 1: 1) gave 409 mg of methyl 5- (6-indolylpyrazin-2-yl) furan-2-carboxylate (yield 75%).
MS (ESI): 320 (M + H) ^+
1 H-NMR (400 MHz, CDCl ₃ ) δ: 3.97 (3H, s), 6.81 (1H, d, J = 3.4 Hz), 7.24-7.28 (1H, m), 7.29-7.39 (3H, m), 7.68 (1H, d, J = 7.8Hz), 7.76-7.78 (1H, m), 8.40 (1H, d, J = 8.3Hz), 8.82 (1H, s), 8.95 (1H, s)

Example 66
5- (6-Indolylpyrazin-2-yl) furan-2-carboxylic acid (66)

Methyl 5- (6-indolylpyrazin-2-yl) furan-2-carboxylate 36.7 mg (0.114 mmo
l) was dissolved in 2 mL of 1,4-dioxane and 1 mL of methanol, 0.5 mL (1.25 mmol) of 2.5 M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 12 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 31.1 mg of 5- (6-indolylpyrazin-2-yl) furan-2-carboxylic acid (yield). Rate 89%).
MS (ESI): 306 (M + H) ^+
1 H-NMR (400 MHz, CD ₃ OD) δ: 6.82 (1H, d, J = 3.7 Hz), 7.21-7.25 (1H, m), 7.33-7.44 (3H, m), 7.65 (1H, d, J = 8.3Hz), 8.02 (1H, d, J = 3.7Hz), 8.56 (1H, d, J = 8.3Hz), 8.92 (1H, s), 8.96 (1H, s)

Example 67
[5- (6-Indolylpyrazin-2-yl) -2-furyl] formaldehyde (67)

Under an argon atmosphere, 56.2 mg (1.48 mmol) of LiAlH ₄ was suspended in 5 mL of anhydrous THF, and at 0 ° C., methyl
A THF solution (5 mL) of 373.0 mg (1.168 mmol) of 5- (6-indolylpyrazin-2-yl) furan-2-carboxylate was added dropwise and stirred for 10 minutes. To the reaction mixture solution, 0.05 mL of water, 0.05 mL of 2.5 M aqueous sodium hydroxide, and 0.15 mL of water were added dropwise at 0 ° C., followed by filtration through Hyflo Supercell, and the filtrate was concentrated. The residue was dissolved in 15 mL of THF, 2.98 g of manganese dioxide was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered through Hyflo Supercel, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 100/1) to obtain 132.4 mg of [5- (6-indolylpyrazin-2-yl) -2-furyl] formaldehyde (yield 40% ).
MS (ESI): 290 (M + H) ^+
1 H-NMR (400 MHz, CDCl ₃ ) δ: 6.83 (1H, d, J = 3.7 Hz), 7.21-7.25 (1H, m), 7.29-7.44 (4H, m), 7.69 (1H, d, J = 8.3Hz), 7.78 (1H, d, J = 3.7Hz), 8.40 (1H, d, J = 8.3Hz), 8.87 (1H, s), 8.99 (1H, s), 9.80 (1H, s)

Example 68
2- [5- (6-Indolylpyrazin-2-yl) -2-furyl] ethanenitrile (68)

  Rhodanine (128.8 mg, 0.966 mmol), acetic acid (19 mL), sodium acetate (141.4 mg, 3.08 mmol) in chloroform solution of [5- (6-indolylpyrazin-2-yl) -2-furyl] formaldehyde (132.0 mg, 0.456 mmol) In addition, the mixture was stirred at 130 ° C. for 8 hours. The precipitate was collected by filtration, dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. After the residue was suspended in 17 mL of 1,4-dioxane, 4.00 mL (10.00 mmol) of 2.5 M aqueous sodium hydroxide solution was added, and the mixture was stirred at 100 ° C. for 24 hours. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated.

After adding 133 mg (5.78 mmol) of sodium to 10 mL of absolute ethanol and stirring at room temperature for 30 minutes, 414 mg (5.95 mmol) of hydroxylamine hydrochloride was added and stirred at room temperature for 30 minutes. 5 mL of a THF solution of the residue obtained above was added dropwise and refluxed for 13 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. To the residue were added 5 mL of THF and 7 mL of acetic anhydride, and the mixture was stirred at 85 ° C. for 3 hours. A saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate), and 13.3 mg of 2- [5- (6-indolylpyrazin-2-yl)-
2-Furyl] ethanenitrile was obtained (yield 10%).
MS (ESI): 301 (M + H) ^+
1 H-NMR (400 MHz, CDCl ₃ ) δ: 3.94 (2H, s), 6.58-6.59 (1H, m), 6.80 (1H, d, J = 3.7 Hz), 7.25-7.29 (2H, m), 7.35 -7.39 (1H, m), 7.68 (1H, d, J = 8.3Hz), 7.76 (1H, d, J = 3.7Hz), 8.39 (1H, d, J = 8.3Hz), 8.74 (1H, s) , 8.75 (1H, s)

Example 69
2- [5- (6-Indolylpyrazin-2-yl) -2-furyl] acetic acid (69)

2- [5- (6-Indolylpyrazin-2-yl) -2-furyl] ethanenitrile (13.3 mg, 0.0442 mmol) is dissolved in 1,4-dioxane (3 mL) and methanol (1 mL), and 1 M aqueous sodium hydroxide solution (1.00 mL) (1 mmol) was added and stirred at room temperature for 19 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 10.0 mg of 2- [5- (6-indolylpyrazin-2-yl) -2-furyl] acetic acid. (Yield 71%).
MS (ESI): 320 (M + H) ^+
1 H-NMR (400 MHz, CDCl ₃ ) δ: 3.33 (2H, s), 6.88 (1H, d, J = 3.7 Hz), 7.24-7.28 (1H, m), 7.34-7.38 (1H, m), 7.47 (1H, d, J = 3.7Hz), 7.55 (1H, d, J = 3.7Hz), 7.69 (1H, d, J = 7.6Hz), 8.29 (1H, d, J = 3.7Hz), 8.67 (1H , d, J = 8.1Hz), 8.92 (1H, s), 9.18 (1H, s), 13.48 (1H, broad s)

Example 70
Ethyl 2- {1- [6- (5-nitro-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetate (70)

Under an argon atmosphere, trans-N, N′-dimethyl-1,2-cyclohexanediamine 16 mg, copper iodide 5 mg, 5-nitroindazole 110 mg, tripotassium phosphate n-hydrate 313 mg, ethyl-2- [1- 200 mg of (6-iodopyrazin-2-yl) pyrrol-3-yl] acetate was suspended in 1 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 7/3), and 89 mg of ethyl 2- {1- [6- (5-nitro-1H-indazolyl) pyrazin-2-yl] pyrrole- 3-yl} acetate was obtained (yield 40%).
MS (ESI): 393 (M ⁺ +1)
NMR (300 MHz, CDCl ₃ ) δ: 1.32 (3H, t, J = 7.1), 3.62 (2H, s), 4.22 (2H, q, J = 7.1), 6.48 (1H, brs), 7.51 (1H, brs), 7.54 (1H, t, J = 2.7), 8.47 (1H, s), 8.49 (1H, dd, J = 2.0, 9.0), 8.63 (1H, s), 8.78 (1H, d, J = 6.6 ), 8.79 (1H, s), 9.20 (1H, s)

Example 71
2- {1- [6- (5-Nitro-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetic acid (71)

Ethyl 2- {1- [6- (5-nitro-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetate 40mg is dissolved in 2mL of methanol and 2mL of 1,4-dioxane, and 1M sodium hydroxide 0.5 mL of an aqueous solution was added and stirred at 60 ° C. for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate.
The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 30 mg of 2- {1- [6- (5-nitro-1H-indazolyl) pyrazin-2-yl] pyrrole- 3-yl} acetic acid was obtained (81% yield).
MS (ESI): 365 (M ⁺ +1)
_{NMR (300MHz, DMSO-d 6} ) δ: 3.51 (2H, s), 6.39 (1H, s), 7.74 (1H, s), 7.79 (1H, m), 8.49 (1H, dd, J = 2.4,9.3 ), 8.73 (1H, d, J = 9.3), 8.81 (1H, s), 8.93 (1H, d, J = 2.2), 9.01 (1H, s), 9.06 (1H, s)

Example 72
Ethyl 2- (1- {6- [4- (2-morpholin-4-ylethoxy) -1H-indazolyl] pyrazin-2-yl} pyrrol-3-yl) acetate (72)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 10 mg, copper iodide 3 mg, 4- (2-morpholin-4-ylethoxy) -1H-indazole 100 mg, tripotassium phosphate / n water 188 mg of the Japanese product and 120 mg of ethyl 2- [1- (6-iodopyrazin-2-yl) pyrrol-3-yl] acetate were suspended in 0.8 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) and 132 mg of ethyl 2- (1- {6- [4- (2-morpholin-4-ylethoxy) -1H-indazolyl] pyrazine-2 -Il} pyrrol-3-yl) acetate was obtained (yield 83%). MS (ESI): 477 (M ⁺ +1)
NMR (300 MHz, CDCl ₃ ) δ: 1.31 (3H, t, J = 7.3), 2.61-2.66 (4H, m), 2.94 (2H, t, J = 5.9), 3.60 (2H, s), 3.72-3.78 (4H, m), 4.21 (2H, q, J = 7.3), 4.33 (2H, t, J = 5.9), 6.44 (1H, brs), 6.69 (1H, d, J = 7.8), 7.47-7.51 ( 2H, m), 7.56 (1H, t, J = 2.7), 8.23 (1H, d, J = 8.3), 8.32 (1H, s), 8.51 (1H, s), 9.18 (1H, s)

Example 73
2- (1- {6- [4- (2-morpholin-4-ylethoxy) -1H-indazolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid (73)

Ethyl 2- (1- {6- [4- (2-morpholin-4-ylethoxy) -1H-indazolyl] pyrazin-2-yl} pyrrol-3-yl) acetate 132 mg, methanol 2 mL, 1,4-dioxane 2 mL 1M sodium hydroxide aqueous solution 1.1mL was added, and it stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 76 mg of 2- (1- {6- [4- (2-morpholin-4-ylethoxy) -1H-indazolyl] Pyrazin-2-yl} pyrrol-3-yl) acetic acid was obtained (61% yield).
MS (ESI): 449 (M ⁺ +1)
NMR (300 MHz, DMSO-d ₆ ) δ: 2.50-2.56 (4H, m), 2.82 (2H, t, J = 5.9), 3.50 (2H, s), 3.56-3.62 (4H, m), 4.33 (2H , t, J = 5.9), 6.38 (1H, brs), 6.91 (1H, d, J = 8.1), 7.59 (1H, t, J = 8.1), 7.73 (1H, brs), 7.76 (1H, t, J = 2.9), 8.18 (1H, d, J = 8.3), 8.50 (1H, s), 8.93 (1H, s), 9.05 (1H, s)

Example 74
Ethyl 2- (1- {6- [3- (2-morpholin-4-ylethoxy) -1H-indazolyl] pyrazin-2-yl} pyrrol-3-yl) acetate (74)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 14 mg, copper iodide 5 mg, 3- (2-morpholin-4-ylethoxy) -1H-indazole 150 mg, tripotassium phosphate / water 282 mg of the Japanese product and 180 mg of ethyl-2- [1- (6-iodopyrazin-2-yl) pyrrol-3-yl] acetate were suspended in 1 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1) and 182 mg of ethyl 2- (1- {6- [3- (2-morpholin-4-ylethoxy) -1H-indazolyl] pyrazine-2 -Il} pyrrol-3-yl) acetate was obtained (76% yield).
MS (ESI): 477 (M ⁺ +1)
_{NMR (300 MHz, CDCl 3)} δ: 1.31 (3H, t, J = 7.1), 2.64-2.68 (4H, m), 2.95 (2H, t, J = 5.6), 3.61 (2H, s), 3.75- 3.79 (4H, m), 4.21 (2H, q, J = 7.1), 4.68 (2H, t, J = 5.6), 6.43 (1H, brs), 7.30 (1H, t, J = 8.1), 7.49 (1H , brs), 7.55 (1H, t, J = 2.2), 7.60 (1H, t, J = 8.1), 7.75 (1H, d, J = 7.8), 8.39 (1H, s), 8.59 (1H, d, J = 8.5), 8.96 (1H, s)

Example 75
2- (1- {6- [3- (2-morpholin-4-ylethoxy) -1H-indazolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid (75)

Ethyl 2- (1- {6- [3- (2-morpholin-4-ylethoxy) -1H-indazolyl] pyrazin-2-yl} pyrrol-3-yl) acetate 182 mg, methanol 2.5 mL, 1,4-dioxane It melt | dissolved in 2.5 mL, 1.5 mL of 1M sodium hydroxide aqueous solution was added, and it stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 126 mg of 2- (1- {6- [3- (2-morpholin-4-ylethoxy) -1H-indazolyl]. Pyrazin-2-yl} pyrrol-3-yl) acetic acid was obtained (74% yield).
MS (ESI): 449 (M ⁺ +1)
NMR (300 MHz, DMSO-d ₆ ) δ: 2.51-2.58 (4H, m), 2.85 (2H, t, J = 5.9), 3.50 (2H, s), 3.54-3.60 (4H, m), 4.63 (2H , t, J = 5.9), 6.37 (1H, brs), 7.36 (1H, t, J = 7.6), 7.68-7.78 (4H, m), 8.54 (1H, d, J = 8.5), 8.77 (1H, s), 8.87 (1H, s)

Example 76
Ethyl 2- {1- [6- (6-amino-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetate (76)

Under an argon atmosphere, trans-N, N′-dimethyl-1,2-cyclohexanediamine 16 mg, copper iodide 5 mg, 6-aminoindazole 89 mg, tripotassium phosphate · n hydrate 313 mg, ethyl-2- [1- 200 mg of (6-iodopyrazin-2-yl) pyrrol-3-yl] acetate was suspended in 1 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/6), and 105 mg of ethyl 2- {1- [6- (6-amino-1H-indazolyl) pyrazin-2-yl] pyrrole- 3-yl} acetate was obtained (52% yield).
MS (ESI): 363 (M ⁺ +1)
_{NMR (300 MHz, CDCl 3)} δ: 1.31 (3H, t, J = 7.1), 3.63 (2H, s), 4.22 (2H, q, J = 7.1), 6.40 (1H, brs), 6.72 (1H, dd, J = 2.0,8.5), 7.49 (1H, t, J = 2.0), 7.54 (1H, d, J = 8.5), 7.67 (1H, brs), 7.97 (1H, brs)
, 8.07 (1H, s), 8.45 (1H, s), 9.12 (1H, s)

Example 77
2- {1- [6- (6-Amino-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetic acid (77)

Ethyl 2- {1- [6- (6-amino-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetate 50 mg is dissolved in 1 mL of methanol and 1 mL of 1,4-dioxane, and 1M sodium hydroxide 0.5 mL of an aqueous solution was added and stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and 40 mg of 2- {1- [6- (6-amino-1H-indazolyl) pyrazin-2-yl] pyrrole- 3-yl} acetic acid was obtained (87% yield).
MS (ESI): 335 (M ⁺ +1)
NMR (300 MHz, DMSO-d ₆ ) δ: 3.52 (2H, s), 5.90 (2H, brs), 6.37 (1H, brs), 6.70 (1H, d, J = 8.5), 7.53 (1H, d, J = 8.5), 7.68 (1H, s), 7.74 (1H, s), 7.81 (1H, t, J = 2.7), 8.21 (1H, s), 8.82 (1H, s), 8.99 (1H, s)

Example 78
Ethyl 2- (1- {6- [6- (acetylamino) -1H-indazolyl] pyrazin-2-yl} pyrrol-3-yl) acetate (78)

Under an argon atmosphere, 50 mg of ethyl 2- {1- [6- (6-amino-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetate was dissolved in 1 mL of acetic anhydride and stirred at room temperature for 24 hours. . To the reaction solution was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and 40 mg of ethyl 2- (1- {6- [6- (acetylamino) -1H-indazolyl] pyrazine-2- Yil} pyrrol-3-yl) acetate was obtained (yield 71%).
MS (ESI): 405 (M ⁺ +1)
_{NMR (300 MHz, CDCl 3)} δ: 1.32 (3H, t, J = 7.1), 2.27 (3H, s), 3.68 (2H, s), 4.22 (2H, q, J = 7.1), 6.42 (1H, brs), 7.36 (1H, d, J = 8.5), 7.57 (1H, brs), 7.63 (1H, d, J = 8.5), 7.83 (1H, brs), 7.91 (1H, brs), 8.13 (1H, s), 8.45 (1H, s), 9.08 (1H, s), 9.12 (1H, brs)

Example 79
2- (1- {6- [6- (acetylamino) -1H-indazolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid (79)

40 mg of ethyl 2- (1- {6- [6- (acetylamino) -1H-indazolyl] pyrazin-2-yl} pyrrol-3-yl) acetate is dissolved in 1 mL of methanol and 1 mL of 1,4-dioxane, and 1M Sodium hydroxide aqueous solution 0.5mL was added and it stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 30 mg of 2- (1- {6- [6- (acetylamino) -1H-indazolyl] pyrazin-2-yl } Pyrrol-3-yl) acetic acid was obtained (yield 81%).
MS (ESI): 377 (M ⁺ +1)
NMR (300 MHz, DMSO-d ₆ ) δ: 2.16 (3H, s), 3.53 (2H, s), 6.37 (1H, brs), 7.21 (1H, d, J = 8.5), 7.83 (1H, d, J = 8.8), 7.95 (1H, brs), 8.02 (1H, brs), 8.45 (1H, s), 8.90 (1H, s), 9.04 (1H, s), 9.57 (1H, s), 10.35 (1H, s)

Example 80
Ethyl 2- {1- [6- (3-methoxy-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetate (80)

  74.5 mg (0.3 mmol) of tert-butyl 3-methoxy-1H-indazolecarboxylate was dissolved in 5 mL of 1M hydrochloric acid-ethanol aqueous solution and stirred at 35 ° C. for 4 hours. The reaction solution was concentrated to obtain 55.4 mg of 3-methoxy-1H-indazole.

Subsequently, under an argon atmosphere, (1R, 2R) -N, N′-dimethylcyclohexane-1,2-diamine 6 mg, copper iodide 1.9 mg, ethyl 2- [1- (6-iodopyrazin-2-yl) pyrrole -3-yl] acetate 71.4 mg, potassium phosphate n-hydrate 106.5 mg, and 3-methoxy-1H-indazole 55.4 mg were suspended in toluene 0.3 mL and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1), and 59.7 mg of ethyl 2- {1- [6- (3-methoxy-1H-indazolyl) pyrazin-2-yl] pyrrole -3-yl} acetate was obtained (yield 79%).
MS (ESI): 378 (M + H) ^+
1 H-NMR (400 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1 Hz), 3.47 (3H, s), 3.57 (2H, s), 4.20 (2H, q, J = 7.2 Hz), 6.40 (1H, s), 7.24-7.37 (2H, m), 7.49-7.54 (2H, m), 7.68 (1H, t, J = 7.5Hz), 7.92 (1H, d, J = 7.9Hz), 8.53 (1H, s), 9.41 (1H, s)

Example 81
2- {1- [6- (3-Methoxy-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetic acid (81)

Ethyl 2- {1- [6- (3-methoxy-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetate 59 mg (0.156 mmol) is dissolved in tetrahydrofuran 3 mL, and 1M aqueous sodium hydroxide solution 0.468 mL (0.468 mmol) and 2 mL of water were added and stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 44 mg of 2- {1- [6- (3-methoxy-1H-indazolyl) pyrazin-2-yl] pyrrole- 3-yl} acetic acid was obtained (yield 80%).
MS (ESI): 350 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ) δ: 4.04 (3H, s), 6.34 (1H, m), 7.31 (3H, t, J = 7.5 Hz), 7.65 to 7.84 (5H, m), 8.92 (1H, s), 9.15 (1H, s), 12.26 (1H, broad)

Example 82
Ethyl 2- (1- {6- [3- (2-methoxyethoxy) -1H-indazolyl] pyrazin-2-yl} pyrrol-3-yl) acetate (82)

Under an argon atmosphere, (1R, 2R) -N, N'-dimethylcyclohexane-1,2-diamine 6 mg, copper iodide 1.9 mg, ethyl 2- [1- (6-iodopyrazin-2-yl) pyrrole-3 -Il] acetate 71.4 mg, potassium phosphate · n hydrate 106.5 mg, 3- (2-methoxyethoxy) -1H-indazole 57.7 mg were suspended in toluene 0.3 mL and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1), and 31.2 mg of ethyl 2- (1- {6- [3- (2-methoxyethoxy) -1H-indazolyl] pyrazine- 2-yl} pyrrol-3-yl) acetate was obtained (yield 37%).
MS (ESI): 422 (M + H) ^+
1 H-NMR (400 MHz, CDCl ₃ ) δ: 1.31 (3H, t, J = 7.2 Hz), 3.50 (3H, s), 3.68 (2H, s), 3.88-3.92 (2H, m), 4.21 (2H , q, J = 7.2Hz), 4.68-4.72 (2H, m), 6.43 (1H, s), 7.29 (1H, m), 7.48-7.63 (3H, m), 7.79 (1H, d, J = 7.8 Hz), 8.38 (1H, s), 8.58 (1H, d, J = 8.5Hz), 8.97 (1H, s)

Example 83
2- (1- {6- [3- (2-methoxyethoxy) -1H-indazolyl] pyrazin-2-yl} pyrrol-3-yl) acetic acid (83)

Ethyl 2- (1- {6- [3- (2-methoxyethoxy) -1H-indazolyl] pyrazin-2-yl} pyrrol-3-yl) acetate 31.2 mg (0.074 mmol) was dissolved in 3 mL of tetrahydrofuran, and 1M Aqueous sodium hydroxide (0.3 mL, 0.3 mmol) and water (2.5 mL) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 10.2 mg of 2- (1- {6- [3- (2-methoxyethoxy) -1H-indazolyl] pyrazine- 2-yl} pyrrol-3-yl) acetic acid was obtained (yield 35%).
MS (ESI): 394 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.37 (3H, s), 3.51 (2H, s), 3.82-3.84 (2H, m), 4.65 to 4.67 (2H, m), 6.39 (1H, s), 7.32-7.41 (2H, m), 7.70-7.82 (3H, m), 8.57 (1H, d, J = 8.5Hz), 8.79 (1H, s), 8.90 (1H, s), 11.90 (1H) , broad-s)

Example 84
Ethyl 2- {1- [6- (3-amino-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetate (84)

Under an argon atmosphere, (1R, 2R) -N, N'-dimethylcyclohexane-1,2-diamine 12 mg, copper iodide 3.8 mg, ethyl 2- [1- (6-iodopyrazin-2-yl) pyrrole-3 -Ill] acetate 142.9 mg, potassium phosphate n-hydrate 213.0 mg, 3-amino-1H-indazole 79.9 mg were suspended in 0.6 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1), and 42.9 mg of ethyl 2- {1- [6- (3-amino-1H-indazolyl) pyrazin-2-yl] pyrrole -3-yl} acetate was obtained (yield 30%).
MS (ESI): 363 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.21 (3H, t, J = 7.1 Hz), 3.58 (2H, s), 4.11 (2H, q, J = 7.1 Hz), 6.36 (1H, m ), 6.46 (2H, broad-s), 7.29 (1H, t, J = 7.6Hz), 7.59-7.74 (3H, m), 7.93 (1H, d, J = 8.1Hz), 8.51 (1H, d, J = 8.6Hz), 8.65 (1H, s), 8.77 (1H, s)

Example 85
2- {1- [6- (3-Amino-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetic acid (85)

Ethyl 2- {1- [6- (3-amino-1H-indazolyl) pyrazin-2-yl] pyrrol-3-yl} acetate 40 mg (0.110 mmol) is dissolved in 1,4-dioxane 2 mL and dimethyl sulfoxide 0.5 mL Then, 0.34 mL (0.34 mmol) of 1M aqueous sodium hydroxide solution and 2 mL of water were added and stirred at room temperature for 2 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and 31.1 mg of 2- {1- [6- (3-amino-1H-indazolyl) pyrazin-2-yl ] Pyrrol-3-yl} acetic acid was obtained (yield 84%).
MS (ESI): 335 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ) δ: 3.49 (2H, s), 6.36 (1H, m), 6.46 (2H, brs), 7.29 (1H, t, J = 7.5 Hz), 7.59-7.73 (3H, m), 7.93 (1H, d, J = 7.8Hz), 8.51 (1H, d, J = 8.5Hz), 8.65 (1H, s), 8.76 (1H, s), 12.27 (1H, brs)

Example 86
Ethyl 2- [1- (6-indolylpyrazin-2-yl) pyrrol-2-yl] carboxylate (86)

Under argon atmosphere, trans-N, N′-dimethyl-1,2-cyclohexanediamine 13 mg, copper iodide 4 mg, ethyl- (pyrrol-2-yl) carboxylate 62 mg, tripotassium phosphate n-hydrate 238 mg, 144 mg of 1- (6-iodopyrazin-2-yl) indole was suspended in 2.2 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1), and 123 mg of ethyl 2- [1- (6-indolylpyrazin-2-yl) pyrrol-2-yl] carboxylate was added. Obtained (yield 82%).
MS (ESI): 333 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1), 4.25 (2H, q, J = 7.1), 6.42-6.44 (1H, m), 6.79 (1H, d, J = 3.7), 7.21-37 (4H, m), 7.67 (1H, d, J = 7.2), 7.77 (1H, d, J = 3.7), 8.31 (1H, d, J = 8.5), 8.48 (1H , s), 8.86 (1H, s)

Example 87
2- [1- (6-Indolylpyrazin-2-yl) pyrrol-2-yl] carboxylic acid (87)

Dissolve 123 mg of ethyl 2- [1- (6-indolylpyrazin-2-yl) pyrrol-2-yl] carboxylate in 1.9 mL of methanol and 1.9 mL of tetrahydrofuran, add 0.7 mL of 1M aqueous sodium hydroxide, Stir overnight. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 88 mg of 2- [1- (6-indolylpyrazin-2-yl) pyrrol-2-yl] carboxylic acid. Obtained (yield 78%).
MS (ESI): 305 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 6.45-6.46 (1H, m), 6.88 (1H, d, J = 3.7), 7.11-7.12 (1H, m), 7.21-7.31 (2H, m), 7.60 (1H, s), 7.68 (1H, d, J = 7.6), 8.25 (1H, d, J = 3.6), 8.39 (1H, d, J = 8.3), 8.66 (1H, s), 9.19 (1H, s)

Example 88
Ethyl 2- [1- (6-indolylpyrazin-2-yl) pyrrol-3-yl] carboxylate (88)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 11 mg, copper iodide 4 mg, ethyl (pyrrol-3-yl) carboxylate 52 mg, tripotassium phosphate n-hydrate 198 mg, 1 120 mg of-(6-iodopyrazin-2-yl) indole was suspended in 1.9 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1), and 122 mg of ethyl 2- [1- (6-indolylpyrazin-2-yl) pyrrol-3-yl] carboxylate was added. Obtained (yield 98%).
MS (ESI): 333 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.38 (3H, t, J = 7.1), 4.33 (2H, q, J = 7.1), 6.81 (1H, d, J = 3.6), 6.84-6.85 ( 1H, m), 7.24-7.29 (1H, m), 7.36-7.40 (1H, m), 7.56-7.7.57 (1H, m), 7.68 (1H, d, J = 8.1), 7.77 (1H, d , J = 3.7), 8.17-8.18 (1H, m), 8.29 (1H, d, J = 8.1), 8.58 (1H, s), 8.76 (1H, s)

Example 89
2- [1- (6-Indolylpyrazin-2-yl) pyrrol-3-yl] carboxylic acid (89)

122 mg of ethyl 2- [1- (6-indolylpyrazin-2-yl) pyrrol-3-yl] carboxylate is dissolved in 1.8 mL of methanol and 1.8 mL of tetrahydrofuran, and 0.7 mL of 1M aqueous sodium hydroxide solution is added to the solution at room temperature. Stir overnight. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 66 mg of 2- [1- (6-indolylpyrazin-2-yl) pyrrol-3-yl] carboxylic acid. Obtained (yield 59%).
MS (ESI): 305 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 6.74-6.75 (1H, m), 6.89 (1H, d, J = 3.4), 7.23-7.27 (1H, m), 7.35-7.39 (1H, m) , 7.69 (1H, d, J = 7.8), 7.85-7.87 (1H, m), 8.26 (1H, d, J = 3.6), 8.36-8.37 (2H, m), 9.08 (2H, s)

Example 90
Ethyl-2- [1- (6-indolylpyrazin-2-yl) pyrrol-2-yl] acetate (90)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 9 mg, copper iodide 3 mg, ethyl (pyrrol-2-yl) acetate 50 mg, tripotassium phosphate n-hydrate 173 mg, 1- 105 mg of (6-iodopyrazin-2-yl) indole was suspended in 1.6 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1), and 46 mg of ethyl
2- [1- (6-Indolylpyrazin-2-yl) pyrrol-2-yl] acetate was obtained (yield 40%).
MS (ESI): 347 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 0.90 (3H, t, J = 7.2), 3.86 (2H, q, J = 7.2), 6.28-6.30 (1H, m), 6.35-6.37 (1H, m), 6.77 (1H, d, J = 3.4), 7.21-7.27 (2H, m), 7.30-7.34 (1H, m) 7.66 (1H, d, J = 7.8), 7.75
(1H, d, J = 3.6), 8.08 (1H, d, J = 8.3), 8.54 (1H, s), 8.77 (1H, s)

Example 91
2- [1- (6-Indolylpyrazin-2-yl) pyrrol-2-yl] acetic acid (91)

46 mg of ethyl 2- [1- (6-indolylpyrazin-2-yl) pyrrol-2-yl] acetate is dissolved in 0.7 mL of methanol and 0.7 ml of tetrahydrofuran, and 0.3 mL of 1M aqueous sodium hydroxide solution is added to the solution at room temperature. Stir for 24 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 15 mg of 2- [1- (6-indolylpyrazin-2-yl) pyrrol-2-yl] acetic acid. (Yield 36%).
MS (ESI): 319 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.97 (2H, s), 6.23 (1H, s), 6.25-30 (1H, m), 6.18 (1H, s), 7.15-7.30 (3H , m), 7.52-7.7.70 (2H, m), 7.92-7.96 (1H, m), 8.47 (1H, s), 8.70 (1H, s)

Example 92
Ethyl 2- [1- (6-indolylpyrazin-2-yl) pyrazol-4-yl] carboxylate (92)

Under argon atmosphere, trans-N, N'-dimethyl-1,2-cyclohexanediamine 10 mg, copper iodide 3 mg, ethyl (pyrazol-4-yl) carboxylate 50 mg, tripotassium phosphate n-hydrate 189 mg, 1 115 mg of-(6-iodopyrazin-2-yl) indole was suspended in 1.8 mL of toluene and stirred at 110 ° C. for 24 hours. The reaction mixture was filtered through silica gel (ethyl acetate) and concentrated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1), and 109 mg of ethyl 2- [1- (6-indolylpyrazin-2-yl) pyrazol-4-yl] carboxylate was added. Obtained (yield 91%).
MS (ESI): 334 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ: 1.41 (3H, t, J = 7.1), 4.39 (2H, q, J = 7.1), 6.83-6.84 (1H, m), 7.28-7.32 (1H, m), 7.39-7.46 (1H, m), 7.70 (1H, d, J = 7.6), 7.79 (1H, d, J = 3.6), 8.20 (1H, s), 8.24 (1H, d, J = 8.3 ), 8.69 (1H, s), 9.01 (1H, s), 9.15 (1H, s)

Example 93
2- [1- (6-Indolylpyrazin-2-yl) pyrazol-4-yl] carboxylic acid (93)

109 mg of ethyl 2- [1- (6-indolylpyrazin-2-yl) pyrazol-4-yl] carboxylate is dissolved in 1.6 mL of methanol and 1.6 mL of tetrahydrofuran, and 0.7 mL of 1M aqueous sodium hydroxide solution is added to the solution at room temperature. For 24 hours. To the reaction solution was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 43 mg of 2- [1- (6-indolylpyrazin-2-yl) pyrazol-4-yl] carboxylic acid. Obtained (43% yield).
MS (ESI): 306 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ) δ: 6.90 (1H, d, J = 3.7), 7.24-7.28 (1H, m), 7.36-7.40 (1H, m), 7.70
(1H, d, J = 7.8), 8.29 (1H, s), 8.33 (1H, d, J = 3.7), 8.47 (1H, d, J = 8.6), 9.05 (2H, d, J = 4.4), 9.20 (1H, s)

Example 94
This example takes up the compound of Example 2, which is a preferred example of the nephritis therapeutic agent of the present invention, and examines the therapeutic effect of nephritis by administration of the nephritis therapeutic agent of the present invention using a rat nephritis model. This was done in order to demonstrate the usefulness of.

  Rats (Wistar-Kyoto strain, male, 7-week-old, Charles River Japan Co., Ltd.) in normal group (n = 4), nephritis control group (n = 6) and Example 2 compound administration group (n = 6) Grouped. Nephritis was induced in rats other than the normal group by administering rabbit anti-glomerular basement membrane (GBM) antiserum into the tail vein at a dose of 0.03 ml per kg body weight. Example 2 The compound of Example 2 was administered intraperitoneally to the rats of Example 2 compound at a dose of 50 mg / kg body weight once a day for 1 week from the day after nephritis induction. Rats not administered with the compound of Example 2 were administered intraperitoneally with a 1: 4 mixture of dimethyl sulfoxide, which is the solvent of Example 2, and 0.5% (w / v) sodium carboxymethylcellulose. One week after nephritis induction, all rats were individually housed in metabolic cages and 24 hours of urine collected. After measuring the amount of urine, it was centrifuged (3000 rpm, 15 minutes), and the urinary protein concentration of the supernatant was quantified by the pyrogallol red method. By multiplying the urine protein concentration by the amount of urine, the amount of urinary protein excretion, which is an indicator of the nephritic disease state, was measured. The results are shown in FIG. In the nephritis control group, urinary protein excretion amounted to 51.1 ± 10.3 mg / day, which was markedly increased compared to the normal group (7.7 ± 0.6 mg / day). did. In contrast, in the Example 2 compound administration group, the urinary protein excretion was 21.2 ± 7.0 mg / day, which was significantly lower than the nephritis control group (p <0.05). From the above results, it was clarified that the compound of Example 2 significantly reduced the urinary protein excretion amount and almost normalized the nephritic pathology. In addition, there was no difference in body weight between the Example 2 compound administration group and the nephritis control group, and no damage to each organ was observed.

Example 95
This example takes up the compound of Example 22, which is a preferred example of the nephritis therapeutic agent of the present invention, and examines the therapeutic effect of nephritis by administration of the nephritis therapeutic agent of the present invention using a rat nephritis model. This was done in order to demonstrate the usefulness of.

Rat (Wistar strain, female, 6 weeks old, Nippon Claire Co., Ltd.) normal group (n = 4), nephritis control group (n = 4), Example 22 compound 5 mg / kg administration group (n = 4) and implementation Example 22 The compound was divided into 50 mg / kg groups (n = 4). In rats other than the normal group, mouse anti-rat Thy-1 antibody (OX-7) was administered into the tail vein at a dose of 1 mg / kg body weight to induce nephritis. Example 22 The compound of Example 22 was administered orally once daily every day to the rats of Example 5 Compound 5 mg / kg administration group and Example 22 Compound 50 mg / kg administration group at a dose of 5 mg / kg body weight. Rats not administered with the compound of Example 22 were orally administered with distilled water as a solvent for the compound of Example 22. Three days after nephritis induction, all rats were individually housed in metabolic cages and 24 hours of urine were collected. After measuring the amount of urine, it was centrifuged (3000 rpm, 15 minutes), and the urine protein concentration of the supernatant was quantified by the pyrogallol red method. By multiplying the urine protein concentration by the amount of urine, the amount of urinary protein excretion, which is an indicator of the nephritic disease state, was measured. The results are shown in FIG. In the nephritis control group, urinary protein excretion amounted to 174.9 ± 22.6 mg / day, which was markedly increased compared to the normal group (2.3 ± 0.6 mg / day), and it was found that nephritis pathological condition was exhibited. did. In contrast, the urinary protein excretion amount in the administration group of Example 22 compound 5 mg / kg is 154.8 ± 19.1 mg / day, and the urinary protein excretion amount in the administration group of Example 22 compound 50 mg / kg is 95.5 ± 16.2 mg. / day, which was significantly lower than the nephritis control group (p <0.05). From the above results, it was clarified that the compound of Example 22 significantly reduced the amount of protein excreted in urine even by oral administration, and almost normalized the pathological condition of nephritis. Note that there was no difference in body weight between the Example 22 compound administration group and the nephritis control group, and no damage was observed in each organ.

It is a figure which shows the effect of the compound of Example 2 in the rat model of anti-glomerular basement membrane (GBM) antibody-induced nephritis. It is a figure which shows the effect of the Example 22 compound in an anti- Thy-1 antibody induction nephritis rat model.

Claims (7)

Formula I

[Wherein, n represents an integer of 0-2, R ₁ represents hydrogen or a C1-C3 linear alkyl group, A represents an indolediyl group, a pyrrolediyl group, a furandiyl group, a thiophenediyl group, Pyrazole diyl group, isoxazole diyl group, isothiazole diyl group, imidazole diyl group, oxazole diyl group, thiazole diyl group or triazole diyl group, E represents a direct bond or -NH-, and E represents -NH- In this case, D is a thiazolyl group, or a phenyl group optionally substituted with one or two substituents selected from a methoxy group, a halogen, a cyano group, an amino group, a hydroxyl group, and a trifluoromethyl group, and E is In the case of a direct bond, D is a phenyl group, 2-phenoxyphenyl group, naphthyl group, quinolyl group, isoquinolyl group, indolyl group, benzofuranyl group, benzothienyl group, Lyl group, thiazolyl group, isothiazolyl group, indazolyl group, benzimidazolyl group, 7-azaindolyl group,
Formula II

(Wherein R ₂ represents hydrogen, a C1-C3 linear alkyl group, a C3-C5 branched alkyl group, —C (O) R _3, —SO ₂ R ₃ , R ₃ represents hydrogen, C1 -C3 linear alkyl group, C3-C5 branched alkyl group, or halogen, nitro group, cyano group, amino group, hydroxyl group, trifluoromethyl group, C1-C3 linear alkyl group, C3-C5 branched alkyl And a phenyl group which may be substituted with one or two substituents selected from a group, a C1-C3 linear alkoxy group and a C3-C5 branched alkoxy group.)
Or a group represented by formula III

(Wherein, X is N or CH, R ₄ is hydrogen, methyl group, halogen, hydroxyl group, methoxy group, trifluoromethyl group, —OCH ₂ CH ₂ OH, —OCH ₂ CH ₂ OMe, amino group , -C (O) NHMe, cyano group, -COOR ₁ , -CH ₂ COOR ₁ , -CH ₂ CH ₂ COOR ₁ (where R ₁ is as defined above), or-(CH ₂ ) _m- Y- (CH ₂ ) _o -R ₇ where Y is a direct bond, -O-, -NH-, -NHC (O)-, -C (O) NH- (where R ₇ is a piperidyl group , A pyrrolidinyl group, or a piperazinyl group optionally substituted by R ₈ ) or -C (O)-, and R ₇ is a C1-C3 linear alkyl group, C3-C5 branched alkyl group, a phenyl group, piperidyl group, pyrrolidinyl group, morpholinyl group, or substituted with R ₈ is also good piperazinyl group, R ₈ is a linear alkyl group of C1-C3, branched C3-C5 alkyl, -C (O) R ₃ (where, R ₃ is defined as the same), - SO ₂ R ₃ (where, R ₃ is the Represents the same) justified, m, o are each an integer of 0 to 3 (provided that, Y is -O- or -NH-, R ₇ is piperidyl group, pyrrolidinyl group, morpholinyl group, or R ₈ In the case of an optionally substituted piperazinyl group, o is 2 or 3), R ₅ and R ₆ are independently hydrogen, halogen, nitro group, cyano group, amino group, hydroxyl group, trifluoromethyl group, C 1 linear alkyl group -C3, branched alkyl groups of C3-C5, C1-C3 straight chain alkoxy group, a C3-C5 branched alkoxy group, _{or, - (CH 2) m -Y-} (CH 2) o - R ₇ (where m, o, Y and R ₇ are the same as defined above) may be bonded to any of the 4, 5, 6 and 7 positions of formula III.)
It is group represented by these. ]
Or a pharmaceutically acceptable salt thereof.   2. The pyrazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is 0 or 1 in formula I. In formula I, E is a direct bond, and D is an indolyl group, benzofuranyl group, benzothienyl group, pyrrolyl group, isothiazolyl group, indazolyl group, benzimidazolyl group, 7-azaindolyl group, or a group represented by formula III The pyrazine derivative according to claim 2 or a pharmaceutically acceptable salt thereof.   The pyrazine derivative or a pharmaceutically acceptable salt thereof according to claim 3, wherein D in the formula I is an indolyl group, an indazolyl group, or a group represented by the formula III.   5. A medicament comprising the pyrazine derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.   A therapeutic agent for nephritis comprising the pyrazine derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.   The nephritis therapeutic agent according to claim 6, wherein the nephritis is acute glomerulonephritis, chronic glomerulonephritis, mesangial proliferative glomerulonephritis, IgA nephropathy, minimal change group nephrotic syndrome, membranoproliferative glomerulonephritis or lupus nephritis.

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