JP2007099640A - Nitrogen-containing heterocyclic compound, method for producing the same and pharmaceutical composition using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a compound that has an inhibitory activity on VEGF (vascular endothelial growth factor), is a therapeutic agent for various VEGF-associated diseases including diabetic nephropathy, to provide a method for producing the same and to obtain a pharmaceutical composition using the same. <P>SOLUTION: The nitrogen-containing heterocyclic compound is represented by general formula (I-A) or its pharmacologically acceptable salt. The method for producing the same is provided. The pharmaceutical composition comprises the nitrogen-containing heterocyclic compound as an active ingredient. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a nitrogen-containing heterocyclic compound, a process for producing the same, and a pharmaceutical composition using the same, and more specifically, a nitrogen-containing heterocyclic compound having a VEGF (Vascular endothelial growth factor) inhibitory action, a process for producing the same, and the use thereof It relates to a pharmaceutical composition.

  VEGF is a glycoprotein having a molecular weight of about 45,000, and is a substance that exhibits endothelial cell-specific cell proliferation activity, angiogenesis promotion action, and vascular permeability enhancement action. VEGF has been implicated in pathological conditions such as diabetic nephropathy, solid tumors, rheumatoid arthritis, diabetic retinopathy or crow-fukase syndrome.

  Diabetic nephropathy is a kidney disease that develops on the basis of diabetes, and is characterized by the expression of microalbuminuria and urine protein and progresses to glomerulosclerosis. Recently, it has been reported that the expression of VEGF is enhanced in podocytes of renal constituent cells, distal tubules and collecting ducts in diabetic animal models, and also in the glomeruli of diabetic patients clinically (non-patent literature). 1 and 2). In animal experiments, it has been reported that neutralizing antibodies to VEGF suppress the increase in the amount of urinary albumin, which is a characteristic finding in diabetic nephropathy (see Non-Patent Documents 3 and 4). These facts suggest that VEGF is involved in diabetic nephropathy and that VEGF inhibitors may be a therapeutic drug for diabetic nephropathy.

As VEGF inhibitors, for example, VEGF receptor antagonists are disclosed in Patent Documents 1 to 3 and the like.
JP 2002-193923 A JP 2002-193922 A JP 2001-72587 A Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes .: `` Diabetes '': 1999, 48: p2229-2239 Quantitative and qualitative changes in vascular endothelial growth factor gene expression in glomeruli of patients with type 2 diabetes .: `` European Journal of Endocrinology '': 2004, 150: p799-807 Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes .: `` Journal of the American Society of Nephrology '': 2001, 12: p.993-1000 Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody.Diabetes: 2002, 51: p3090-3094

  To date, it is a well-known fact that VEGF inhibitors, including the compounds described in Patent Documents 1 to 3 above, have been developed as anticancer agents in various countries around the world. However, for example, in diabetic nephropathy, in recent years, information indicating that VEGF is deeply involved in diabetic nephropathy has been scattered as described above, but it is still effective for animal models of diabetic nephropathy. There are no reports of low molecular weight compounds that exhibit sex, and no therapeutic drugs have been developed. Under such circumstances, further VEGF inhibitors are desired.

  Accordingly, an object of the present invention is to provide a compound that has a VEGF inhibitory action and can be a therapeutic agent for various VEGF-related diseases including diabetic nephropathy, a method for producing the compound, and a pharmaceutical composition using the compound There is to do.

  As a result of intensive studies to solve the above problems, the present inventors have found that a nitrogen-containing heterocyclic compound having a specific structure has a VEGF inhibitory action, and further has an inhibitory action on albumin excretion in urine. The invention has been completed.

[式中、Ｒ^1aは、水素原子；ハロゲン原子が置換されてもよいフェニル基、アルコキシ基、水酸基およびハロゲン原子からなる群から選択される置換基が置換されていてもよいアルキル基；−Ｘ^1a−Ｃ（Ｏ）ＯＲ^10a（Ｘ^1aは単結合またはアルキレン、Ｒ^10aは水素原子またはアルキル基である）；−Ｘ^2a−Ｃ（Ｏ）ＮＲ^11aＲ^12a（Ｘ^2aは単結合またはアルキレン、Ｒ^11aおよびＲ^12aはそれぞれ独立に水素原子またはアルキル基であり、Ｒ^11aおよびＲ^12aが隣接する窒素原子とともに下記一般式、

（式中、Ｗ^1aは−ＣＨ₂−または−Ｏ−である）で表わされる環を形成していてもよい）；−ＳＯ₂−Ｒ^13a（Ｒ^13aはフェニル基である）；−Ｘ^3a−ＮＲ^14aＲ^15a（Ｘ^3aはアルキレン、Ｒ^14aおよびＲ^15aはそれぞれ独立にアルキル基であり、Ｒ^14aおよびＲ^15aが隣接する窒素原子とともに下記一般式、

（式中、Ｗ^2aは−ＣＨ₂−、−ＮＲ^16a−（Ｒ^16aはアルキル基である）または−Ｏ−である）で表わされる環を形成していてもよい）であり、
Ｒ^2a、Ｒ^3aおよびＲ^4aは、それぞれ独立に水素原子；シアノ基；ハロゲン原子；テトラゾリル基；−ＯＲ^17a（Ｒ^17aは、水素原子、アルキル基または下記式、

で表わされる置換基である）；−Ｏ−Ｘ^4a−ＮＲ^18aＲ^19a（Ｘ^4aはアルキレン、Ｒ^18aおよびＲ^19aはそれぞれ独立にアルキル基であり、Ｒ^18aおよびＲ^19aが隣接する窒素原子とともに環を形成していてもよい）；−ＮＲ^20aＲ^21a（Ｒ^20aおよびＲ^21aは、それぞれ独立にフェニル基が置換されていてもよいアルキル基、水素原子、−Ｃ（Ｏ）Ｒ^22a（Ｒ^22aはハロゲン原子が置換されていてもよいアルキル基である）、−Ｃ（Ｏ）ＯＲ^23a（Ｒ^23aは、ニトロ基を有していてもよいフェニル基、アルキル基、または下記式、

で表わされる置換基である）、−Ｘ^5a−ＮＲ^24aＲ^25a（Ｘ^5aは単結合またはアルキレン、Ｒ^24aおよびＲ^25aはそれぞれ独立にアルキル基であり、Ｒ^24aおよびＲ^25aが隣接する窒素原子とともに下記一般式、

（式中、ｍ１およびｍ２はそれぞれ独立に０〜５の整数、Ｗ^3aは−ＣＨ₂−または−Ｏ−であり、ｍ１およびｍ２が同時に０である場合を除く）で表わされる環を形成していてもよい）、または下記一般式、

（式中、Ｒ^26aはアルキル基である）で表わされる置換基であり、Ｒ^20aおよびＲ^21aが隣接する窒素原子とともに下記一般式、

（式中、ｍ３およびｍ４はそれぞれ独立に０〜５の整数、Ｗ^4aは−ＣＨ₂−または−ＮＲ^27a−（Ｒ^27aはアルキル基であり、置換基を有していてもよい）であり、ｍ１およびｍ２が同時に０である場合を除く）で表わされる環を形成していてもよく、該環は置換基を有していてもよい）；−ＮＲ^28a−Ｃ（Ｏ）−Ｘ^6a−ＮＲ^29aＲ^30a（Ｘ^6aは単結合またはアルキレン、Ｒ^28aは水素原子またはアルキル基、Ｒ^29aおよびＲ^30aはそれぞれ独立に水素原子；ハロゲン原子もしくはアルコキシ基が置換されていてもよいフェニル基、水酸基、アルコキシ基および複素環からなる群から選択される置換基が置換されていてもよいアルキル基（該アルキル基は鎖中にスルフィド結合を有していてもよい）；−Ｘ^7a−Ｒ^31a（Ｘ^7aは単結合またはアルキレン、Ｒ^31aは下記式、

で表わされる基である）；アルケニル基；または置換基を有していてもよいフェニル基であり、Ｒ^29aおよびＲ^30aが隣接する窒素原子とともに下記一般式、

（式中、ｍ５およびｍ６はそれぞれ独立に０〜５の整数、Ｗ^5aは−ＣＨ₂−、−Ｓ−、−Ｏ−または−ＮＲ^32a−（Ｒ^32aは置換基を有していてもよいアルキル基、フェニル基、複素環または−Ｃ（Ｏ）−ＯＲ^33a（Ｒ^33aはアルキル基である）である）であり、ｍ５およびｍ６が同時に０である場合を除く）で表わされる環を形成していてもよく、該環は置換基を有していてもよく、また、該環は他の芳香環と縮合環を形成していてもよく、該縮合環は置換基が有していてもよい）；−Ｃ（Ｏ）−ＮＨ−Ｘ^8a−ＮＲ^34aＲ^35a（Ｘ^8aは単結合またはアルキレン、Ｒ^34aおよびＲ^35aはそれぞれ独立にアルキル基であり、Ｒ^34aおよびＲ^35aが隣接する窒素原子とともに下記一般式、

（式中、ｍ７およびｍ８はそれぞれ独立に０〜５の整数、Ｗ^6aは−ＣＨ₂−または−Ｏ−であり、ｍ７およびｍ８が同時に０である場合を除く）で表わされる環を形成していてもよい）；−Ｏ−Ｃ（Ｏ）−ＮＲ^36aＲ^37a（Ｒ^36aおよびＲ^37aはそれぞれ独立に水素原子またはアルキル基であり、Ｒ^36aおよびＲ^37aが隣接する窒素原子とともに下記一般式、

（式中、ｍ９およびｍ１０はそれぞれ独立に０〜５の整数、Ｗ^7aは−ＣＨ₂−、−Ｏ−または−ＮＲ^38a−（Ｒ^38aはアルキル基である）であり、ｍ９およびｍ１０が同時に０である場合を除く）で表わされる環を形成してもよく、また、該環は置換基を有していてもよい）； −Ｃ（Ｏ）ＯＲ^39a（Ｒ^39aは、水素原子またはアルキル基である）：または−Ｃ（Ｏ）−ＮＲ^40aＲ^41a（Ｒ^40aおよびＲ^41aはそれぞれ独立にアルキル基であり、Ｒ^40aおよびＲ^41aが隣接する窒素原子とともに下記一般式、

（式中、ｍ１１およびｍ１２はそれぞれ独立に０〜５の整数、Ｒ^42aはフェニル基が置換されていてもよいアルキル基であり、ｍ１１およびｍ１２が同時に０である場合を除く）で表わされる環を形成していてもよい）であり、
Ｒ^5aは水素原子またはアルキル基であり、
Ｒ^6a、Ｒ^7a、Ｒ^8aおよびＲ^9aは、それぞれ独立に水素原子；−Ｃ（Ｏ）ＯＲ^43a（Ｒ^43aはアルキル基である）；水酸基が置換されていてもよいアルキル基；ニトロ基；ハロゲン原子；またはアミノ基であり、Ｒ^6aおよびＲ^7aと、Ｒ^7aおよびＲ^8aと、またはＲ^8aおよびＲ^9aとにより、隣接するベンゼン環と下記式、

で表わされる縮合環を形成してもよい]で表わされることを特徴とするもの、またはその医薬上許容される塩である。 That is, the nitrogen-containing heterocyclic compound of the present invention has the following general formula (IA),

[Wherein, R ^1a is a hydrogen atom; an alkyl group which may be substituted with a substituent selected from the group consisting of a phenyl group, an alkoxy group, a hydroxyl group and a halogen atom, which may be substituted with a halogen atom; ^{1a -C (O) oR 10a (} X 1a is a single bond or alkylene, R ^10a is a hydrogen atom or an alkyl ^{group); - X 2a -C (O} ) NR 11a R 12a (X 2a is a single bond or alkylene, R ^11a and R ^12a are each independently a hydrogen atom or an alkyl group, and R ^11a and R ^12a together with the adjacent nitrogen atom have the following general formula:

(Wherein W ^1a may be —CH ₂ — or —O—) may be formed); —SO ₂ —R ^13a (R ^13a is a phenyl group); —X ^3a —NR ^14a R ^15a (X ^3a is alkylene, R ^14a and R ^15a are each independently an alkyl group, and R ^14a and R ^15a together with the adjacent nitrogen atom are represented by the following general formula:

(Wherein W ^2a may form a ring represented by —CH ₂ —, —NR ^16a — (R ^16a is an alkyl group) or —O—)),
R ^2a , R ^3a and R ^4a are each independently a hydrogen atom; a cyano group; a halogen atom; a tetrazolyl group; —OR ^17a (R ^17a is a hydrogen atom, an alkyl group,

-O-X < ^4a > -NR <^18a> R ^<19a> (X ^<4a> is alkylene, R ^<18a> and R ^<19a> are each independently an alkyl group, and R ^<18a> and R ^<19a> together with the adjacent nitrogen atom -NR ^20a R ^21a (R ^20a and R ^21a each independently represents an alkyl group, a hydrogen atom, -C (O) R ^22a (R ^22a is an alkyl group which may be substituted with a halogen atom), -C (O) OR ^23a (R ^23a is a phenyl group optionally having a nitro group, an alkyl group, or a group represented by the following formula:

In which a substituent ^{represented), - X 5a -NR 24a R} 25a (X 5a represents a single bond or alkylene, R ^24a and R ^25a are each independently an alkyl group, the nitrogen atom to which R ^24a and R ^25a are adjacent Together with the following general formula:

(Wherein m1 and m2 are each independently an integer of 0 to 5, W ^3a is —CH ₂ — or —O—, and m1 and m2 are simultaneously 0). Or the following general formula:

(Wherein R ^26a is an alkyl group), and R ^20a and R ^21a together with the adjacent nitrogen atom have the following general formula:

(Wherein m3 and m4 are each independently an integer of 0 to 5, W ^4a is —CH ₂ — or —NR ^27a — (R ^27a is an alkyl group, which may have a substituent). , M1 and m2 may be 0 at the same time), and the ring may have a substituent); —NR ^28a —C (O) —X ^6a -NR ^29a R ^30a (X ^6a represents a single bond or alkylene, R ^28a is a hydrogen atom or an alkyl group, R ^29a and R ^30a each independently represents a hydrogen atom, a halogen atom or a phenyl group which may alkoxy group substituted, An alkyl group that may be substituted with a substituent selected from the group consisting of a hydroxyl group, an alkoxy group, and a heterocyclic ring (the alkyl group may have a sulfide bond in the chain); -X ^7a -R ^31a (X ^7a is a single bond or alkylene. , R ^31a is the following formula:

An alkenyl group; or a phenyl group which may have a substituent, and R ^29a and R ^30a together with the adjacent nitrogen atom have the following general formula:

(In the formula, m5 and m6 are each independently an integer of 0 to 5, W ^5a is —CH ₂ —, —S—, —O— or —NR ^32a — (R ^32a may have a substituent. An alkyl group, a phenyl group, a heterocyclic ring, or —C (O) —OR ^33a (R ^33a is an alkyl group), and a ring represented by m5 and m6 is 0 at the same time) The ring may have a substituent, and the ring may form a condensed ring with another aromatic ring, and the condensed ring has a substituent. may also be); - C (O) -NH -X 8a -NR 34a R 35a (X 8a represents a single bond or alkylene, R ^34a and R ^35a are each independently an alkyl group, R ^34a and R ^35a are adjacent The following general formula together with the nitrogen atom:

(Wherein m7 and m8 are each independently an integer of 0 to 5, W ^6a is —CH ₂ — or —O—, except that m7 and m8 are 0 at the same time). -O-C (O) -NR ^36a R ^37a (R ^36a and R ^37a are each independently a hydrogen atom or an alkyl group, and R ^36a and R ^37a together with the adjacent nitrogen atom are represented by the following general formula: ,

Wherein m9 and m10 are each independently an integer of 0 to 5, W ^7a is —CH ₂ —, —O— or —NR ^38a — (R ^38a is an alkyl group), and m9 and m10 are simultaneously And the ring may have a substituent); —C (O) OR ^39a (R ^39a represents a hydrogen atom or an alkyl group). Or —C (O) —NR ^40a R ^41a (R ^40a and R ^41a are each independently an alkyl group, and R ^40a and R ^41a together with the adjacent nitrogen atom have the following general formula:

(Wherein m11 and m12 are each independently an integer of 0 to 5, R ^42a is an alkyl group which may be substituted with a phenyl group, and m11 and m12 are 0 at the same time) May be formed), and
R ^5a is a hydrogen atom or an alkyl group,
R ^6a , R ^7a , R ^8a and R ^9a are each independently a hydrogen atom; —C (O) OR ^43a (R ^43a is an alkyl group); an alkyl group on which a hydroxyl group may be substituted; a nitro group; A halogen atom; or an amino group, and R ^6a and R ^7a , R ^7a and R ^8a , or R ^8a and R ^9a ,

Or a pharmaceutically acceptable salt thereof.

[式中、Ｒ^1bは、水素原子；ハロゲン原子が置換されてもよいフェニル基、アルコキシ基、水酸基およびハロゲン原子からなる群から選択される置換基が置換されていてもよいアルキル基；−Ｘ^1b−Ｃ（Ｏ）ＯＲ^10b（Ｘ^1bは単結合またはアルキレン、Ｒ^10bは水素原子またはアルキル基である）；−Ｘ^2b−Ｃ（Ｏ）ＮＲ^11bＲ^12b（Ｘ^2bは単結合またはアルキレン、Ｒ^11bおよびＲ^12bはそれぞれ独立に水素原子またはアルキル基であり、Ｒ^11bおよびＲ^12bが隣接する窒素原子とともに下記一般式、

（式中、Ｗ^1bは−ＣＨ₂−または−Ｏ−である）で表わされる環を形成していてもよい）；−ＳＯ₂−Ｒ^13b（Ｒ^13bはフェニル基である）；−Ｘ^3b−ＮＲ^14bＲ^15b（Ｘ^3bはアルキレン、Ｒ^14bおよびＲ^15bはそれぞれ独立にアルキル基であり、Ｒ^14bおよびＲ^15bが隣接する窒素原子とともに下記一般式、

（式中、Ｗ^2bは−ＣＨ₂−、−ＮＲ^16b−（Ｒ^16bはアルキル基である）または−Ｏ−である）で表わされる環を形成していてもよい）であり、
Ｒ^2b、Ｒ^3bおよびＲ^4bは、それぞれ独立に水素原子；シアノ基；ハロゲン原子；テトラゾリル基；−ＯＲ^17b（Ｒ^17bは、水素原子、アルキル基または下記式、

で表わされる置換基である）；−Ｏ−Ｘ^4b−ＮＲ^18bＲ^19b（Ｘ^4bはアルキレン、Ｒ^18bおよびＲ^19bはそれぞれ独立にアルキル基であり、Ｒ^18bおよびＲ^19bが隣接する窒素原子とともに環を形成していてもよい）；−ＮＲ^20bＲ^21b（Ｒ^20bおよびＲ^21bは、それぞれ独立にフェニル基が置換されていてもよいアルキル基、水素原子、−Ｃ（Ｏ）Ｒ^22b（Ｒ^22bはハロゲン原子が置換されていてもよいアルキル基である）、−Ｃ（Ｏ）ＯＲ^23b（Ｒ^23bは、ニトロ基を有していてもよいフェニル基、アルキル基、または下記式、

で表わされる置換基である）、−Ｘ^5b−ＮＲ^24bＲ^25b（Ｘ^5bは単結合またはアルキレン、Ｒ^24bおよびＲ^25bはそれぞれ独立にアルキル基であり、Ｒ^24bおよびＲ^25bが隣接する窒素原子とともに下記一般式、

（式中、ｎ１およびｎ２はそれぞれ独立に０〜５の整数、Ｗ^3bは−ＣＨ₂−または−Ｏ−であり、ｎ１およびｎ２が同時に０である場合を除く）で表わされる環を形成していてもよい）、または下記一般式、

（式中、Ｒ^26bはアルキル基である）で表わされる置換基であり、Ｒ^20bおよびＲ^21bが隣接する窒素原子とともに下記一般式、

（式中、ｎ３およびｎ４はそれぞれ独立に０〜５の整数、Ｗ^4bは−ＣＨ₂−または−ＮＲ^27b−（Ｒ^27bはアルキル基であり、置換基を有していてもよい）であり、ｎ１およびｎ２が同時に０である場合を除く）で表わされる環を形成していてもよく、該環は置換基を有していてもよい）；−ＮＲ^28b−Ｃ（Ｏ）−Ｘ^6b−ＮＲ^29bＲ^30b（Ｘ^6bは単結合またはアルキレン、Ｒ^28bは水素原子またはアルキル基、Ｒ^29bおよびＲ^30bはそれぞれ独立に水素原子；ハロゲン原子もしくはアルコキシ基が置換されていてもよいフェニル基、水酸基、アルコキシ基および複素環からなる群から選択される置換基が置換されていてもよいアルキル基（該アルキル基は鎖中にスルフィド結合を有していてもよい）；−Ｘ^7b−Ｒ^31b（Ｘ^7bは単結合またはアルキレン、Ｒ^31bは下記式、

で表わされる基である）；アルケニル基；または置換基を有していてもよいフェニル基であり、Ｒ^29bおよびＲ^30bが隣接する窒素原子とともに下記一般式、

（式中、ｎ５およびｎ６はそれぞれ独立に０〜５の整数、Ｗ^5bは−ＣＨ₂−、−Ｓ−、−Ｏ−または−ＮＲ^32b−（Ｒ^32bは置換基を有していてもよいアルキル基、フェニル基、複素環または−Ｃ（Ｏ）−ＯＲ^33b（Ｒ^33bはアルキル基である）である）であり、ｎ５およびｎ６が同時に０である場合を除く）で表わされる環を形成していてもよく、該環は置換基を有していてもよく、また、該環は他の芳香環と縮合環を形成していてもよく、該縮合環は置換基が有していてもよい）；−Ｃ（Ｏ）−ＮＨ−Ｘ^8b−ＮＲ^34bＲ^35b（Ｘ^8bは単結合またはアルキレン、Ｒ^34bおよびＲ^35bはそれぞれ独立にアルキル基であり、Ｒ^34bおよびＲ^35bが隣接する窒素原子とともに下記一般式、

（式中、ｎ７およびｎ８はそれぞれ独立に０〜５の整数、Ｗ^6bは−ＣＨ₂−または−Ｏ−であり、ｎ７およびｎ８が同時に０である場合を除く）で表わされる環を形成していてもよい）；−Ｏ−Ｃ（Ｏ）−ＮＲ^36bＲ^37b（Ｒ^36bおよびＲ^37bはそれぞれ独立に水素原子またはアルキル基であり、Ｒ^36bおよびＲ^37bが隣接する窒素原子とともに下記一般式、

（式中、ｎ９およびｎ１０はそれぞれ独立に０〜５の整数、Ｗ^7bは−ＣＨ₂−、−Ｏ−または−ＮＲ^38b−（Ｒ^38bはアルキル基である）であり、ｎ９およびｎ１０が同時に０である場合を除く）で表わされる環を形成してもよく、また、該環は置換基を有していてもよい）； −Ｃ（Ｏ）ＯＲ^39b（Ｒ^39bは、水素原子またはアルキル基である）：または−Ｃ（Ｏ）−ＮＲ^40bＲ^41b（Ｒ^40bおよびＲ^41bはそれぞれ独立にアルキル基であり、Ｒ^40bおよびＲ^41bが隣接する窒素原子とともに下記一般式、

（式中、ｎ１１およびｎ１２はそれぞれ独立に０〜５の整数、Ｒ^42bはフェニル基が置換されていてもよいアルキル基であり、ｎ１１およびｎ１２が同時に０である場合を除く）で表わされる環を形成していてもよい）であり、
Ｒ^5bは水素原子またはアルキル基であり、
Ｒ^6b、Ｒ^7b、Ｒ^8bおよびＲ^9bは、それぞれ独立に水素原子；−Ｃ（Ｏ）ＯＲ^43b（Ｒ^43bはアルキル基である）；水酸基が置換されていてもよいアルキル基；ニトロ基；ハロゲン原子；またはアミノ基であり、Ｒ^6bおよびＲ^7bと、Ｒ^7bおよびＲ^8bと、またはＲ^8bおよびＲ^9bとにより、隣接するベンゼン環と下記式、

で表わされる縮合環を形成してもよい]で表わされることを特徴とするもの、またはその医薬上許容される塩である。 In addition, other nitrogen-containing heterocyclic compounds of the present invention are represented by the following general formula (IB),

[Wherein, R ^1b represents a hydrogen atom; an alkyl group which may be substituted with a substituent selected from the group consisting of a phenyl group, an alkoxy group, a hydroxyl group and a halogen atom which may be substituted with a halogen atom; ^1b -C (O) OR ^10b (X ^1b is a single bond or alkylene, R ^10b is a hydrogen atom or an alkyl group); -X ^2b -C (O) NR ^11b R ^12b (X ^2b is a single bond or alkylene, R ^11b and R ^12b are each independently a hydrogen atom or an alkyl group, and R ^11b and R ^12b together with the adjacent nitrogen atom have the following general formula:

(Wherein W ^1b may be a ring represented by —CH ₂ — or —O—); —SO ₂ —R ^13b (R ^13b is a phenyl group); —X ^3b —NR ^14b R ^15b (X ^3b is alkylene, R ^14b and R ^15b are each independently an alkyl group, and R ^14b and R ^15b together with the adjacent nitrogen atom are represented by the following general formula:

(Wherein W ^2b may form a ring represented by —CH ₂ —, —NR ^16b — (R ^16b is an alkyl group) or —O—)),
R ^2b , R ^3b and R ^4b are each independently a hydrogen atom; a cyano group; a halogen atom; a tetrazolyl group; —OR ^17b (where R ^17b is a hydrogen atom, an alkyl group,

-O-X ^4b -NR ^18b R ^19b (X ^4b is alkylene, R ^18b and R ^19b are each independently an alkyl group, and R ^18b and R ^19b together with the adjacent nitrogen atom) -NR ^20b R ^21b (R ^20b and R ^21b each independently represents an alkyl group on which a phenyl group may be substituted, a hydrogen atom, -C (O) R ^22b (R ^22b is an alkyl group which may be substituted with a halogen atom), -C (O) OR ^23b (R ^23b is a phenyl group optionally having a nitro group, an alkyl group, or the following formula:

In which a substituent ^{represented), - X 5b -NR 24b R} 25b (X 5b is a single bond or alkylene, R ^24b and R ^25b are each independently an alkyl group, the nitrogen atom to which R ^24b and R ^25b are adjacent Together with the following general formula:

In which n1 and n2 are each independently an integer of 0 to 5, W ^3b is —CH ₂ — or —O—, and n1 and n2 are both 0 at the same time. Or the following general formula:

(Wherein R ^26b is an alkyl group), and R ^20b and R ^21b together with the adjacent nitrogen atom have the following general formula:

(Wherein n3 and n4 are each independently an integer of 0 to 5, W ^4b is —CH ₂ — or —NR ^27b — (R ^27b is an alkyl group and may have a substituent). , Except that n1 and n2 are 0 at the same time, the ring may have a substituent); —NR ^28b —C (O) —X ^6b —NR ^29b R ^30b (where X ^6b is a single bond or alkylene, R ^28b is a hydrogen atom or an alkyl group, R ^29b and R ^30b are each independently a hydrogen atom; a phenyl group which may be substituted with a halogen atom or an alkoxy group, An alkyl group that may be substituted with a substituent selected from the group consisting of a hydroxyl group, an alkoxy group, and a heterocyclic ring (the alkyl group may have a sulfide bond in the chain); -X ^7b -R ^31b (X ^7b is a single bond or alkylene. , R ^31b is the following formula:

An alkenyl group; or a phenyl group which may have a substituent, and R ^29b and R ^30b together with the adjacent nitrogen atom have the following general formula:

Wherein n5 and n6 are each independently an integer of 0 to 5, W ^5b is —CH ₂ —, —S—, —O— or —NR ^32b — (R ^32b may have a substituent. An alkyl group, a phenyl group, a heterocyclic ring, or —C (O) —OR ^33b (R ^33b is an alkyl group), and a ring represented by n5 and n6 are 0 at the same time) The ring may have a substituent, and the ring may form a condensed ring with another aromatic ring, and the condensed ring has a substituent. may also be); - C (O) -NH -X 8b -NR 34b R 35b (X 8b is a single bond or alkylene, R ^34b and R ^35b are each independently an alkyl group, R ^34b and R ^35b are adjacent The following general formula together with the nitrogen atom:

(Wherein n7 and n8 are each independently an integer of 0 to 5, W ^6b is —CH ₂ — or —O—, and n7 and n8 are 0 at the same time). may be); - O-C (O ) -NR 36b R 37b (R 36b and R ^37b are each independently a hydrogen atom or an alkyl group, following general formula together with the nitrogen atom to which R ^36b and R ^37b are adjacent ,

Wherein n9 and n10 are each independently an integer of 0 to 5, W ^7b is —CH ₂ —, —O— or —NR ^38b — (R ^38b is an alkyl group), and n9 and n10 are simultaneously And the ring may have a substituent); —C (O) OR ^39b (R ^39b represents a hydrogen atom or an alkyl group). Or —C (O) —NR ^40b R ^41b (R ^40b and R ^41b are each independently an alkyl group, and R ^40b and R ^41b together with the adjacent nitrogen atom have the following general formula:

(Wherein n11 and n12 are each independently an integer of 0 to 5, R ^42b is an alkyl group which may be substituted with a phenyl group, and n11 and n12 are simultaneously 0) May be formed), and
R ^5b is a hydrogen atom or an alkyl group,
R ^6b , R ^7b , R ^8b and R ^9b are each independently a hydrogen atom; —C (O) OR ^43b (R ^43b is an alkyl group); an alkyl group on which a hydroxyl group may be substituted; a nitro group; A halogen atom; or an amino group, and R ^6b and R ^7b , R ^7b and R ^8b , or R ^8b and R ^9b, and the adjacent benzene ring,

Or a pharmaceutically acceptable salt thereof.

（式中、Ｒ^1a、Ｒ^2a、Ｒ^3aおよびＲ^4aは上記のものと同じである）で表わされる７−アザインドール誘導体またはその前駆体と、下記一般式（ＩＩＩ−Ａ）、

（式中、Ｒ^5a、Ｒ^6a、Ｒ^7a、Ｒ^8aおよびＲ^9aは上記のものと同じである）で表わされるキノキサロン誘導体またはその前駆体と、を反応させる工程を含むことを特徴とするものである。 The production method of the present invention is a method for producing the nitrogen-containing heterocyclic compound (IA) or a pharmaceutically acceptable salt thereof according to the present invention, which comprises the following general formula (II-A):

(Wherein R ^1a , R ^2a , R ^3a, and R ^4a are the same as those described above), a 7-azaindole derivative represented by the following formula (III-A),

(Wherein R ^5a , R ^6a , R ^7a , R ^8a, and R ^9a are the same as those described above) and a step of reacting them with a precursor thereof. It is.

  The pharmaceutical composition of the present invention comprises the nitrogen-containing heterocyclic compound (IA) or (IB) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. is there.

  In addition, the definition of each substituent etc. used in this specification is as follows. The “alkyl group” may be linear, branched or cyclic. Although carbon number is not specifically limited, Preferably it is 1-12, More preferably, it is 1-6. The alkyl group portion of the “alkoxy group” may be linear or branched or cyclic, and the number of carbon atoms is not particularly limited, but preferably 1 to 12, more preferably 1-6. The “alkenyl group” may be linear, branched or cyclic as long as it has a double bond in the chain. Although carbon number is not specifically limited, Preferably it is 1-12, More preferably, it is 1-6. “Alkylene” may be linear or branched, and the number of carbon atoms is not particularly limited, but is preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. A “heterocycle” is a ring containing one or more heteroatoms, and has aromaticity such as a pyridyl group or pyrimidinyl.

  The nitrogen-containing heterocyclic compound of the present invention or a pharmaceutically acceptable salt thereof is a compound having a VEGF inhibitory action. The pharmaceutical composition of the present invention containing them as an active ingredient is used as a therapeutic agent having a VEGF inhibitory action to various diseases such as diabetic nephropathy, solid tumor, rheumatoid arthritis, diabetic retinopathy or crow-fukase syndrome. The application of can be expected. Further, by using the production method of the present invention as a method for producing the nitrogen-containing heterocyclic compound of the present invention or a pharmaceutically acceptable salt thereof, generation of by-products can be suppressed.

で表されることを特徴するものである。式中、Ｒ^1aは、水素原子；ハロゲン原子が置換されてもよいフェニル基、アルコキシ基、水酸基およびハロゲン原子からなる群から選択される置換基が置換されていてもよいアルキル基；−Ｘ^1a−Ｃ（Ｏ）ＯＲ^10a（Ｘ^1aは単結合またはアルキレンである。Ｒ^10aは水素原子またはアルキル基である。）；−Ｘ^2a−Ｃ（Ｏ）ＮＲ^11aＲ^12a（Ｘ^2aは単結合またはアルキレンである。Ｒ^11aおよびＲ^12aはそれぞれ独立に水素原子またはアルキル基であり、Ｒ^11aおよびＲ^12aが隣接する窒素原子とともに下記一般式、

（式中、Ｗ^1aは−ＣＨ₂−または−Ｏ−である。）で表わされる環を形成していてもよい。）；−ＳＯ₂−Ｒ^13a（Ｒ^13aはフェニル基である。）；−Ｘ^3a−ＮＲ^14aＲ^15a（Ｘ^3aはアルキレンである。Ｒ^14aおよびＲ^15aはそれぞれ独立にアルキル基であり、Ｒ^14aおよびＲ^15aが隣接する窒素原子とともに下記一般式、

（式中、Ｗ^2aは−ＣＨ₂−、−ＮＲ^16a−（Ｒ^16aはアルキル基である。）または−Ｏ−である。）で表わされる環を形成していてもよい。）である。 Hereinafter, preferred embodiments of the present invention will be described in detail.
The nitrogen-containing heterocyclic compound of the present invention has the following general formula (IA),

It is characterized by being represented by. Wherein, R ^1a is a hydrogen atom, a halogen atom an optionally substituted phenyl group, an alkoxy group, a hydroxyl group and an alkyl group which may substituent substituted selected from the group consisting of halogen atoms; -X ^1a -C (O) OR ^10a (X ^1a is a single bond or alkylene. R ^10a is a hydrogen atom or an alkyl group); -X ^2a -C (O) NR ^11a R ^12a (X ^2a is a single bond or R ^11a and R ^12a are each independently a hydrogen atom or an alkyl group, and R ^11a and R ^12a together with the adjacent nitrogen atom have the following general formula:

(Wherein W ^1a is —CH ₂ — or —O—). —SO ₂ —R ^13a (R ^13a is a phenyl group); —X ^3a —NR ^14a R ^15a (X ^3a is alkylene. R ^14a and R ^15a are each independently an alkyl group; ^14a and R ^15a together with the adjacent nitrogen atom have the general formula:

In the formula, W ^2a may form a ring represented by —CH ₂ —, —NR ^16a — (R ^16a is an alkyl group) or —O—. ).

R ^1a is a hydrogen atom; an alkyl group that may be substituted with a substituent selected from the group consisting of a phenyl group, an alkoxy group, a hydroxyl group, and a halogen atom that may be substituted with a halogen atom; or —X ^1a -C ( O) OR ^10a (X ^1a and R ^10a are as defined above) is preferred. In particular, R ^1a is a hydrogen atom; an alkyl group that may be substituted with a hydroxyl group; or —X ^1a —C (O) OR ^10a (X ^1a is a single bond, and R ^10a is an alkyl group). Those are more preferred. When R ^1a is an alkyl group, those having 1 to 6 carbon atoms are preferred.

で表わされる置換基である。）；−Ｏ−Ｘ^4a−ＮＲ^18aＲ^19a（Ｘ^4aはアルキレンである。Ｒ^18aおよびＲ^19aはそれぞれ独立にアルキル基であり、Ｒ^18aおよびＲ^19aが隣接する窒素原子とともに環を形成していてもよい。）；−ＮＲ^20aＲ^21a（Ｒ^20aおよびＲ^21aは、それぞれ独立にフェニル基が置換されていてもよいアルキル基、水素原子、−Ｃ（Ｏ）Ｒ^22a（Ｒ^22aはハロゲン原子が置換されていてもよいアルキル基である。）、−Ｃ（Ｏ）ＯＲ^23a（Ｒ^23aは、ニトロ基を有していてもよいフェニル基、アルキル基、または下記式、

で表わされる置換基である。）、−Ｘ^5a−ＮＲ^24aＲ^25a（Ｘ^5aは単結合またはアルキレンである。Ｒ^24aおよびＲ^25aはそれぞれ独立にアルキル基であり、Ｒ^24aおよびＲ^25aが隣接する窒素原子とともに下記一般式、

（式中、ｍ１およびｍ２はそれぞれ独立に０〜５の整数である。Ｗ^3aは−ＣＨ₂−または−Ｏ−であり、ｍ１およびｍ２が同時に０である場合を除く。）で表わされる環を形成していてもよい。）、または下記一般式、

（式中、Ｒ^26aはアルキル基である。）で表わされる置換基であり、Ｒ^20aおよびＲ^21aが隣接する窒素原子とともに下記一般式、

（式中、ｍ３およびｍ４はそれぞれ独立に０〜５の整数である。Ｗ^4aは−ＣＨ₂−または−ＮＲ^27a−（Ｒ^27aはアルキル基であり、置換基を有していてもよい。）であり、ｍ１およびｍ２が同時に０である場合を除く。）で表わされる環を形成していてもよく、該環は置換基を有していてもよい。）；−ＮＲ^28a−Ｃ（Ｏ）−Ｘ^6a−ＮＲ^29aＲ^30a（Ｘ^6aは単結合またはアルキレンである。Ｒ^28aは水素原子またはアルキル基である。Ｒ^29aおよびＲ^30aはそれぞれ独立に水素原子；ハロゲン原子もしくはアルコキシ基が置換されていてもよいフェニル基、水酸基、アルコキシ基および複素環からなる群から選択される置換基が置換されていてもよいアルキル基（該アルキル基は鎖中にスルフィド結合を有していてもよい。）；−Ｘ^7a−Ｒ^31a（Ｘ^7aは単結合またはアルキレンである。Ｒ^31aは下記式、

で表わされる基である。）；アルケニル基；または置換基を有していてもよいフェニル基であり、Ｒ^29aおよびＲ^30aが隣接する窒素原子とともに下記一般式、

（式中、ｍ５およびｍ６はそれぞれ独立に０〜５の整数である。Ｗ^5aは−ＣＨ₂−、−Ｓ−、−Ｏ−または−ＮＲ^32a−（Ｒ^32aは置換基を有していてもよいアルキル基、フェニル基、複素環または−Ｃ（Ｏ）−ＯＲ^33a（Ｒ^33aはアルキル基である。）である。）であり、ｍ５およびｍ６が同時に０である場合を除く。）で表わされる環を形成していてもよく、該環は置換基を有していてもよい。また、該環は他の芳香環と縮合環を形成していてもよく、該縮合環は置換基が有していてもよい。）；−Ｃ（Ｏ）−ＮＨ−Ｘ^8a−ＮＲ^34aＲ^35a（Ｘ^8aは単結合またはアルキレンである。Ｒ^34aおよびＲ^35aはそれぞれ独立にアルキル基であり、Ｒ^34aおよびＲ^35aが隣接する窒素原子とともに下記一般式、

（式中、ｍ７およびｍ８はそれぞれ独立に０〜５の整数である。Ｗ^6aは−ＣＨ₂−または−Ｏ−であり、ｍ７およびｍ８が同時に０である場合を除く。）で表わされる環を形成していてもよい。）；−Ｏ−Ｃ（Ｏ）−ＮＲ^36aＲ^37a（Ｒ^36aおよびＲ^37aはそれぞれ独立に水素原子またはアルキル基であり、Ｒ^36aおよびＲ^37aが隣接する窒素原子とともに下記一般式、

（式中、ｍ９およびｍ１０はそれぞれ独立に０〜５の整数である。Ｗ^7aは−ＣＨ₂−、−Ｏ−または−ＮＲ^38a−（Ｒ^38aはアルキル基である。）であり、ｍ９およびｍ１０が同時に０である場合を除く。）で表わされる環を形成してもよく、また、該環は置換基を有していてもよい。）； −Ｃ（Ｏ）ＯＲ^39a（Ｒ^39aは、水素原子またはアルキル基である。）：または−Ｃ（Ｏ）−ＮＲ^40aＲ^41a（Ｒ^40aおよびＲ^41aはそれぞれ独立にアルキル基であり、Ｒ^40aおよびＲ^41aが隣接する窒素原子とともに下記一般式、

（式中、ｍ１１およびｍ１２はそれぞれ独立に０〜５の整数である。Ｒ^42aはフェニル基が置換されていてもよいアルキル基であり、ｍ１１およびｍ１２が同時に０である場合を除く。）で表わされる環を形成していてもよい。）である。 R ^2a , R ^3a and R ^4a are each independently a hydrogen atom; a cyano group; a halogen atom; a tetrazolyl group; —OR ^17a (R ^17a is a hydrogen atom, an alkyl group,

It is a substituent represented by these. ); —O—X ^4a —NR ^18a R ^19a (X ^4a is alkylene. R ^18a and R ^19a are each independently an alkyl group, and R ^18a and R ^19a form a ring together with the adjacent nitrogen atom). -NR ^20a R ^21a (R ^20a and R ^21a are each independently an alkyl group which may be substituted with a phenyl group, a hydrogen atom, -C (O) R ^22a (R ^22a is a halogen atom) Is an optionally substituted alkyl group), -C (O) OR ^23a (R ^23a is a phenyl group optionally having a nitro group, an alkyl group, or a group represented by the following formula:

It is a substituent represented by these. ^{), - X 5a -NR 24a R} 25a (X 5a is .R ^24a and R ^25a represents a single bond or alkylene are each independently an alkyl group, following general formula together with the nitrogen atom to which R ^24a and R ^25a are adjacent,

(Wherein m1 and m2 are each independently an integer of 0 to 5. W ^3a is —CH ₂ — or —O—, except that m1 and m2 are 0 at the same time). May be formed. ), Or the following general formula:

(Wherein R ^26a is an alkyl group), and R ^20a and R ^21a together with the adjacent nitrogen atom have the following general formula:

(Wherein m3 and m4 are each independently an integer of 0 to 5. W ^4a is —CH ₂ — or —NR ^27a — (R ^27a is an alkyl group, which may have a substituent). Except that m1 and m2 are 0 at the same time.) May be formed, and the ring may have a substituent. ); —NR ^28a —C (O) —X ^6a —NR ^29a R ^30a (X ^6a is a single bond or alkylene. R ^28a is a hydrogen atom or an alkyl group. R ^29a and R ^30a are each independently hydrogen. An atom; a halogen atom or an alkoxy group which may be substituted; a substituent selected from the group consisting of a phenyl group, a hydroxyl group, an alkoxy group and a heterocyclic ring; an alkyl group which may be substituted (the alkyl group is in the chain) -X ^7a -R ^31a (X ^7a is a single bond or alkylene. R ^31a is represented by the following formula:

It is group represented by these. ); An alkenyl group; or a phenyl group which may have a substituent, and R ^29a and R ^30a together with the adjacent nitrogen atom have the following general formula:

(Wherein m5 and m6 are each independently an integer of 0 to ^5. W ^5a is —CH ₂ —, —S—, —O— or —NR ^32a — (R ^32a has a substituent). An alkyl group, a phenyl group, a heterocyclic ring, or —C (O) —OR ^33a (R ^33a is an alkyl group).), Except that m5 and m6 are 0 at the same time. The ring represented may be formed, and this ring may have a substituent. In addition, the ring may form a condensed ring with another aromatic ring, and the condensed ring may have a substituent. ); —C (O) —NH—X ^8a —NR ^34a R ^35a (X ^8a is a single bond or alkylene. R ^34a and R ^35a are each independently an alkyl group, and R ^34a and R ^35a are adjacent to each other). The following general formula together with the nitrogen atom:

(Wherein m7 and m8 are each independently an integer of 0 to 5. W ^6a is —CH ₂ — or —O—, except when m7 and m8 are 0 at the same time). May be formed. ); —O—C (O) —NR ^36a R ^37a (R ^36a and R ^37a are each independently a hydrogen atom or an alkyl group, and R ^36a and R ^37a together with the adjacent nitrogen atom have the following general formula:

(Wherein, m9 and m10 are each independently an integer of 0 to 5. W ^7a is —CH ₂ —, —O— or —NR ^38a — (R ^38a is an alkyl group), and m9 and except for the case where m10 is 0 at the same time.), and the ring may have a substituent. -C (O) OR ^39a (R ^39a is a hydrogen atom or an alkyl group): or -C (O) -NR ^40a R ^41a (R ^40a and R ^41a are each independently an alkyl group; R ^40a and R ^41a together with the adjacent nitrogen atom have the general formula:

(Wherein, m11 and m12 are each independently an integer of 0 to 5 .R ^42a is an alkyl group which may be substituted is a phenyl group, excluded. Where m11 and m12 are 0 at the same time) in The ring represented may be formed. ).

R ^2a , R ^3a and R ^4a are each independently a hydrogen atom; a cyano group; a halogen atom; —OR ^17a (R ^17a is the same as described above); —NR ^20a R ^21a (R ^20a and R ^21a is the same as described above.); —NR ^28a —C (O) —X ^6a —NR ^29a R ^30a (X ^6a , R ^28a , R ^29a and R ^30a are the same as described above.) Or —O—C (O) —NR ^36a R ^37a (R ^36a and R ^37a are the same as those described above).

R ^5a is a hydrogen atom or an alkyl group, preferably a hydrogen atom.

で表わされる縮合環を形成してもよい。 R ^6a , R ^7a , R ^8a and R ^9a are each independently a hydrogen atom; —C (O) OR ^43a (R ^43a is an alkyl group); an alkyl group on which a hydroxyl group may be substituted; a nitro group A halogen atom; or an amino group, and R ^6a and R ^7a , R ^7a and R ^8a , or R ^8a and R ^9a , an adjacent benzene ring and the following formula:

You may form the condensed ring represented by these.

R ^6a , R ^7a , R ^8a and R ^9a are preferably each independently a hydrogen atom; an alkyl group which may be substituted with a hydroxyl group; or a halogen atom.

で表されることを特徴するものである。式中、Ｒ^1bは、水素原子；ハロゲン原子が置換されてもよいフェニル基、アルコキシ基、水酸基およびハロゲン原子からなる群から選択される置換基が置換されていてもよいアルキル基；−Ｘ^1b−Ｃ（Ｏ）ＯＲ^10b（Ｘ^1bは単結合またはアルキレンである。Ｒ^10bは水素原子またはアルキル基である。）；−Ｘ^2b−Ｃ（Ｏ）ＮＲ^11bＲ^12b（Ｘ^2bは単結合またはアルキレンである。Ｒ^11bおよびＲ^12bはそれぞれ独立に水素原子またはアルキル基であり、Ｒ^11bおよびＲ^12bが隣接する窒素原子とともに下記一般式、

（式中、Ｗ^1bは−ＣＨ₂−または−Ｏ−である。）で表わされる環を形成していてもよい。）；−ＳＯ₂−Ｒ^13b（Ｒ^13bはフェニル基である。）；−Ｘ^3b−ＮＲ^14bＲ^15b（Ｘ^3bはアルキレンである。Ｒ^14bおよびＲ^15bはそれぞれ独立にアルキル基であり、Ｒ^14bおよびＲ^15bが隣接する窒素原子とともに下記一般式、

（式中、Ｗ^2bは−ＣＨ₂−、−ＮＲ^16b−（Ｒ^16bはアルキル基である。）または−Ｏ−である。）で表わされる環を形成していてもよい。）である。 Other nitrogen-containing heterocyclic compounds of the present invention include the following general formula (IB),

It is characterized by being represented by. Wherein, R ^1b is a hydrogen atom; a halogen atom which may be substituted phenyl group, an alkoxy group, a hydroxyl group and an alkyl group substituent selected from the group consisting of halogen atoms which may be substituted; -X ^1b —C (O) OR ^10b (X ^1b is a single bond or alkylene; R ^10b is a hydrogen atom or an alkyl group); —X ^2b —C (O) NR ^11b R ^12b (X ^2b is a single bond or R ^11b and R ^12b are each independently a hydrogen atom or an alkyl group, and R ^11b and R ^12b together with the adjacent nitrogen atom have the following general formula:

(Wherein W ^1b is —CH ₂ — or —O—). ^{_{); - SO 2 -R 13b (}} R 13b is a phenyl ^{group); -. X 3b -NR 14b} R 15b (X 3b is .R ^14b and R ^15b is an alkylene are each independently an alkyl radical, R ^14b and R ^15b together with the adjacent nitrogen atom have the general formula:

In the formula, W ^2b may form a ring represented by —CH ₂ —, —NR ^16b — (R ^16b is an alkyl group) or —O—. ).

R ^1b is preferably a hydrogen atom or an alkyl group, more preferably an alkyl group.

で表わされる置換基である。）；−Ｏ−Ｘ^4b−ＮＲ^18bＲ^19b（Ｘ^4bはアルキレンである。Ｒ^18bおよびＲ^19bはそれぞれ独立にアルキル基であり、Ｒ^18bおよびＲ^19bが隣接する窒素原子とともに環を形成していてもよい。）；−ＮＲ^20bＲ^21b（Ｒ^20bおよびＲ^21bは、それぞれ独立にフェニル基が置換されていてもよいアルキル基、水素原子、−Ｃ（Ｏ）Ｒ^22b（Ｒ^22bはハロゲン原子が置換されていてもよいアルキル基である。）、−Ｃ（Ｏ）ＯＲ^23b（Ｒ^23bは、ニトロ基を有していてもよいフェニル基、アルキル基、または下記式、

で表わされる置換基である。）、−Ｘ^5b−ＮＲ^24bＲ^25b（Ｘ^5bは単結合またはアルキレンである。Ｒ^24bおよびＲ^25bはそれぞれ独立にアルキル基であり、Ｒ^24bおよびＲ^25bが隣接する窒素原子とともに下記一般式、

（式中、ｎ１およびｎ２はそれぞれ独立に０〜５の整数である。Ｗ^3bは−ＣＨ₂−または−Ｏ−であり、ｎ１およびｎ２が同時に０である場合を除く。）で表わされる環を形成していてもよい。）、または下記一般式、

（式中、Ｒ^26bはアルキル基である。）で表わされる置換基であり、Ｒ^20bおよびＲ^21bが隣接する窒素原子とともに下記一般式、

（式中、ｎ３およびｎ４はそれぞれ独立に０〜５の整数である。Ｗ^4bは−ＣＨ₂−または−ＮＲ^27b−（Ｒ^27bはアルキル基であり、置換基を有していてもよい。）であり、ｎ１およびｎ２が同時に０である場合を除く。）で表わされる環を形成していてもよく、該環は置換基を有していてもよい。）；−ＮＲ^28b−Ｃ（Ｏ）−Ｘ^6b−ＮＲ^29bＲ^30b（Ｘ^6bは単結合またはアルキレンである。Ｒ^28bは水素原子またはアルキル基である。Ｒ^29bおよびＲ^30bはそれぞれ独立に水素原子；ハロゲン原子もしくはアルコキシ基が置換されていてもよいフェニル基、水酸基、アルコキシ基および複素環からなる群から選択される置換基が置換されていてもよいアルキル基（該アルキル基は鎖中にスルフィド結合を有していてもよい。）；−Ｘ^7b−Ｒ^31b（Ｘ^7bは単結合またはアルキレンである。Ｒ^31bは下記式、

で表わされる基である。）；アルケニル基；または置換基を有していてもよいフェニル基であり、Ｒ^29bおよびＲ^30bが隣接する窒素原子とともに下記一般式、

（式中、ｎ５およびｎ６はそれぞれ独立に０〜５の整数である。Ｗ^5bは−ＣＨ₂−、−Ｓ−、−Ｏ−または−ＮＲ^32b−（Ｒ^32bは置換基を有していてもよいアルキル基、フェニル基、複素環または−Ｃ（Ｏ）−ＯＲ^33b（Ｒ^33bはアルキル基である。）である。）であり、ｎ５およびｎ６が同時に０である場合を除く。）で表わされる環を形成していてもよく、該環は置換基を有していてもよい。また、該環は他の芳香環と縮合環を形成していてもよく、該縮合環は置換基が有していてもよい。）；−Ｃ（Ｏ）−ＮＨ−Ｘ^8b−ＮＲ^34bＲ^35b（Ｘ^8bは単結合またはアルキレンである。Ｒ^34bおよびＲ^35bはそれぞれ独立にアルキル基であり、Ｒ^34bおよびＲ^35bが隣接する窒素原子とともに下記一般式、

（式中、ｎ７およびｎ８はそれぞれ独立に０〜５の整数である。Ｗ^6bは−ＣＨ₂−または−Ｏ−であり、ｎ７およびｎ８が同時に０である場合を除く。）で表わされる環を形成していてもよい。）；−Ｏ−Ｃ（Ｏ）−ＮＲ^36bＲ^37b（Ｒ^36bおよびＲ^37bはそれぞれ独立に水素原子またはアルキル基であり、Ｒ^36bおよびＲ^37bが隣接する窒素原子とともに下記一般式、

（式中、ｎ９およびｎ１０はそれぞれ独立に０〜５の整数である。Ｗ^7bは−ＣＨ₂−、−Ｏ−または−ＮＲ^38b−（Ｒ^38bはアルキル基である。）であり、ｎ９およびｎ１０が同時に０である場合を除く。）で表わされる環を形成してもよく、また、該環は置換基を有していてもよい。）； −Ｃ（Ｏ）ＯＲ^39b（Ｒ^39bは、水素原子またはアルキル基である。）：または−Ｃ（Ｏ）−ＮＲ^40bＲ^41b（Ｒ^40bおよびＲ^41bはそれぞれ独立にアルキル基であり、Ｒ^40bおよびＲ^41bが隣接する窒素原子とともに下記一般式、

（式中、ｎ１１およびｎ１２はそれぞれ独立に０〜５の整数である。Ｒ^42bはフェニル基が置換されていてもよいアルキル基であり、ｎ１１およびｎ１２が同時に０である場合を除く。）で表わされる環を形成していてもよい。）である。 R ^2b , R ^3b and R ^4b are each independently a hydrogen atom; a cyano group; a halogen atom; a tetrazolyl group; —OR ^17b (where R ^17b is a hydrogen atom, an alkyl group,

It is a substituent represented by these. ); —O—X ^4b —NR ^18b R ^19b (X ^4b is alkylene. R ^18b and R ^19b are each independently an alkyl group, and R ^18b and R ^19b form a ring together with the adjacent nitrogen atom). -NR ^20b R ^21b (R ^20b and R ^21b are each independently an alkyl group which may be substituted with a phenyl group, a hydrogen atom, -C (O) R ^22b (R ^22b is a halogen atom) Is an optionally substituted alkyl group), —C (O) OR ^23b (R ^23b is a phenyl group optionally having a nitro group, an alkyl group, or a group represented by the following formula:

It is a substituent represented by these. ), -X ^5b -NR ^24b R ^25b (X ^5b is a single bond or alkylene. R ^24b and R ^25b are each independently an alkyl group, and R ^24b and R ^25b together with the adjacent nitrogen atom have the following general formula:

Wherein n1 and n2 are each independently an integer of 0 to 5. W ^3b is —CH ₂ — or —O—, except that n1 and n2 are 0 at the same time. May be formed. ), Or the following general formula:

(Wherein R ^26b is an alkyl group), and R ^20b and R ^21b together with the adjacent nitrogen atom have the following general formula:

(Wherein n3 and n4 are each independently an integer of 0 to 5. W ^4b is —CH ₂ — or —NR ^27b — (R ^27b is an alkyl group, which may have a substituent). Except that n1 and n2 are 0 at the same time.) May be formed, and the ring may have a substituent. ); —NR ^28b —C (O) —X ^6b —NR ^29b R ^30b (X ^6b is a single bond or alkylene. R ^28b is a hydrogen atom or an alkyl group. R ^29b and R ^30b are each independently hydrogen. An atom; a halogen atom or an alkoxy group which may be substituted; a substituent selected from the group consisting of a phenyl group, a hydroxyl group, an alkoxy group and a heterocyclic ring; an alkyl group which may be substituted (the alkyl group is in the chain) -X ^7b -R ^31b (X ^7b is a single bond or alkylene. R ^31b is represented by the following formula:

It is group represented by these. ); An alkenyl group; or an optionally substituted phenyl group, wherein R ^29b and R ^30b together with the adjacent nitrogen atom have the following general formula:

(Wherein, n5 and n6 is .W ^5b are each independently an integer of _{0~5 -CH 2 -, - S -} , - O- or -NR ^32b - (R ^32b is substituted And may be an alkyl group, a phenyl group, a heterocyclic ring, or —C (O) —OR ^33b (R ^33b is an alkyl group.), Except that n5 and n6 are 0 at the same time. The ring represented may be formed, and this ring may have a substituent. In addition, the ring may form a condensed ring with another aromatic ring, and the condensed ring may have a substituent. ); —C (O) —NH—X ^8b —NR ^34b R ^35b (X ^8b is a single bond or alkylene. R ^34b and R ^35b are each independently an alkyl group, and R ^34b and R ^35b are adjacent to each other). The following general formula together with the nitrogen atom:

(Wherein n7 and n8 are each independently an integer of 0 to 5. W ^6b is —CH ₂ — or —O—, except when n7 and n8 are 0 at the same time). May be formed. ); —O—C (O) —NR ^36b R ^37b (R ^36b and R ^37b are each independently a hydrogen atom or an alkyl group, and R ^36b and R ^37b together with the adjacent nitrogen atom have the following general formula:

Wherein n9 and n10 are each independently an integer of 0 to 5. W ^7b is —CH ₂ —, —O— or —NR ^38b — (R ^38b is an alkyl group), and n9 and except for the case where n10 is 0 at the same time.), and the ring may have a substituent. ); —C (O) OR ^39b (R ^39b is a hydrogen atom or an alkyl group): or —C (O) —NR ^40b R ^41b (R ^40b and R ^41b are each independently an alkyl group; R ^40b and R ^41b together with the adjacent nitrogen atom have the following general formula:

(Wherein, n11 and n12 are each independently an integer of 0 to 5 .R ^42b is an alkyl group which may be substituted is a phenyl group, excluded. Where n11 and n12 are 0 at the same time) in The ring represented may be formed. ).

R ^2b , R ^3b and R ^4b are each independently a hydrogen atom; a cyano group; a halogen atom; —OR ^17b (R ^17b is the same as described above); —NR ^20b R ^21b (R ^20b and R ^21b is the same as described above.); —NR ²⁸ —C (O) —X ^6b —NR ^29b R ^30b (X ^6b , R ^28b , R ^29b and R ^30b are the same as described above. ); -C (O) -NH-X ^<8b > -NR <^34b> R ^<35b> (X ^<8b> , R ^<34b> and R ^<35b> are the same as described above); -O-C (O) -NR <^36b> R ^<37b> (R ^36b and R ^37b are the same as described above); —C (O) OR ^39b (R ^39b is the same as described above): or —C (O) —NR ^40b R ^41b (R ^40b and R ^41b are the same as those described above).

Among them, R ^2b , R ^3b and R ^4b are each independently a hydrogen atom; —OR ^17b (R ^17b is the same as described above); —NR ^20b R ^21b (R ^20b and R ^21b are is the same as that ^{of); -.. NR 28b -C} (O) -X 6b -NR 29b R 30b (X 6b, R 28b, R 29b and R ^30b are the same as those described above) or; - More preferred is O—C (O) —NR ^36b R ^37b (where R ^36b and R ^37b are the same as those described above).

R ^5b is a hydrogen atom or an alkyl group, preferably a hydrogen atom.

で表わされる縮合環を形成してもよい。 R ^6b , R ^7b , R ^8b and R ^9b are each independently a hydrogen atom; —C (O) OR ^43b (R ^43b is an alkyl group); an alkyl group on which a hydroxyl group may be substituted; a nitro group A halogen atom; or an amino group, and R ^6b and R ^7b , R ^7b and R ^8b , or R ^8b and R ^9b , an adjacent benzene ring and the following formula:

You may form the condensed ring represented by these.

R ^6b , R ^7b , R ^8b and R ^9b are preferably each independently a hydrogen atom or a halogen atom.

  In the nitrogen-containing heterocyclic compound of the present invention, the pharmaceutically acceptable salt thereof is not particularly limited, and examples thereof include hydrochloride, sulfate, phosphate, nitrate, acetate, propionate, and succinate. , Glycolate, lactate, malate, oxalate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate and Examples include ascorbate. Hydrates and solvates may also be used.

（式中、Ｒ^1a、Ｒ^2a、Ｒ^3aおよびＲ^4aは上記のものと同じである）で表わされる７−アザインドール誘導体またはその前駆体と、下記一般式（ＩＩＩ−Ａ）、

（式中、Ｒ^5a、Ｒ^6a、Ｒ^7a、Ｒ^8aおよびＲ^9aは上記のものと同じである）で表わされるキノキサロン誘導体またはその前駆体と、を反応させる工程を含む。 The method for synthesizing the nitrogen-containing heterocyclic compound (IA) of the present invention is not particularly limited, and can be synthesized by combining known reactions, but is preferably synthesized by the production method of the present invention. It is advantageous in terms of reaction conditions and yield. In producing the nitrogen-containing heterocyclic compound (IA) or the pharmaceutically acceptable salt thereof according to the invention, the production method of the invention comprises the following general formula (II-A),

(Wherein R ^1a , R ^2a , R ^3a, and R ^4a are the same as those described above), a 7-azaindole derivative represented by the following formula (III-A),

(Wherein, R ^5a , R ^6a , R ^7a , R ^8a and R ^9a are the same as those described above) and a step of reacting them with a precursor thereof.

  This reaction is preferably performed in the presence of a Bronsted acid, and acetic acid or trifluoroacetic acid can be suitably used as the Bronsted acid.

Hereinafter, the synthesis method of the nitrogen-containing heterocyclic compound (IA) will be described in detail. For example, the nitrogen-containing heterocyclic compound of the present invention can be synthesized according to the following reaction formula (see “Schaefer, JP; Corey, EJ; J Org Chem. 1959, 24, 1825”).

  The methyl ester derivative (A-3) can be easily synthesized by reacting 7-azaindole (A-1) with bromoacetyl bromide and oxidizing with zerin dioxide. Subsequently, NH of the 7-azaindole moiety is protected with a substituent to obtain an α-ketocarboxylic acid compound (A-4). Compound (A-6) can be synthesized by reacting the obtained α-ketocarboxylic acid compound (A-4) with a dianiline derivative (A-5). The above compound (A-6) is introduced into the raw material or intermediate product by introducing the same substituent as that of the target compound or by introducing a leaving group such as a halogen atom, and the elimination reaction and substitution are appropriately performed. A compound having a desired substituent can be obtained by utilizing a group exchange reaction (see “Marie-Claude Viaud et al., HETEROCYCLES, Vol. 50, No.2.1999, 1065-1080”).

Examples of the reaction conditions for the α-ketocarboxylic acid compound (A-4) and the dianiline derivative (A-5) include the following.
The target compound can be synthesized by dissolving the α-ketocarboxylic acid compound (A-4) and the dianiline derivative (A-5) in a mixed solvent of ethanol and hydrochloric acid, adding 2-mercaptoethanol and heating ( Synthesis method A). The target compound can also be synthesized by suspending the α-ketocarboxylic acid compound (A-4) and the dianiline derivative (A-5) in sulfuric acid and heating to reflux (Synthesis Method B).

  In the reaction of the α-ketocarboxylic acid compound (A-4) and the dianiline derivative (A-5), when the dianiline derivative (A-5) has a substituent, the product is obtained as a mixture of regioisomers, Since the separation is difficult, the synthesis method is preferably used only when the dianiline derivative (A-5) is unsubstituted or has a substituent symmetrically.

The nitrogen-containing heterocyclic compound of the present invention can also be synthesized according to the following reaction formula. The following reaction is an example of the production method of the present invention.

  The desired compound (A-9) is obtained by direct coupling of 7-azaindole derivative (A-7) and quinoxalin-2 (1H) -one (A-8) with acetic acid or trifluoroacetic acid. Obtainable. The target compound (A-9) has no substituent, but the 7-azaindole derivative (A-7) and / or quinoxalin-2 (1H) -one (A-8) A compound having a desired substituent can be obtained by introducing a similar substituent or by introducing a leaving group such as a halogen atom and appropriately utilizing a leaving reaction and a substituent exchange reaction. . By using this synthesis method, the target compound can be obtained without becoming a mixture of regioisomers.

  In the above reaction, for example, a 7-azaindole derivative (A-7) and quinoxalin-2 (1H) -one (A-8) are dissolved in acetic acid or trifluoroacetic acid and heated to reflux to obtain the target. Compound (A-9) can be synthesized (Synthesis Method C).

The method for synthesizing the nitrogen-containing heterocyclic compound (IB) of the present invention is not particularly limited, and can be synthesized by combining known reactions. For example, it can be synthesized according to the following reaction formula.

  The 3-position of 7-azaindole (B-1) is iodinated to obtain compound (B-2). After protecting NH of the 7-azaindole moiety with a methyl group or the like to obtain compound (B-3), compound (B-5) can be obtained by coupling with compound (B-4). it can. The nitrogen-containing heterocyclic compound (B-6) which is the target compound can be obtained by refluxing it in an acetic acid solvent. The target compound (B-6) does not have a substituent. However, by introducing the same substituent as the target compound into the raw material or intermediate product, or a leaving group such as a halogen atom is introduced. As appropriate, a compound having a desired substituent can be obtained by utilizing elimination reaction and substituent exchange reaction. By using this synthesis method, the target compound can be obtained without becoming a mixture of regioisomers.

  The pharmaceutical composition of the present invention comprises the above-mentioned nitrogen-containing heterocyclic compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition of the present invention is suitable as a VEGF inhibitor, and is useful as a therapeutic agent for diabetic nephropathy, an anticancer agent, an angiogenesis inhibitor or the like.

  The form of the pharmaceutical composition of the present invention is not particularly limited, and can be appropriately selected as necessary. For example, oral preparations such as tablets, capsules, granules, fine granules, powders or liquids, or parenteral preparations such as injections, external preparations, or suppositories can be mentioned. Can do.

  When the pharmaceutical composition of the present invention is used as a therapeutic agent for diabetic nephropathy, an anticancer agent, an angiogenesis inhibitor or the like, it varies depending on the age, sex, weight or degree of disease of the patient, but usually for adults. It is administered once to several times a day in the range of 1 mg to 1 g per day.

合成法Ａ：適宜、置換基を導入したα−ケトカルボン酸化合物(0.8mmol)およびジアニリン誘導体(1.6mmol)をエタノール(10mL)および2mol/L HCl(9.2mL)の混合溶媒に溶解させ、２−メルカプトエタノール(0.84mL)を加え、100℃で、数時間還流した。反応液に飽和炭酸水素ナトリウム水溶液および酢酸エチルを加えて抽出し、有機層を飽和食塩水にて洗浄、無水硫酸マグネシウムにて乾燥後、溶媒を減圧濃縮した。得られた残渣をシリカゲルカラムで精製(CH₂Cl₂:MeOH=20:1)することにより、目的化合物を得た。 In synthesizing the nitrogen-containing heterocyclic compound of the present invention, the following synthesis methods A to C were appropriately used.

Synthesis method A: The α-ketocarboxylic acid compound (0.8 mmol) and the dianiline derivative (1.6 mmol) into which substituents are introduced are appropriately dissolved in a mixed solvent of ethanol (10 mL) and 2 mol / L HCl (9.2 mL). Mercaptoethanol (0.84 mL) was added, and the mixture was refluxed at 100 ° C. for several hours. The reaction solution was extracted with a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified with a silica gel column (CH ₂ Cl ₂ : MeOH = 20: 1) to obtain the target compound.

Synthesis method B: The α-ketocarboxylic acid compound (0.8 mmol) into which the substituent was introduced and the dianiline derivative (1.6 mmol) were appropriately suspended in 2 mol / L concentrated sulfuric acid (6 mL) and refluxed at 120 ° C. for several hours. After returning to room temperature after the reaction, the precipitate was collected by filtration and washed with water. The target compound was obtained by drying under reduced pressure. Purification was performed by the same procedure as in Synthesis Method A.

合成法Ｃ：７−アザインドール誘導体（0.163mmol)を酢酸(2mL)に溶解させ、キノキサリン−２（１Ｈ）−オン誘導体(1.02当量)を加え、140℃で攪拌還流した。反応後、室温に戻し、炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、減圧濃縮することにより、目的化合物を得た。精製は、合成法Ａと同様の手順により行った。

Synthesis method C: 7-azaindole derivative (0.163 mmol) was dissolved in acetic acid (2 mL), quinoxalin-2 (1H) -one derivative (1.02 equivalent) was added, and the mixture was stirred and refluxed at 140 ° C. After the reaction, the temperature was returned to room temperature, an aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the target compound. Purification was performed by the same procedure as in Synthesis Method A.

Synthesis of Intermediate A The target compound was synthesized according to the following reaction formula.

Under an argon atmosphere, 5-bromo-7-azaindole (3.86 g, 19.7 mmol) was dissolved in CS ₂ (138 mL), AlCl ₃ (33 g) was added to 50 ° C., and bromoacetyl bromide (2.05 mL, 23.6 mmol) was added. ) Was slowly added dropwise, and the mixture was further stirred for 1 hour. The reaction mixture was cooled under ice-cooling, water (about 150 mL) was slowly added, and the mixture was stirred for 2 hr. The precipitate was collected by filtration, washed with water, and dried under reduced pressure. The target product was obtained as a light brown solid (6.47 g, quantitative).
¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 4.71 (s, 2H), 8.45 (d, 1H, J = 2.2 Hz), 8.56 (d, 1H, J = 2.2 Hz), 8.70 (d, 1H , J = 3.2Hz), 12.9 (s, 1H).

Synthesis of Intermediate B The target compound was synthesized according to the following reaction formula.

Under an argon atmosphere, Intermediate A (6.26 g, 19.7 mmol) was dissolved in a mixed solvent of methanol (150 mL) and DMSO (50 mL), SeO ₂ (3.28 g, 30 mmol) was added, and the mixture was stirred and refluxed for 48 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate.The extract was concentrated under reduced pressure, and the residue was purified on a silica gel column (ethyl acetate: hexane = 2: 1) to give the desired product as a colorless oil (crude product). 6.45g as a product).
¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 3.91 (s, 3H), 8.49 (d, 1H, J = 2.1 Hz), 8.57 (d, 1H, J = 2.1 Hz), 8.66 (d, 1H , J = 2.9Hz), 13.2 (s, 1H).

Synthesis of Intermediate C The target compound was synthesized according to the following reaction formula.

Under an argon atmosphere, Intermediate B (2.45 g, 8.7 mmol) was dissolved in DMF (66 mL), and NaH (1.18 g, 13.1 mmol) was added under ice cooling, followed by stirring for 0.5 hour. Iodomethane (1.84 mL, 13.1 mmol) was added, and the mixture was further stirred for 0.5 hour. After the reaction, water was added and the mixture was extracted with ethyl acetate.The extract was concentrated under reduced pressure, and the residue was purified with a silica gel column (ethyl acetate: hexane = 1: 1) to obtain the desired product (2.04 g, 2 steps 79%).
¹ H-NMR (CDCl ₃ , 200 MHz) δ: 3.95 (s, 3H), 3.97 (s, 3H), 8.46 (d, 1H, J = 2.2 Hz), 8.52 (s, 1H), 8.81 (d, 1H , J = 2.2Hz).

Synthesis of Compound 1 The target compound was synthesized according to the following reaction formula.

  Compound 1 was synthesized by “Synthesis Method B” (yield 68%).

Synthesis of Compound 2 The target compound was synthesized according to the following reaction formula.

Under an argon atmosphere, Compound 1 (355 mg, 1 mmol) was dissolved in anhydrous DMF (10 mL), CuI (190.5 mg, 1 mmol) and NaOCH ₃ (28% in CH ₃ OH, 20 mL) were added, and the mixture was refluxed for 2 hours. After the reaction, ethyl acetate and water were added for extraction, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to obtain the desired product (250 mg, yield 83%).

Synthesis of Compound 3 The target compound was synthesized according to the following reaction formula.

Under argon atmosphere, compound 1 (21 mg, 0.06 mmol) and Zn (CN) ₂ (58 mg) were dissolved in DMF (1 mL), tetrakis (triphenylphosphine) palladium (0) (28 mg) was added, and the mixture was kept at 130 ° C. overnight. Stir. After the reaction, the temperature was returned to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to obtain the desired product (13.9 mg, yield 78%).

Synthesis of Compound 4 The target compound was synthesized according to the following reaction formula.

Compound 1 (88 mg, 0.25 mmol) and CuSO ₄ · 5H ₂ O (101 mg) are dissolved in a mixed solvent of DMF (4 mL) and NH ₃ —H ₂ O (28%, 4 mL), and then autoclaved at 130 ° C. overnight. Reacted. After the reaction, the temperature was returned to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to obtain the desired product (59 mg, yield 80%).

Synthesis of Compound 5 The target compound was synthesized according to the following reaction formula.

Compound 2 (31 mg, 0.1 mmol) was dissolved in a mixed solvent of acetic acid (1 mL) and hydrogen bromide (47%, 1 mL) and refluxed for 6 hours. After the reaction, the temperature was returned to room temperature, H ₂ O was added, and the precipitate was collected by filtration to obtain the desired product (23.2 mg, yield 79%).

Synthesis of Compound 6 The target compound was synthesized according to the following reaction formula.

Under an argon atmosphere, Compound 4 (15 mg, 0.052 mmol) was dissolved in THF (2 mL), ethyl isocyanate (3 drops) and Et ₃ N (3 drops) were added, and the mixture was reacted at room temperature for 24 hours. After the reaction, H ₂ O was added and the precipitate was collected by filtration to obtain the desired product (22.7 mg, quantitative).

Synthesis of Compound 7 The target compound was synthesized according to the following reaction formula.

Compound 4 (10 mg) was dissolved in THF (1 mL), NaHCO ₃ (20 mg) and acetyl chloride (3 drops) were added, and the mixture was reacted at room temperature overnight. After the reaction, H ₂ O was added and the precipitate was collected by filtration to obtain the desired product (5.4 mg, yield 32%).

Synthesis of Compound 8 The target compound was synthesized according to the following reaction formula.

  Compound 8 was synthesized by the same synthesis method as Compound 7 (79%).

Synthesis of Compound 9 The target compound was synthesized according to the following reaction formula.

  Compound 9 was synthesized by the same synthesis method as Compound 7 (78%).

Synthesis of Compound 10 The target compound was synthesized according to the following reaction formula.

  Compound 9 (20 mg) was dissolved in DMF (1 mL), p-fluorobenzylamine (50 mg) and sodium bicarbonate (40 mg) were added, and the mixture was reacted at 80 ° C. for 5 hours. After the reaction, water was added and the precipitate was collected by filtration to obtain the desired product (12.7 mg, 57%).

Synthesis of Compound 11 The target compound was synthesized according to the following reaction formula.

Compound 5 (292 mg, 1 mmol) and potassium carbonate (276 mg) are dissolved in a mixed solvent of DMF (10 mL) and ethanol (20 mL), and potassium iodide (16 mg) and 1- (2-chloroethyl) piperidine (92 mg) are added. The mixture was stirred at 100 ° C. for 1 hour. The reaction solution was extracted with ethyl acetate and water, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column (CH ₂ Cl ₂ : MeOH = 30: 1) to obtain the desired product (63.1 mg, yield 16%).

Synthesis of Compound 12 The target compound was synthesized according to the following reaction formula.

  Compound 12 was synthesized by the same synthesis method as Compound 2 (11%).

Synthesis of Intermediate D The target compound was synthesized according to the following reaction formula.

Intermediate D was synthesized by the same synthesis method as Intermediate C (yield 88%).
¹ H-NMR (CDCl ₃ , 200 MHz) δ: 3.80 (s, 3H), 6.31 (d, 1H, J = 3.4 Hz), 7.11 (d, 1H, J = 3.4 Hz), 7.94 (d, 1H, J = 2.1Hz), 8.27 (d, 1H, J = 2.1Hz.)

Synthesis of Intermediate F The target compound was synthesized according to the following reaction formula.

Intermediate E was synthesized by the same synthesis method as Compound 2 (yield 95%). Intermediate F was synthesized by the same synthesis method as Compound 5 (yield 87%).
Intermediate F
¹ H-NMR (CDCl ₃ , 200 MHz) δ: 6.33 (d, 1H, J = 3.4 Hz), 6.80 (bro, 1H), 7.14 (d, 1H, J = 3.4 Hz), 7.44 (d, 1H, J = 2.6Hz), 8.10 (d, 1H, J = 2.6Hz).

Synthesis of Intermediate G The target compound was synthesized according to the following reaction formula.

Under an argon atmosphere, Intermediate F (148 mg, 1 mmol) was dissolved in ethyl acetate (5.0 mL), pyridine (0.165 mL, 2.05 eq) and chloroformic acid 4-nitrophenyl ester (212 mg, 1.05 eq) were added, and at room temperature. The reaction was performed for 0.5 hour. 3- (Dimethylamino) pyridine (0.14 mL, 1.2 equivalents) was added, and the mixture was further reacted at 60 ° C. for 7 hours. After the reaction, the temperature was returned to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column (ethyl acetate: hexane = 1: 2) to obtain the desired product (268 mg, 93%).
¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 1.74 to 2.20 (m, 3H), 2.30 (s, 3H), 2.32 (s, 3H), 2.65 to 2.92 (m, 1H), 3.20 to 3.92 ( m, 3H), 3.90 (s, 3H), 6.41 (d, 1H, J = 3.5Hz), 7.19 (d, 1H, J = 3.5Hz), 7.68 (d, 1H, J = 2.5Hz), 8.15 ( s, 1H).

Synthesis of Compound 13 The target compound was synthesized according to the following reaction formula.

Compound 13 was synthesized according to the following procedure according to “Synthesis Method C”.
Intermediate G (47 mg, 0.163 mmol) was dissolved in acetic acid (2 mL), 2-hydroxyquinoxaline (24 mg, 1.02 equivalent) was added, and the mixture was stirred and refluxed at 140 ° C. for 30 hr. After the reaction, the temperature was returned to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane: methanol = 10: 1) to obtain the desired product (20.4 mg, 29%).

Synthesis of Intermediate H The target compound was synthesized according to the following reaction formula.

Intermediate H was synthesized by the same synthesis method as Compound 3 (918 mg, 67%).
¹ H-NMR (CDCl ₃ , 200 MHz) δ: 3.96 (s, 3H), 6.56 (d, 1H, J = 3.6 Hz), 7.32 (d, 1H, J = 3.6 Hz), 8.18 (d, 1H, J = 1.9Hz), 8.57 (d, 1H, J = 1.9Hz).

Synthesis of Intermediate I The target compound was synthesized according to the following reaction formula.

Intermediate H (732 mg, 4.66 mmol) was dissolved in a mixed solvent of isopropanol (20 mL) and water (20 mL), potassium hydroxide (2.0 g) was added, and the mixture was refluxed at 130 ° C. overnight. After the reaction, the temperature was returned to room temperature, acetic acid (6 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the desired product (889 mg, quantitative). .
¹ H-NMR (CDCl ₃ , 200 MHz) δ: 2.07 (s, 3H), 3.95 (s, 3H), 6.59 (d, 1H, J = 3.4 Hz), 7.27 (d, 1H, J = 3.4 Hz), 7.24 (d, 1H, J = 1.3Hz), 7.93 (d, 1H, J = 1.3Hz), 9.10 (s, 3H).

Synthesis of Intermediate J The target compound was synthesized according to the following reaction formula.

Intermediate I (516 mg, 2.71 mmol) was dissolved in methanol (25 mL), concentrated sulfuric acid (0.5 mL) was added, and the mixture was refluxed for 8 hours. After the reaction, the temperature was returned to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to obtain the desired product (471 mg, 85%).
¹ H-NMR (CDCl ₃ , 200 MHz) δ: 3.93 (s, 3H), 3.96 (s, 3H), 6.55 (d, 1H, J = 3.5 Hz), 7.24 (d, 1H, J = 3.5 Hz), 8.57 (d, 1H, J = 1.9Hz), 9.00 (d, 1H, J = 1.9Hz).

Synthesis of Compound 14 The target compound was synthesized according to the following reaction formula.

  Compound 14 was synthesized by “Synthesis Method C” (yield 74%).

Synthesis of Compound 15 The target compound was synthesized according to the following reaction formula.

  Compound 14 (227 mg, 0.68 mmol) was dissolved in DMF (4 mL), water (2 mL) and sodium hydroxide (200 mg) were added, and the mixture was stirred at 60 ° C. for 2 hr. After the reaction, the temperature was returned to room temperature, the pH of the reaction solution was adjusted to 3-4 with 2N hydrochloric acid, and the precipitated solid was collected by filtration. The solid collected by filtration was washed with water and dried under reduced pressure to obtain the desired product (167 mg, yield 76%).

Synthesis of Compound 16 and Compound 17 The target compound was synthesized according to the following reaction formula.

  Under an argon atmosphere, Compound 15 (82 mg, 0.26 mmol) and 1,1′-carbonylbis-1H-imidazole (64 mg, 1.5 equivalents) were dissolved in DMF (5 mL) and stirred at room temperature for 2 hours. 1- (2-Aminoethyl) piperidine (0.1 mL) or N- (2-aminoethyl) morpholine (0.1 mL) was added, and the mixture was further reacted at 60 ° C. for 16 hours. After the reaction, the temperature was returned to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified with a silica gel column (dichloromethane: methanol = 10: 1 → 2: 1) to give compound 16 (31.4 mg, 28%) or compound 17 (28.8 mg, 26%).

Synthesis of Intermediate K and Intermediate L The target compound was synthesized according to the following reaction formula.

Under an argon atmosphere, 5-bromo-7-azaindole (5.0 g, 25.5 mmol) was dissolved in chloroform (210 mL), N-iodosuccinimide (5.9 g, 26 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour. I let you. After the reaction, an aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude intermediate K was dissolved in DMF (67 mL) under an argon atmosphere, sodium hydride (1.22 g, 30.6 mmol) was added under ice cooling, and the mixture was stirred for 0.5 hr. Subsequently, methyl iodide (67 mL) was added, and the mixture was further stirred for 0.5 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain Intermediate L (7.53 g, 88%).
¹ H-NMR (CDCl ₃ , 200 MHz) δ: 3.88 (s, 1H), 7.29 (s, 1H), 7.84 (d, 1H, J = 2.2 Hz), 8.35 (d, 1H, J = 2.2 Hz).

Synthesis of Compound 18 The target compound was synthesized according to the following reaction formula.

Under an argon atmosphere, intermediate L (270 mg, 0.8 mmol) and 2-chloroquinoline-3-boronic acid (183 mg, 0.88 mmol) were dissolved in degassed THF (2% water, 20 mL) and Ag ₂ O (222 mg , 0.96 mmol) and tetrakis (triphosphine) palladium (92 mg, 0.08 mmol) were added, and the mixture was stirred at room temperature for 4 hours. After the reaction, ethyl acetate was added and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column purification with silica gel (ethyl acetate: hexane = 1: 1) to obtain Intermediate M (202 mg, 68%).

  Intermediate M (200 mg, 1.06 mmol) was dissolved in a mixed solvent of acetic acid (3 mL) and water (3 mL) and refluxed for 16 hours. Water was added to the reaction solution to cause precipitation, followed by filtration, washing with a small amount of water, and drying to obtain Compound 18 (178 mg, 94% yield).

Synthesis of Compound 19 The target compound was synthesized according to the following reaction formula.

  Compound 19 was synthesized by the same synthesis method as Compound 2 (yield 79%).

Synthesis of Compound 20 The target compound was synthesized according to the following reaction formula.

  Compound 20 was synthesized by the same synthesis method as Compound 5.

Synthesis of Compound 21 The target compound was synthesized according to the following reaction formula.

  Compound 21 was synthesized by the same synthesis method as compound 3 (yield 71%).

Synthesis of Compound 22 The target compound was synthesized according to the following reaction formula.

  Compound 22 was synthesized by the same synthesis method as for compound 18 (yield 58%).

Synthesis of Compound 23 The target compound was synthesized according to the following reaction formula.

  Compound 23 was synthesized by the same synthesis method as for compound 4 (yield 57%).

Synthesis of Compound 24 The target compound was synthesized according to the following reaction formula.

  Compound 24 was synthesized by the same synthesis method as for compound 7 (yield 80%).

Synthesis of Compound 25 The target compound was synthesized according to the following reaction formula.

  Compound 25 was synthesized by the same synthesis method as Compound 7 (yield 85%).

Synthesis of Compound 26 The target compound was synthesized according to the following reaction formula.

  Compound 26 was synthesized by the same synthesis method as for compound 7 (yield 80%).

Synthesis of Compound 27 The target compound was synthesized according to the following reaction formula.

  Compound 27 was synthesized by the same synthesis method as Compound 6 (yield 83%).

Synthesis of Compound 28 The target compound was synthesized according to the following reaction formula.

  Compound 28 was synthesized by the same synthesis method as Compound 10 (yield 85%).

Synthesis of Intermediate N The target compound was synthesized according to the following reaction formula.

Intermediate N was synthesized by the same synthesis method as Intermediate K (yield 86%).
1H-NMR (CDCl ₃ , 200 MHz) δ: 3.93 (s, 3H), 3.98 (s, 3H), 7.36 (s, 1H), 8.37 (d, 1H, J = 1.9Hz), 8.99 (d, 1H, J = 1.9Hz).

Synthesis of Compound 29 The target compound was synthesized according to the following reaction formula.

  Compound 29 was synthesized by the same synthesis method as compound 18 (yield 88%).

Synthesis of Compound 30 The target compound was synthesized according to the following reaction formula.

  Compound 30 was synthesized by the same synthesis method as compound 15 (quantitative yield).

Synthesis of Compound 31 and Compound 32 The target compound was synthesized according to the following reaction formula.

  Compound 31 and compound 32 were synthesized by the same synthesis method as compound 16 and compound 17.

Synthesis of Compound 33 The target compound was synthesized according to the following reaction formula.

  Compound 20 (50 mg, 0.17 mmol) was dissolved in DMSO (1.0 mL), sodium hydride (60%, 14 mg) was added, and the mixture was stirred at room temperature for 1 hr. 4-Methylpiperazine carbonyl chloride (0.05 mL) was added and reacted at room temperature overnight. After the reaction, water was added, and the mixture was collected by filtration and dried to obtain 296 mg of the desired product (yield 41%).

Synthesis of Compound 34 The target compound was synthesized according to the following reaction formula.

  Compound 34 was synthesized by the same synthesis method as Compound 4 (yield 93%).

Synthesis of Compound 35 The target compound was synthesized according to the following reaction formula.

  Compound 34 (206 mg, 0.86 mmol) was dissolved in THF (60 mL), sodium bicarbonate (171 mg, 3 eq) and chloroformic acid 4-nitrophenyl ester (273 mg, 2.0 eq) were added, and the mixture was stirred at room temperature for 3 days. After the reaction, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to obtain the desired product (293 mg, 92%).

Synthesis of Compound 36 and Compound 37 The target compound was synthesized according to the following reaction formula.

  Compound 35 (75 mg, 0.16 mmol) was dissolved in a mixed solvent of THF (10 mL) and DMF (4 mL), and 1- (2-aminoethyl) piperidine (0.1 mL) or 1- (2-aminoethyl) morpholine ( 0.1 mL) was added, and the mixture was reacted at 60 ° C. overnight. After the reaction, the temperature was returned to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized with a mixed solution of ethyl acetate-hexane to obtain Compound 36 (42 mg, 57%) or Compound 37 (28.6 mg, 39%).

Synthesis of Compound 38 The target compound was synthesized according to the following reaction formula.

  Compound 38 was synthesized by “Synthesis Method C” (yield 92%).

Synthesis of Compound 39 The target compound was synthesized according to the following reaction formula.

  Compound 39 was synthesized by the same synthesis method as for compound 4 (yield 52%).

Synthesis of Compound 40 and Compound 41 The target compound was synthesized according to the following reaction formula.

  To a suspension of compound 39 (150 mg, 0.5 mmol) and triphosgene (160 mg, 0.55 mmol) in tetrahydrofuran (10 mL) was added n-propylamine (0.2 mL, 2.5 mmol) and triethylamine (0.1 mL), and 50 ° C. For 15 hours. Ethanol and water were added to the reaction mixture, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain Compound 40 (yield 16%). Similarly, compound 41 was obtained using cyclopentanol.

Synthesis of Intermediate O The target compound was synthesized according to the following reaction formula.

  16 mL of an acetone solution of 7-azaindole 1.0 g (8.5 mmol) was cooled to 0 ° C. and 3.9 g (17 mmol) of m-chloroperbenzoic acid was added. After stirring for 2 hours, the precipitated solid was collected by filtration and dried under reduced pressure. It was. 18 mL of water was added to 1.8 g of this solid, and a pH 9 alkaline solution was further formed with saturated potassium carbonate. The alkaline solution was cooled to 0 ° C., and the precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain the desired product as a white solid (0.53 g, yield 46%).

Synthesis of Intermediate P The target compound was synthesized according to the following reaction formula.

  Add 1,1,1,3,3,3-hexamethyldisilazane (HMDS) 7 mL (33 mmol) to 200 mL of a solution of intermediate O (4.02 g, 30 mmol) in tetrahydrofuran at room temperature, and keep the internal temperature at 30 degrees. Then, 8.8 mL (75 mmol) of benzoyl chloride was added dropwise over 30 minutes, followed by stirring for 4 hours. Ice was added to the reaction mixture, and the mixture was made alkaline with saturated sodium hydrogen carbonate, extracted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. 15 mL of ethanol was added to the concentrate, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 4.3 g of a white solid. The solid obtained without purification was dissolved in 300 mL of methanol, 160 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred overnight. The methanol solution was concentrated to half volume under reduced pressure, poured into ice water, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the desired product as a white powder (2.2 g, yield 48%). .

Synthesis of Intermediate Q The target compound was synthesized according to the following reaction formula.

  Intermediate P (0.50 g, 3.3 mmol) was dissolved in 10 mL of dimethylaldehyde, 0.18 g (4.3 mmol) of sodium hydride was added at 0 degree, and the mixture was stirred for 30 minutes. Dimethyl sulfate (0.40 mL, 4.3 mmol) was added to this mixed solution at 0 ° C., and the mixture was further stirred for 3 hours, poured into ice water, extracted with ethyl acetate, washed with water, dried, and then the solvent was distilled off under reduced pressure. The concentrate was purified by column chromatography (eluent, ethyl acetate-hexane = 1: 10) to obtain the desired product (560 mg, quantitative).

Synthesis of Intermediate R The target compound was synthesized according to the following reaction formula.

Under an argon atmosphere, Intermediate Q (0.56 g, 3.3 mmol), R-(+)-2,2′-bis (diphenylphosphine) -1,1′-binaphthyl (BINAP) 50 mg (0.08 mmol) and Tris ( Dibenzylideneacetone) -dipalladium (0) -chloroform adduct (Pd ₂ (dba) ₃ ) 30 mg (0.029 mmol) in toluene 25 mL suspension, 1- (2-aminoethyl) piperidine 0.6 mL (4.2 mmol) Sodium (t) -butoxide 0.5 g (5.0 mol) was added, and the mixture was stirred at 80 ° C. overnight. The suspension was returned to room temperature, filtered using Celite, and the filtrate was concentrated. The concentrate was purified by column chromatography (eluent, chloroform-methanol = 30: 1) to obtain the desired product as a brown oil (730 mg, 86%).

Synthesis of Compound 42 The target compound was synthesized according to the following reaction formula.

  To a suspension of Intermediate R (300 mg, 1.16 mmol) and 2-hydroxyquinoxaline 130 mg (0.9 mmol) in 1,2-dichloroethane (5 mL) was added 0.5 mL of trifluoroacetic acid and stirred at 80 ° C. overnight. The reaction mixture was returned to room temperature and diluted with water and methanol. Further, after weak alkalinity with saturated sodium hydrogen carbonate, the precipitated solid was collected by filtration and washed again with ether to obtain a reddish orange target product (150 mg, yield 32%).

  The structural formulas, compound names, and NMR data of the nitrogen-containing heterocyclic compounds of the present invention synthesized in the above synthesis examples and the compounds synthesized according to them are shown in Tables 1 to 33 below.

(1) VEGF-induced renal glomerular endothelial cell growth inhibition test After suspending human renal glomerular endothelial cells in D-MEM / F-12 medium (10% fetal bovine serum, 100 U / mL penicillin, 100 μg / mL streptomycin) Inoculated on a type I collagen-coated 96-well culture plate at a concentration of 4 × 10 ³ cells / well and left overnight. Immediately before the test, the medium in each well was removed, washed with Hanks' solution, and a new medium was added. Next, DMSO (final concentration 0.1%) as a solvent was added to unstimulated and stimulated control wells, and test substances (final concentration 0.001 to 10 μmol / L) were added to the other wells, followed by incubation for 1 hour. Subsequently, recombinant human VEGF (final concentration 10 ng / mL) was added and cultured for 48 hours. After removing the medium and washing each well with Hanks' solution, fresh medium was added. A viable cell count reagent (WST-8) was added and further cultured for 4 to 5 hours. Thereafter, the absorbance (450-630 nm) was measured with a microplate reader. The growth inhibition rate was calculated from the absorbance of each well by the following formula.
Growth inhibition rate (%) = {1− (A−C) / (B−C)} × 100
In the above formula, A is the absorbance of the sample addition well, B is the absorbance of the control well, and C is the absorbance of the unstimulated well. The test substance concentration at which the growth inhibition rate was 50% relative to the control was defined as IC _50, which was used as an activity index. The results are shown in Tables 34 and 35 below.

(2) Cytotoxicity test In the above-mentioned method, the influence of a test substance on living cells under no VEGF stimulation was examined and determined as cytotoxicity. The test substance concentration at which the number of viable cells decreased by 50% relative to the control was defined as CC _50, which was used as a toxicity index. The results are shown in Tables 34 and 35 below.

The following pharmacological tests were further performed using the synthesized compounds.
(3) Rat dorsal skin VEGF-induced vascular permeability inhibition test Six-week-old male wistar rats were used for the test. A few hours before the test, the hair on the back of the rat was shaved, and then the solvent (0.5% sodium carboxymethylcellulose solution) and the test substance (25 mg / kg) were orally administered using a rat sonde. Two hours later, under ether anesthesia, raw food was given to two places on the back and recombinant rat VEGF (final concentration: 200 ng / mL) was given intradermally to four places at a dose of 0.1 mL / site. Immediately thereafter, 0.5 mL of 0.5% Evans blue solution was administered via the tail vein. Thirty minutes later, the rats were exsanguinated under ether anesthesia, and the dorsal skin in the range including all the pigment leakage sites was excised. After cutting the cut skin with scissors, it was immersed in 2 mL of formamide per piece of skin and left at 55 ° C. for about 48 hours to extract Evans blue. After completion of the extraction operation, the mixture was centrifuged at 3000 rpm for 15 minutes to precipitate the skin pieces and suspended matter, and the absorbance was measured at a wavelength of 620 nm using the supernatant as a sample. The amount of dye leakage (μg / site) was calculated by preparing a calibration curve from the absorbance of Evans blue at a known concentration and measuring the amount of Evans Blue in the extract. The inhibition rate of the Evans blue amount relative to the test substance non-administered group was calculated and used as an index of drug efficacy. Table 36 below shows the results obtained.

(4) A 7-week-old male db / db mouse was used in the drug efficacy evaluation test using the effect on the amount of urinary albumin in the spontaneous type II diabetes model db / db mouse as an index. Grouping was performed using the amount of urinary albumin measured by ELISA as an index. The test article was suspended in a 0.5% sodium carboxymethylcellulose solution at a dose of 25 mg / kg, and was forcibly orally administered twice a day using a mouse sonde for 4 weeks. The urinary albumin amount was measured at 2 and 4 weeks, and the inhibition rate of the urinary albumin amount relative to the test substance non-administered group was calculated and used as an index of drug efficacy. The results obtained in Table 36 below are also shown.

Claims (22)

The following general formula (IA),

[Wherein, R ^1a is a hydrogen atom; an alkyl group which may be substituted with a substituent selected from the group consisting of a phenyl group, an alkoxy group, a hydroxyl group and a halogen atom, which may be substituted with a halogen atom; ^{1a -C (O) oR 10a (} X 1a is a single bond or alkylene, R ^10a is a hydrogen atom or an alkyl ^{group); - X 2a -C (O} ) NR 11a R 12a (X 2a is a single bond or alkylene, R ^11a and R ^12a are each independently a hydrogen atom or an alkyl group, and R ^11a and R ^12a together with the adjacent nitrogen atom have the following general formula:

(Wherein W ^1a may be —CH ₂ — or —O—) may be formed); —SO ₂ —R ^13a (R ^13a is a phenyl group); —X ^3a —NR ^14a R ^15a (X ^3a is alkylene, R ^14a and R ^15a are each independently an alkyl group, and R ^14a and R ^15a together with the adjacent nitrogen atom are represented by the following general formula:

(Wherein W ^2a may form a ring represented by —CH ₂ —, —NR ^16a — (R ^16a is an alkyl group) or —O—)),
R ^2a , R ^3a and R ^4a are each independently a hydrogen atom; a cyano group; a halogen atom; a tetrazolyl group; —OR ^17a (R ^17a is a hydrogen atom, an alkyl group,

-O-X < ^4a > -NR <^18a> R ^<19a> (X ^<4a> is alkylene, R ^<18a> and R ^<19a> are each independently an alkyl group, and R ^<18a> and R ^<19a> together with the adjacent nitrogen atom -NR ^20a R ^21a (R ^20a and R ^21a each independently represents an alkyl group, a hydrogen atom, -C (O) R ^22a (R ^22a is an alkyl group which may be substituted with a halogen atom), -C (O) OR ^23a (R ^23a is a phenyl group optionally having a nitro group, an alkyl group, or a group represented by the following formula:

In which a substituent ^{represented), - X 5a -NR 24a R} 25a (X 5a represents a single bond or alkylene, R ^24a and R ^25a are each independently an alkyl group, the nitrogen atom to which R ^24a and R ^25a are adjacent Together with the following general formula:

(Wherein m1 and m2 are each independently an integer of 0 to 5, W ^3a is —CH ₂ — or —O—, and m1 and m2 are simultaneously 0). Or the following general formula:

(Wherein R ^26a is an alkyl group), and R ^20a and R ^21a together with the adjacent nitrogen atom have the following general formula:

(Wherein m3 and m4 are each independently an integer of 0 to 5, W ^4a is —CH ₂ — or —NR ^27a — (R ^27a is an alkyl group, which may have a substituent). , M1 and m2 may be 0 at the same time), and the ring may have a substituent); —NR ^28a —C (O) —X ^6a -NR ^29a R ^30a (X ^6a represents a single bond or alkylene, R ^28a is a hydrogen atom or an alkyl group, R ^29a and R ^30a each independently represents a hydrogen atom, a halogen atom or a phenyl group which may alkoxy group substituted, An alkyl group that may be substituted with a substituent selected from the group consisting of a hydroxyl group, an alkoxy group, and a heterocyclic ring (the alkyl group may have a sulfide bond in the chain); -X ^7a -R ^31a (X ^7a is a single bond or alkylene. , R ^31a is the following formula:

An alkenyl group; or a phenyl group which may have a substituent, and R ^29a and R ^30a together with the adjacent nitrogen atom have the following general formula:

(In the formula, m5 and m6 are each independently an integer of 0 to 5, W ^5a is —CH ₂ —, —S—, —O— or —NR ^32a — (R ^32a may have a substituent. An alkyl group, a phenyl group, a heterocyclic ring, or —C (O) —OR ^33a (R ^33a is an alkyl group), and a ring represented by m5 and m6 is 0 at the same time) The ring may have a substituent, and the ring may form a condensed ring with another aromatic ring, and the condensed ring has a substituent. may also be); - C (O) -NH -X 8a -NR 34a R 35a (X 8a represents a single bond or alkylene, R ^34a and R ^35a are each independently an alkyl group, R ^34a and R ^35a are adjacent The following general formula together with the nitrogen atom:

(Wherein m7 and m8 are each independently an integer of 0 to 5, W ^6a is —CH ₂ — or —O—, except that m7 and m8 are 0 at the same time). -O-C (O) -NR ^36a R ^37a (R ^36a and R ^37a are each independently a hydrogen atom or an alkyl group, and R ^36a and R ^37a together with the adjacent nitrogen atom are represented by the following general formula: ,

Wherein m9 and m10 are each independently an integer of 0 to 5, W ^7a is —CH ₂ —, —O— or —NR ^38a — (R ^38a is an alkyl group), and m9 and m10 are simultaneously And the ring may have a substituent); —C (O) OR ^39a (R ^39a represents a hydrogen atom or an alkyl group). Or —C (O) —NR ^40a R ^41a (R ^40a and R ^41a are each independently an alkyl group, and R ^40a and R ^41a together with the adjacent nitrogen atom have the following general formula:

(Wherein m11 and m12 are each independently an integer of 0 to 5, R ^42a is an alkyl group which may be substituted with a phenyl group, and m11 and m12 are 0 at the same time) May be formed), and
R ^5a is a hydrogen atom or an alkyl group,
R ^6a , R ^7a , R ^8a and R ^9a are each independently a hydrogen atom; —C (O) OR ^43a (R ^43a is an alkyl group); an alkyl group on which a hydroxyl group may be substituted; a nitro group; A halogen atom; or an amino group, and R ^6a and R ^7a , R ^7a and R ^8a , or R ^8a and R ^9a ,

A nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof, wherein the condensed ring is represented by the formula: R ^1a is a hydrogen atom; an alkyl group that may be substituted with a substituent selected from the group consisting of a phenyl group, an alkoxy group, a hydroxyl group, and a halogen atom that may be substituted with a halogen atom; or —X ^1a — The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, which is C (O) OR ^10a (X ^1a and R ^10a are as defined above). The R ^1a is a hydrogen atom; an alkyl group that may be substituted with a hydroxyl group; or —X ^1a —C (O) OR ^10a (where X ^1a is a single bond, and R ^10a is an alkyl group). The described nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein R ^1a is an alkyl group having 1 to 6 carbon atoms. R ^2a , R ^3a and R ^4a are each independently a hydrogen atom; a cyano group; a halogen atom; —OR ^17a (R ^17a is as defined above); —NR ^20a R ^21a (R ^20a and R ^21a are the same as those described ^{above); - NR 28a -C (O} ) -X 6a -NR 29a R 30a (X 6a, R 28a, R 29a and R ^30a are the same as those described above); or -O-C (O) -NR <^36a> R ^<37a> (R ^<36a> and R ^<37a> are the same as those described above) or the nitrogen-containing heterocyclic compound or pharmaceutical thereof according to any one of claims 1 to 4 Top acceptable salt. Said R ^<5a> is a hydrogen atom, The nitrogen-containing heterocyclic compound as described in any one of Claims 1-5, or its pharmaceutically acceptable salt. The R ^6a , R ^7a , R ^8a and R ^9a are each independently a hydrogen atom; an alkyl group which may be substituted with a hydroxyl group; or a halogen atom. A nitrogen heterocyclic compound or a pharmaceutically acceptable salt thereof. The following general formula (IB),

[Wherein, R ^1b represents a hydrogen atom; an alkyl group which may be substituted with a substituent selected from the group consisting of a phenyl group, an alkoxy group, a hydroxyl group and a halogen atom which may be substituted with a halogen atom; ^1b -C (O) OR ^10b (X ^1b is a single bond or alkylene, R ^10b is a hydrogen atom or an alkyl group); -X ^2b -C (O) NR ^11b R ^12b (X ^2b is a single bond or alkylene, R ^11b and R ^12b are each independently a hydrogen atom or an alkyl group, and R ^11b and R ^12b together with the adjacent nitrogen atom have the following general formula:

(Wherein W ^1b may be a ring represented by —CH ₂ — or —O—); —SO ₂ —R ^13b (R ^13b is a phenyl group); —X ^3b —NR ^14b R ^15b (X ^3b is alkylene, R ^14b and R ^15b are each independently an alkyl group, and R ^14b and R ^15b together with the adjacent nitrogen atom are represented by the following general formula:

(Wherein W ^2b may form a ring represented by —CH ₂ —, —NR ^16b — (R ^16b is an alkyl group) or —O—)),
R ^2b , R ^3b and R ^4b are each independently a hydrogen atom; a cyano group; a halogen atom; a tetrazolyl group; —OR ^17b (where R ^17b is a hydrogen atom, an alkyl group,

-O-X ^4b -NR ^18b R ^19b (X ^4b is alkylene, R ^18b and R ^19b are each independently an alkyl group, and R ^18b and R ^19b together with the adjacent nitrogen atom) -NR ^20b R ^21b (R ^20b and R ^21b each independently represents an alkyl group on which a phenyl group may be substituted, a hydrogen atom, -C (O) R ^22b (R ^22b is an alkyl group which may be substituted with a halogen atom), -C (O) OR ^23b (R ^23b is a phenyl group optionally having a nitro group, an alkyl group, or the following formula:

In which a substituent ^{represented), - X 5b -NR 24b R} 25b (X 5b is a single bond or alkylene, R ^24b and R ^25b are each independently an alkyl group, the nitrogen atom to which R ^24b and R ^25b are adjacent Together with the following general formula:

In which n1 and n2 are each independently an integer of 0 to 5, W ^3b is —CH ₂ — or —O—, and n1 and n2 are both 0 at the same time. Or the following general formula:

(Wherein R ^26b is an alkyl group), and R ^20b and R ^21b together with the adjacent nitrogen atom have the following general formula:

(Wherein n3 and n4 are each independently an integer of 0 to 5, W ^4b is —CH ₂ — or —NR ^27b — (R ^27b is an alkyl group and may have a substituent). , Except that n1 and n2 are 0 at the same time, the ring may have a substituent); —NR ^28b —C (O) —X ^6b —NR ^29b R ^30b (where X ^6b is a single bond or alkylene, R ^28b is a hydrogen atom or an alkyl group, R ^29b and R ^30b are each independently a hydrogen atom; a phenyl group which may be substituted with a halogen atom or an alkoxy group, An alkyl group that may be substituted with a substituent selected from the group consisting of a hydroxyl group, an alkoxy group, and a heterocyclic ring (the alkyl group may have a sulfide bond in the chain); -X ^7b -R ^31b (X ^7b is a single bond or alkylene. , R ^31b is the following formula:

An alkenyl group; or a phenyl group which may have a substituent, and R ^29b and R ^30b together with the adjacent nitrogen atom have the following general formula:

Wherein n5 and n6 are each independently an integer of 0 to 5, W ^5b is —CH ₂ —, —S—, —O— or —NR ^32b — (R ^32b may have a substituent. An alkyl group, a phenyl group, a heterocyclic ring, or —C (O) —OR ^33b (R ^33b is an alkyl group), and a ring represented by n5 and n6 are 0 at the same time) The ring may have a substituent, and the ring may form a condensed ring with another aromatic ring, and the condensed ring has a substituent. may also be); - C (O) -NH -X 8b -NR 34b R 35b (X 8b is a single bond or alkylene, R ^34b and R ^35b are each independently an alkyl group, R ^34b and R ^35b are adjacent The following general formula together with the nitrogen atom:

(Wherein n7 and n8 are each independently an integer of 0 to 5, W ^6b is —CH ₂ — or —O—, and n7 and n8 are 0 at the same time). may be); - O-C (O ) -NR 36b R 37b (R 36b and R ^37b are each independently a hydrogen atom or an alkyl group, following general formula together with the nitrogen atom to which R ^36b and R ^37b are adjacent ,

Wherein n9 and n10 are each independently an integer of 0 to 5, W ^7b is —CH ₂ —, —O— or —NR ^38b — (R ^38b is an alkyl group), and n9 and n10 are simultaneously And the ring may have a substituent); —C (O) OR ^39b (R ^39b represents a hydrogen atom or an alkyl group). Or —C (O) —NR ^40b R ^41b (R ^40b and R ^41b are each independently an alkyl group, and R ^40b and R ^41b together with the adjacent nitrogen atom have the following general formula:

(Wherein n11 and n12 are each independently an integer of 0 to 5, R ^42b is an alkyl group which may be substituted with a phenyl group, and n11 and n12 are simultaneously 0) May be formed), and
R ^5b is a hydrogen atom or an alkyl group,
R ^6b , R ^7b , R ^8b and R ^9b are each independently a hydrogen atom; —C (O) OR ^43b (R ^43b is an alkyl group); an alkyl group on which a hydroxyl group may be substituted; a nitro group; A halogen atom; or an amino group, and R ^6b and R ^7b , R ^7b and R ^8b , or R ^8b and R ^9b, and the adjacent benzene ring,

A nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof, wherein the condensed ring is represented by the formula: The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 8, wherein R ^1b is a hydrogen atom or an alkyl group. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein R ^1b is an alkyl group. R ^2b , R ^3b and R ^4b are each independently a hydrogen atom; a cyano group; a halogen atom; —OR ^17b (R ^17b is the same as described above); —NR ^20b R ^21b (R ^20b and R ^21b is the same as ^{above); - NR 28 -C (O} ) -X 6b -NR 29b R 30b (X 6b, R 28b, R 29b and R ^30b are the same as those described above); ^{-C (O) -NH-X 8b} -NR 34b R 35b (X 8b, R 34b and R ^35b are the same as those described above); - O-C (O ) -NR 36b R 37b (R 36b And R ^37b are the same as above; -C (O) OR ^39b (R ^39b is the same as above): or -C (O) -NR ^40b R ^41b (R ^40b and R ^41b is acceptable nitrogen-containing heterocyclic compound or a pharmaceutically as claimed in any one of claims 1 to 10 is the same as above) . R ^2b , R ^3b and R ^4b are each independently a hydrogen atom; —OR ^17b (R ^17b is the same as above); —NR ^20b R ^21b (R ^20b and R ^21b are the same as above) —NR ^28b —C (O) —X ^6b —NR ^29b R ^30b (where X ^6b , R ^28b , R ^29b and R ^30b are the same as above) or; —O—C ( ^{O) -NR 36b R 37b (R} 36b and R ^37b are acceptable salt same as is) a is a nitrogen-containing heterocyclic compound according to claim 11, wherein or its pharmaceutically those described above. Said R ^<5b> is a hydrogen atom, The nitrogen-containing heterocyclic compound as described in any one of Claims 1-12, or its pharmaceutically acceptable salt. 14. The nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ^6b , R ^7b , R ^8b and R ^9b are each independently a hydrogen atom or a halogen atom. . A method for producing a nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, comprising the following general formula (II-A):

(Wherein R ^1a , R ^2a , R ^3a, and R ^4a are the same as those described above), a 7-azaindole derivative represented by the following formula (III-A),

(Wherein R ^5a , R ^6a , R ^7a , R ^8a and R ^9a are the same as those described above) and a step of reacting them with a quinoxalone derivative or a precursor thereof. A method for producing a nitrogen heterocyclic compound or a pharmaceutically acceptable salt thereof.   The method for producing a nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 15, wherein the reaction is carried out in the presence of a Bronsted acid.   The method for producing a nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 16, wherein the Bronsted acid is acetic acid or trifluoroacetic acid.   A pharmaceutical composition comprising the nitrogen-containing heterocyclic compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.   The pharmaceutical composition according to claim 18, which is a VEGF inhibitor.   The pharmaceutical composition according to claim 19, which is a therapeutic agent for diabetic nephropathy.   The pharmaceutical composition according to claim 19, which is an anticancer agent.   The pharmaceutical composition according to claim 19, which is an angiogenesis inhibitor.