JPWO2019156929A5

JPWO2019156929A5 -

Info

Publication number: JPWO2019156929A5
Application number: JP2020542552A
Authority: JP
Publication date: 2022-02-14
Anticipated expiration: 2039-02-04

Description

表９について：Ｃａｃｏ－２透過性（Ｐ_ａｐｐ）：「Ｐ」は、≦１０×１０^－６ｃｍ／ｓを示し；「Ｑ」は、１１～３０×１０^－６ｃｍ／ｓを示し；「Ｒ」は、３１～５０×１０^－６ｃｍ／ｓを示し；「Ｓ」は、＞５０×１０^－６ｃｍ／ｓを示し；「Ｔ」は、データが利用可能でないまたは決定されていないことを示す。
水可溶性：「Ｕ」は、≦１０μＭを示し；「Ｖ」は、１０～１００μＭを示し；「Ｗ」は、＞１００μＭを示し；Ｘは、データが利用可能でないまたは決定されていないことを示す。
ＰＰＢ：「Ｙ」は、＞５０％を示し；「Ｚ」は、５０～９０％を示し；「ＡＡ」は、９１～９５％を示し；「ＢＢ」は、＞９５％を示し；「ＣＣ」は、データが利用可能でないまたは決定されていないことを示す。
イヌ生物学的利用能：「ＤＤ」は、≦１０％を示し；「ＥＥ」は、１１～３０％を示し；「ＦＦ」は、＞３０％を示し；「ＧＧ」は、データが利用可能でないまたは決定されていないことを示す。
本発明の実施形態において、例えば以下の項目が提供される。
（項目１）
式（ＩＩ）：

［式中、
Ｒ ^１は、水素または－ＮＲ ^８Ｒ ^９であり；
Ｒ ^ａは、Ｃ _１～６アルキル、Ｃ _１～６ハロアルキル、ハロ、シアノまたは－ＯＲ ^６であり；
Ｒ ^ｂは、水素またはＣ _１～６アルキルであり；
Ｒ ^２は、必要に応じて置換されている５員ヘテロアリールまたは必要に応じて置換されている５員ヘテロシクリルであり；
Ｒ ^３は、水素、Ｃ _１～６アルキルまたはＣ _１～６ハロアルキルであり；
Ｒ ^４は、Ｃ _１～６アルキル、Ｃ _１～６ハロアルキル、シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールであり、ここで前記シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールは、ハロ、Ｃ _１～６アルキル、Ｃ _１～６ハロアルキル、シアノまたは－ＯＲ ^６の１個、２個または３個の独立した出現で必要に応じて置換されており；
Ｒ ^５は、水素、Ｃ _１～６アルキル、Ｃ _１～６ハロアルキル、シクロアルキルまたはアリールであり、ここで前記シクロアルキルまたはアリールは、ハロ、Ｃ _１～６アルキル、Ｃ _１～６ハロアルキル、シアノまたは－ＯＲ ^６の１個、２個または３個の独立した出現で必要に応じて置換されているか、または
Ｒ ^４およびＲ ^５は、それらが結合している炭素原子と一緒になって、環を形成し；
Ｒ ^６は、水素、Ｃ _１～６アルキルまたはＣ _１～６ハロアルキルであり；
各Ｒ ^８およびＲ ^９は、独立に、水素、Ｃ _１～６アルキル、－Ｃ（Ｏ）Ｒ ^１０または－Ｃ（Ｏ）ＯＲ ^１０であり；
Ｒ ^１０は、Ｃ _１～６アルキルまたはＣ _１～６ハロアルキルであり；
Ｒ ^ｘは、－Ｏであるか、または存在せず、ここでＲ ^ｘが－Ｏである場合、ピリジル環の窒素原子は、正に荷電されており、Ｒ ^ｘは、負に荷電されており、それによって、ピリジルＮ－オキシドを形成し；
ｍは、０、１、２または３であり；
ｎは、０または１であり、ここでｎが０であるならば、Ｒ ^５は、水素であり、Ｒ ^４は、存在しない］
の化合物またはその薬学的に許容される塩。
（項目２）
式（Ｉ）：

の化合物である、項目１に記載の化合物。
（項目３）
Ｒ ^ｘが、存在しない、項目１に記載の化合物。
（項目４）
Ｒ ^６が、Ｃ _１～６アルキルまたはＣ _１～６ハロアルキルである、項目１～３のいずれか一項に記載の化合物。
（項目５）
Ｒ ^６が、－ＣＨ _３または－ＣＦ _３である、項目１～４のいずれか一項に記載の化合物。
（項目６）
Ｒ ^１が、水素、－ＮＨ _２または－ＮＨＣＨ _３である、項目１～５のいずれか一項に記載の化合物。
（項目７）
Ｒ ^１が、水素である、項目１～６のいずれか一項に記載の化合物。
（項目８）
Ｒ ^１が、－ＮＨ _２である、項目１～６のいずれか一項に記載の化合物。
（項目９）
Ｒ ^１が、－ＮＨＣＨ _３である、項目１～６のいずれか一項に記載の化合物。
（項目１０）
Ｒ ^２が、Ｃ _１～６アルキルの１個または２個の独立した出現で必要に応じて置換されている５員ヘテロアリールである、項目１～９のいずれか一項に記載の化合物。
（項目１１）
Ｒ ^２が、ピラゾリル、イミダゾリル、チエニル、イソチアゾリル、チアゾリル、オキサジアゾリルまたはチアジアゾリルであり、ここで前記イミダゾリル、チエニル、イソチアゾリル、チアゾリル、オキサジアゾリルまたはチアジアゾリルは、Ｃ _１～６アルキルの１個または２個の独立した出現で必要に応じて置換されている、項目１～１０のいずれか一項に記載の化合物。
（項目１２）
Ｒ ^２が、ピラゾリル、イミダゾリル、チエニル、イソチアゾリル、チアゾリル、オキサジアゾリルまたはチアジアゾリルであり、ここで前記イミダゾリル、チエニル、イソチアゾリル、チアゾリル、オキサジアゾリルまたはチアジアゾリルは、－ＣＨ _３の１個または２個の出現で必要に応じて置換されている、項目１～１１のいずれか一項に記載の化合物。
（項目１３）
Ｒ ^２が、

である、項目１～１２のいずれか一項に記載の化合物。
（項目１４）
Ｒ ^２が、Ｃ _１～６アルキルの１個または２個の独立した出現で必要に応じて置換されている５員ヘテロシクリルである、項目１～９のいずれか一項に記載の化合物。
（項目１５）
Ｒ ^３が、Ｃ _１～６アルキルである、項目１～１４のいずれか一項に記載の化合物。
（項目１６）
Ｒ ^３が、－ＣＨ _３である項目１～１５のいずれか一項に記載の化合物。
（項目１７）
Ｒ ^４が、Ｃ _１～６アルキル、シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールであり、ここで前記シクロアルキル、アリールまたはヘテロアリールは、ハロまたはＣ _１～６アルキルの１個、２個または３個の独立した出現で必要に応じて置換されている、項目１～１６のいずれか一項に記載の化合物。
（項目１８）
Ｒ ^４が、シクロヘキシル、シクロプロピル、フェニル、テトラヒドロピラニル、ピリジル、ピラゾリル、チエニルまたはＣ _１～６アルキルであり、ここで前記シクロヘキシル、シクロプロピル、フェニル、テトラヒドロピラニル、ピリジル、ピラゾリルまたはチエニルは、ハロまたはＣ _１～６アルキルの１個、２個または３個の独立した出現で必要に応じて置換されている、項目１～１７のいずれか一項に記載の化合物。
（項目１９）
Ｒ ^４が、シクロヘキシル、フェニル、ピリジル、ピラゾリルまたはチエニルであり、ここで前記シクロヘキシル、フェニル、ピリジル、ピラゾリルまたはチエニルは、ハロまたはＣ _１～６アルキルの１個、２個または３個の独立した出現で必要に応じて置換されている、項目１～１８のいずれか一項に記載の化合物。
（項目２０）
Ｒ ^４が、－Ｆ、－ＣｌまたはＣ _１～６アルキルの１個、２個または３個の出現で必要に応じて置換されているフェニルである、項目１～１９のいずれか一項に記載の化合物。
（項目２１）
Ｒ ^５が、水素、－ＣＨ _３、－ＣＨ _２ＣＨ _３、－ＣＨ _２ＣＨ _２ＣＨ _３、－ＣＨ（ＣＨ _３） _２、－ＣＨ _２ＣＨ _２ＣＨ _２ＣＨ _３、－ＣＦ _３または非置換シクロプロピルである、項目１～２０のいずれか一項に記載の化合物。
（項目２２）
Ｒ ^５が、－ＣＨ _２ＣＨ _３、－ＣＦ _３または非置換シクロプロピルである、項目１～２１のいずれか一項に記載の化合物。
（項目２３）
式（Ｉ－ａ）：

の化合物である、項目１～２２のいずれか一項に記載の化合物。
（項目２４）
式（Ｉ－ｂ）：

の化合物である、項目１～２３のいずれか一項に記載の化合物。
（項目２５）
式（Ｉ－ｃ）、式（Ｉ－ｄ）、式（Ｉ－ｅ）、式（Ｉ－ｆ）、式（Ｉ－ｇ）、式（Ｉ－ｉ）または式（Ｉ－ｊ）：

の化合物である、項目１～２４のいずれか一項に記載の化合物。
（項目２６）
式（Ｉ－ｃ）：

の化合物である、項目１～２５のいずれか一項に記載の化合物。
（項目２７）
式（Ｉ－ｅ）、式（Ｉ－ｋ）、式（Ｉ－ｌ）、式（Ｉ－ｍ）、式（Ｉ－ｏ）、式（Ｉ－ｐ）、式（Ｉ－ｔ）、式（Ｉ－ｕ）または式（Ｉ－ｖ）：

［式中、Ｒ ^ｂ２の各々は、独立に、ハロ、Ｃ _１～６アルキル、Ｃ _１～６ハロアルキル、シアノまたは－ＯＲ ^６であり；ｐは、０、１、２または３である］
の化合物である、項目１～２６のいずれか一項に記載の化合物。
（項目２８）
Ｒ ^ａが、ハロまたは－Ｃ _１～６アルキルである、項目１～２２のいずれか一項に記載の化合物。
（項目２９）
Ｒ ^ａが、Ｆまたは－ＣＨ _３である、項目１～２２または２８のいずれか一項に記載の化合物。
（項目３０）
ｍが、１である、項目１～２２または２８～２９のいずれか一項に記載の化合物。
（項目３１）
Ｒ ^ａが、－ＣＨ _３であり、ｍが、１である、項目１～２２または２８～３０のいずれか一項に記載の化合物。
（項目３２）
式（Ｉ－ｑ）：

の化合物である、項目１～２２のいずれか一項に記載の化合物。
（項目３３）
式（Ｉ－ｒ）：

の化合物である、項目１～２２または３２のいずれか一項に記載の化合物。
（項目３４）
式（Ｉ－ｓ）：

の化合物である、項目１～２２、３２または３３のいずれか一項に記載の化合物。
（項目３５）
式（Ｉ－ｓ１）または式（Ｉ－ｓ２）：

［式中、Ｒ ^ｂ２の各々は、独立に、ハロ、Ｃ _１～６アルキル、Ｃ _１～６ハロアルキル、シアノまたは－ＯＲ ^６であり；ｐは、０、１、２または３である］
の化合物である、項目１～２２または３２～３４のいずれか一項に記載の化合物。
（項目３６）
Ｒ ^ｂが、Ｃ _１～６アルキルである、項目１または３～２２のいずれか一項に記載の化合物。
（項目３７）
Ｒ ^ｂが、－ＣＨ _３である、項目１、３～２２または３６のいずれか一項に記載の化合物。
（項目３８）
式：

の化合物。
（項目３９）
項目１～３８のいずれか一項に記載の化合物の薬学的に許容される塩。
（項目４０）
項目１～３８のいずれか一項に記載の化合物またはその薬学的に許容される塩および１種または複数種の薬学的に許容される賦形剤を含む医薬組成物。
（項目４１）
液体製剤として提供される、項目４０に記載の医薬組成物。
（項目４２）
固体製剤として提供される、項目４０に記載の医薬組成物。
（項目４３）
虚血事象に罹患している被験体における脳卒中の危険性を低減する方法であって、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を前記被験体に投与するステップを含む、方法。
（項目４４）
前記投与するステップが、前記化合物を投与されない被験体と比較して、被験体における脳卒中の危険性を低減する、項目４３に記載の方法。
（項目４５）
心房細動を罹患している被験体において脳卒中または全身性塞栓症の危険性を低減する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目４６）
虚血事象に罹患している被験体において非中枢神経系の全身性塞栓症を低減する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目４７）
前記投与するステップが、前記化合物を投与されない被験体と比較して、被験体における非中枢神経系の全身性塞栓症を低減する、項目４６に記載の方法。
（項目４８）
虚血事象に罹患している被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物に投与するステップを含む、深部静脈血栓症を処置する方法。
（項目４９）
深部静脈血栓症の再発の危険性を低減する方法であって、深部静脈血栓症に罹患している被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目５０）
前記投与するステップが、前記化合物を投与されない被験体と比較して、被験体における深部静脈血栓症の再発の危険性を低減する、項目４９に記載の方法。
（項目５１）
被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、被験体における深部静脈血栓症の予防の方法。
（項目５２）
前記被験体が、整形外科手術または膝もしくは股関節置換外科手術を受けている、項目５１に記載の方法。
（項目５３）
肺塞栓症の再発の危険性を低減する方法であって、肺塞栓症に罹患している被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目５４）
肺塞栓症の再発の危険性を低減する方法であって、深部静脈血栓症に罹患している被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目５５）
前記投与するステップが、前記化合物を投与されない被験体と比較して、被験体における肺塞栓症の再発の危険性を低減する、項目５３または５４に記載の方法。
（項目５６）
深部静脈血栓症に罹患している被験体において肺塞栓症を処置する方法であって、被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目５７）
肺塞栓症に罹患している被験体における肺塞栓症の予防の方法であって、被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目５８）
肺塞栓症に罹患している被験体における肺塞栓症の予防の方法であって、被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目５９）
深部静脈血栓症に罹患している被験体における肺塞栓症の予防の方法であって、被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目６０）
虚血事象を有する被験体を処置する方法であって、項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を、前記被験体に、前記被験体における前記虚血事象の発症後、１２時間もしくはそれ未満、１０時間もしくはそれ未満、９時間もしくはそれ未満、８時間もしくはそれ未満、７時間もしくはそれ未満、６時間もしくはそれ未満、または１時間もしくはそれ未満の内に投与するステップを含む、方法。
（項目６１）
抗凝固剤を以前に投与されている被験体への、深部静脈血栓症を処置する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目６２）
抗凝固剤を以前に投与されている被験体への、肺塞栓症を処置する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目６３）
前記抗凝固剤が５～１０日の間非経口的に投与されている、項目６１または６２に記載の方法。
（項目６４）
虚血事象を有する被験体を処置する方法であって、項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を、前記被験体に、前記被験体における前記虚血事象の発症後、２時間超から１２時間、例えば、２時間超から１０時間またはそれ未満、２時間超から８時間またはそれ未満の内に投与するステップを含む、方法。
（項目６５）
被験体において急性冠症候群を処置する方法であって、それを必要とする被験体に、項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目６６）
虚血に罹患している被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、被験体における第ＸＩａ因子を阻害する方法。
（項目６７）
前記虚血が、冠動脈虚血である、項目６６に記載の方法。
（項目６８）
浮腫を有する被験体を処置する方法であって、項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目６９）
浮腫を有する被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、被験体におけるカリクレインを阻害する方法。
（項目７０）
被験体において血栓塞栓性の結果または合併症を処置する方法であって、被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目７１）
前記血栓塞栓性の結果または合併症が、末梢血管介入、血液透析、カテーテルアブレーション、脳血管介入、臓器の移植、外科手術、経カテーテル大動脈弁埋込、動脈瘤を処置するために使用される大口径介入、経皮冠動脈介入または血友病治療と関連する、項目７０に記載の方法。
（項目７２）
前記外科手術が、整形外科手術、肺外科手術、腹部外科手術または心臓外科手術である、項目７１に記載の方法。
（項目７３）
被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、被験体における動脈傷害に続く再狭窄を処置する方法。
（項目７４）
前記動脈傷害が、頭蓋動脈ステント留置後に生じる、項目７３に記載の方法。
（項目７５）
被験体において肝血管血栓症を処置する方法であって、被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目７６）
非ＳＴ上昇型心筋梗塞もしくはＳＴ上昇型心筋梗塞を処置する方法であって、被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目７７）
被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物に投与するステップを含む、血管開存性を維持する方法。
（項目７８）
前記被験体が、急性腎臓傷害を有する、項目７７に記載の方法。
（項目７９）
前記被験体が、連続的な腎置換療法をさらに受ける、項目７８に記載の方法。
（項目８０）
被験体において高血圧を処置する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目８１）
前記高血圧が、動脈高血圧である、項目８０に記載の方法。
（項目８２）
被験体において高血圧の危険性を低減する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目８３）
前記高血圧が、動脈高血圧である、項目８２に記載の方法。
（項目８４）
被験体における高血圧の予防の方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目８５）
前記高血圧が、動脈高血圧である、項目８４に記載の方法。
（項目８６）
被験体における炎症を低減する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目８７）
前記炎症が、血管炎症である、項目８６に記載の方法。
（項目８８）
前記血管炎症が、アンギオテンシンＩＩ誘発血管炎症である、項目８７に記載の方法。
（項目８９）
被験体における血管の白血球浸潤を予防する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目９０）
被験体におけるアンギオテンシンＩＩ誘発内皮機能障害を予防する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目９１）
被験体におけるトロンビン増殖を予防する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目９２）
被験体において高血圧関連の腎機能障害を処置する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目９３）
被験体における高血圧関連の腎機能障害の予防の方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目９４）
被験体において高血圧関連の腎機能障害の危険性を低減する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目９５）
被験体において高血圧関連の腎機能障害を処置する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目９６）
被験体における高血圧関連の腎機能障害の予防の方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目９７）
被験体において高血圧関連の腎機能障害の危険性を低減する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目９８）
被験体において腎臓線維症を処置する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目９９）
被験体における腎臓線維症の予防の方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目１００）
被験体において腎臓線維症の危険性を低減する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目１０１）
被験体において腎臓傷害を処置する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目１０２）
被験体における腎臓傷害の予防の方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目１０３）
被験体において腎臓傷害の危険性を低減する方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目１０４）
血栓塞栓性障害の処置を必要とする被験体においてそれを行う方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含み、前記被験体が人工表面に曝露されている、方法。
（項目１０５）
血栓塞栓性障害の危険性の低減を必要とする被験体においてそれを行う方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含み、前記被験体が人工表面に曝露されている、方法。
（項目１０６）
血栓塞栓性障害の予防を必要とする被験体においてそれを行う方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含み、前記被験体が人工表面に曝露されている、方法。
（項目１０７）
ヘパリン誘発性血小板減少症の処置を必要とする被験体においてそれを行う方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目１０８）
ヘパリン誘発性血小板減少症の危険性の低減を必要とする被験体においてそれを行う方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目１０９）
ヘパリン誘発性血小板減少症の予防を必要とする被験体においてそれを行う方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目１１０）
ヘパリン誘発性血小板減少症血栓症の処置を必要とする被験体においてそれを行う方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目１１１）
ヘパリン誘発性血小板減少症血栓症の危険性の低減を必要とする被験体においてそれを行う方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目１１２）
ヘパリン誘発性血小板減少症血栓症の予防を必要とする被験体においてそれを行う方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目１１３）
血栓塞栓性障害の予防を必要とする被験体においてそれを行う方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含み、前記被験体はがんを有する、方法。
（項目１１４）
血栓性微小血管症の処置を必要とする被験体においてそれを行う方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の式（ＩＩ）の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目１１５）
血栓性微小血管症の危険性の低減を必要とする被験体においてそれを行う方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目１１６）
血栓性微小血管症の予防をそれを必要とする被験体において行う方法であって、前記被験体に、有効量の項目１～３８のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または項目４０～４２のいずれか一項に記載の組成物を投与するステップを含む、方法。
（項目１１７）
前記被験体が、非弁性心房細動を有する被験体である、項目４３～１１６のいずれか一項に記載の方法。
（項目１１８）
前記被験体が、脳卒中の以下の危険因子：過去の脳卒中、一過性脳虚血発作、または非ＣＮＳの全身性塞栓症の１つまたは複数を有する、項目１１７に記載の方法。
（項目１１９）
前記被験体が、脳卒中の以下の危険因子：７５歳またはそれ超の年齢、高血圧、心不全もしくは左心室駆出率、または糖尿病の１つまたは複数を有する、項目１１８に記載の方法。
（項目１２０）
前記化合物が、虚血事象後に投与される、項目１１７に記載の方法。
（項目１２１）
前記化合物が、虚血事象の約１日後、２日後、３日後、４日後、５日後、６日後、７日後、８日後、９日後、１０日後、１１日後、１２日後、１３日後もしくは１４日後、またはそれより後に投与される、項目１２０に記載の方法。
（項目１２２）
前記化合物が、虚血事象の約１週間後、２週間後、３週間後、４週間後、５週間後、６週間後、７週間後もしくは８週間後、またはそれより後に投与される、項目１２０に記載の方法。
（項目１２３）
前記化合物が、虚血事象の約１カ月後、２カ月後、３カ月後、４カ月後、５カ月後もしくは６カ月後、またはそれより後に投与される、項目１２０に記載の方法。
（項目１２４）
前記化合物が、追加の治療剤と組み合わせて投与される、項目１１７に記載の方法。
（項目１２５）
前記追加の治療剤が、前記化合物の投与後に投与される、項目１２４に記載の方法。
（項目１２６）
前記追加の治療剤が、経口投与される、項目１２４に記載の方法。
（項目１２７）
前記追加の治療剤が、前記化合物の投与の少なくとも１時間後、２時間後、３時間後、４時間後、５時間後、６時間後、７時間後、８時間後、１０時間後、１２時間後、１４時間後、１６時間後、１８時間後、２０時間後もしくは２４時間後、またはそれより後に投与される、項目１２４に記載の方法。
（項目１２８）
前記追加の治療剤が、前記化合物の投与の少なくとも１日後、２日後、３日後、４日後、５日後、６日後、７日後、１４日後、２１日後もしくは２８日後、またはそれより後に投与される、項目１２４に記載の方法。
（項目１２９）
前記追加の治療剤が、前記化合物の投与の約１日後、約２日後、約３日後、約４日後、約５日後、約６日後、約７日後、またはそれより後に投与される、項目１２４に記載の方法。
（項目１３０）
前記追加の治療剤が、前記化合物の投与後に長期投与される、項目１２４に記載の方法。
（項目１３１）
前記追加の治療剤が、ＮＳＡＩＤ、血小板凝集阻害剤または抗凝固剤である、項目１２４に記載の方法。
（項目１３２）
前記追加の治療剤が、相加的な治療効果をもたらす、項目１２４に記載の方法。
（項目１３３）
前記追加の治療剤が、相乗的な治療効果をもたらす、項目１２４に記載の方法。
（項目１３４）
前記化合物が、経口的または非経口的に投与される、項目４３～１３３のいずれか一項に記載の方法。
（項目１３５）
前記化合物が、経口的に投与される、項目４３～１３３のいずれか一項に記載の方法。
（項目１３６）
前記化合物が、非経口的に投与される、項目４３～１３３のいずれか一項に記載の方法。
（項目１３７）
前記被験体が直接経口抗凝固剤の使用を中断した後に、前記化合物もしくはその薬学的に許容される塩またはその薬学的組成物が投与される、項目４３～１３３のいずれか一項に記載の方法。
（項目１３８）
前記被験体が、前記直接経口抗凝固剤を使用した被験体である、項目１３７に記載の方法。
（項目１３９）
前記被験体が、哺乳動物である、項目４３～１３８のいずれか一項に記載の方法。
（項目１４０）
前記哺乳動物が、ヒトである、項目４３～１３９のいずれか一項に記載の方法。

For Table 9: Caco-2 permeability (Papp): "P" indicates _≤10 x ^10-6 cm / s; "Q" indicates 11-30 x ^10-6 cm / s; ""R" indicates 31-50 x ^10-6 cm / s; "S"indicates> 50 x ^10-6 cm / s; "T" indicates data is not available or has not been determined. Is shown.
Water soluble: "U" indicates ≤10 μM; "V" indicates 10-100 μM; “W” indicates> 100 μM; X indicates data is not available or determined. ..
PPB: "Y"indicates>50%;"Z" indicates 50-90%; "AA" indicates 91-95%; "BB"indicates>95%;"CC""Indicates that the data is not available or has not been determined.
Canine bioavailability: "DD" indicates ≤10%; "EE" indicates 11-30%; "FF"indicates>30%;"GG" indicates data available Indicates that it is not or has not been determined.
In the embodiment of the present invention, for example, the following items are provided.
(Item 1)
Equation (II):

[During the ceremony,
R ¹ is hydrogen or -NR ⁸ R ⁹ ;
Ra is C _1-6 alkyl, C _1-6 ^haloalkyl , halo, cyano or -OR ⁶ ;
R ^b is hydrogen or C _1-6 alkyl;
R2 is a 5 ^- membered heteroaryl or optionally substituted 5-membered heterocyclyl;
R ³ is hydrogen, C _1-6 alkyl or C _1-6 haloalkyl;
R4 is C ^1-6 alkyl, C _1-6 _haloalkyl , cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is halo, C _1-6 alkyl, C _1-6 haloalkyl, cyano or -OR ⁶ with one, two or three independent appearances substituted as needed;
R ⁵ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, cycloalkyl or aryl, wherein the cycloalkyl or aryl is halo, C _1-6 alkyl, C _1-6 haloalkyl, cyano or -Replaced or replaced as needed with one, two or three independent appearances of OR ⁶
R ⁴ and R ⁵ together with the carbon atoms to which they are bonded form a ring;
R ⁶ is hydrogen, C _1-6 alkyl or C _1-6 haloalkyl;
Each R ⁸ and R ⁹ are independently hydrogen, C _1-6 alkyl, -C (O) R ¹⁰ or -C (O) OR ¹⁰ ;
R ¹⁰ is C _1-6 alkyl or C _1-6 haloalkyl;
If R ^x is -O or absent, where R ^x is -O, then the nitrogen atom of the pyridyl ring is positively charged and R ^x is negatively charged. , Thereby forming pyridyl N-oxide;
m is 0, 1, 2 or 3;
n is 0 or 1, where n is 0, then R ⁵ is hydrogen and R ⁴ is absent]
Compound or pharmaceutically acceptable salt thereof.
(Item 2)
Equation (I):

The compound according to item 1, which is a compound of.
(Item 3)
The compound according to item 1, wherein R ^x does not exist.
(Item 4)
The compound according to any one of items 1 to 3, wherein R ⁶ is C _{1 to 6} alkyl or C _{1 to 6} haloalkyl.
(Item 5)
The compound according to any one of items 1 to 4, wherein R ⁶ is -CH ₃ or -CF ₃ .
(Item 6)
The compound according to any one of items 1 to 5 , wherein R ¹ is hydrogen, -NH ₂ or -NHCH ₃ .
(Item 7)
The compound according to any one of items 1 to 6, wherein R ¹ is hydrogen.
(Item 8)
The compound according to any one of items 1 to 6, wherein R ¹ is -NH ₂ .
(Item 9)
The compound according to any one of items 1 to 6, wherein R ¹ is -NHCH ₃ .
(Item 10)
The compound according to any one of items 1 to 9, wherein R ² is a 5-membered heteroaryl optionally substituted with one or two independent appearances of C _{1 to 6} alkyl.
(Item 11)
R2 is pyrazolyl, imidazolyl, thienyl, isothiazolyl, thiazolyl, oxadiazolyl or thiaziazolyl, wherein the imidazolyl, thienyl, isothiazolyl, thiazolyl, oxadiazolyl or thiaziazolyl is _one or ^two independent C1-6 alkyl. The compound according to any one of items 1 to 10, which is substituted as necessary at the time of appearance.
(Item 12)
R ² is pyrazolyl, imidazolyl, thienyl, isothiazolyl, thiazolyl, oxadiazolyl or thiaziazolyl, wherein the imidazolyl, thienyl, isothiazolyl, thiazolyl, oxadiazolyl or thiaziazolyl is required in the appearance of one or two of -CH ₃ . The compound according to any one of items 1 to 11, which is substituted accordingly.
(Item 13)
R ² is

The compound according to any one of items 1 to 12.
(Item 14)
The compound according to any one of items 1 to 9, wherein R ² is a 5-membered heterocyclyl in which one or two independent appearances of C _{1 to 6} alkyl are optionally substituted.
(Item 15)
The compound according to any one of items 1 to 14, wherein R ³ is C _{1 to 6} alkyl.
(Item 16)
The compound according to any one of items 1 to 15, wherein R ³ is −CH ₃ .
(Item 17)
R4 is C _1-6 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or heteroaryl is one, two or three of ^halo or C _1-6 alkyl. The compound according to any one of items 1 to 16, which is optionally substituted with the independent appearance of.
(Item 18)
R4 is cyclohexyl, ^cyclopropyl , phenyl, tetrahydropyranyl, pyridyl, pyrazolyl, thienyl or C _1-6 alkyl, wherein the cyclohexyl, cyclopropyl, phenyl, tetrahydropyranyl, pyridyl, pyrazolyl or thienyl The compound according to any one of items 1 to 17, which is optionally substituted with one, two or three independent appearances of halo or C _1-6 alkyl.
(Item 19)
R4 is cyclohexyl, phenyl, pyridyl, pyrazolyl or thienyl, wherein said cyclohexyl, phenyl, pyridyl, pyrazolyl or thienyl is one, two or three independent appearances of halo or C ^1-6 alkyl _. The compound according to any one of items 1 to 18, which is optionally substituted with.
(Item 20)
Item ⁶ . _ _{_} Compound.
(Item 21)
R ⁵ is hydrogen, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CF ₃ or unsubstituted cyclopropyl . The compound according to any one of items 1 to 20.
(Item 22)
The compound according to any one of items 1 to 21, wherein R ⁵ is -CH ₂ CH ₃ , -CF ₃ or unsubstituted cyclopropyl.
(Item 23)
Equation (Ia):

The compound according to any one of items 1 to 22, which is a compound of.
(Item 24)
Equation (I-b):

The compound according to any one of items 1 to 23, which is the compound of.
(Item 25)
Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ii) or Formula (Ij) :.

The compound according to any one of items 1 to 24, which is the compound of.
(Item 26)
Equation (Ic):

The compound according to any one of items 1 to 25, which is the compound of.
(Item 27)
Formula (I-e), formula (Ik), formula (Il), formula (Im), formula (I-o), formula (Ip), formula (It), formula. (Iu) or formula (Iv):

[In the formula, each of R ^b2 is independently halo, C _1-6 alkyl, C _1-6 haloalkyl, cyano or -OR ⁶ ; p is 0, 1, 2 or 3].
The compound according to any one of items 1 to 26, which is the compound of.
(Item 28)
The compound according to any one of items 1 to 22, wherein Ra is ^halo or -C _{1 to 6} alkyl.
(Item 29)
The compound according to any one of items 1 to 22 or 28, wherein Ra is F or -CH ³ _.
(Item 30)
The compound according to any one of items 1 to 22 or 28 to 29, wherein m is 1.
(Item 31)
The compound according to any one of items 1 to 22 or 28 to 30, wherein R ^a is -CH ₃ and m is 1.
(Item 32)
Equation (Iq):

The compound according to any one of items 1 to 22, which is a compound of.
(Item 33)
Equation (Ir):

The compound according to any one of items 1 to 22 or 32, which is a compound of.
(Item 34)
Equation (Is):

The compound according to any one of items 1 to 22, 32 or 33, which is a compound of.
(Item 35)
Equation (I-s1) or Equation (I-s2):

[In the formula, each of R ^b2 is independently halo, C _1-6 alkyl, C _1-6 haloalkyl, cyano or -OR ⁶ ; p is 0, 1, 2 or 3].
The compound according to any one of items 1 to 22 or 32 to 34, which is the compound of.
(Item 36)
The compound according to any one of items 1 or 3 to 22, wherein R ^b is C _{1 to 6} alkyl.
(Item 37)
The compound according to any one of items 1, 3 to 22 or 36, wherein R ^b is -CH ₃ .
(Item 38)
formula:

Compound.
(Item 39)
A pharmaceutically acceptable salt of the compound according to any one of items 1 to 38.
(Item 40)
A pharmaceutical composition comprising the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
(Item 41)
The pharmaceutical composition according to item 40, which is provided as a liquid preparation.
(Item 42)
The pharmaceutical composition according to item 40, which is provided as a solid preparation.
(Item 43)
A method for reducing the risk of stroke in a subject suffering from an ischemic event, wherein an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. A method comprising the step of administering to said subject the composition according to any one of items 40-42.
(Item 44)
43. The method of item 43, wherein the administering step reduces the risk of stroke in a subject as compared to a subject not receiving the compound.
(Item 45)
A method for reducing the risk of stroke or systemic embolism in a subject suffering from atrial fibrillation, wherein the compound according to any one of items 1 to 38 in an effective amount is used for the subject. A method comprising the step of administering the pharmaceutically acceptable salt or the composition according to any one of items 40-42.
(Item 46)
A method for reducing systemic embolism of the non-central nervous system in a subject suffering from an ischemic event, wherein the compound according to any one of items 1 to 38 in an effective amount is used for the subject. A method comprising the step of administering the pharmaceutically acceptable salt or the composition according to any one of items 40-42.
(Item 47)
46. The method of item 46, wherein the administering step reduces systemic embolism of the non-central nervous system in the subject as compared to the subject not receiving the compound.
(Item 48)
For a subject suffering from an ischemic event, an effective amount of the compound according to any one of items 1-38 or a pharmaceutically acceptable salt thereof, or any one of items 40-42. A method of treating deep vein thrombosis, comprising the step of administering to the composition of.
(Item 49)
A method for reducing the risk of recurrence of deep vein thrombosis, which is an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutical drug thereof for a subject suffering from deep vein thrombosis. A method comprising the step of administering an acceptable salt to, or the composition according to any one of items 40-42.
(Item 50)
49. The method of item 49, wherein the administering step reduces the risk of recurrence of deep vein thrombosis in the subject as compared to the subject not receiving the compound.
(Item 51)
The step of administering to the subject an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or the composition according to any one of items 40 to 42. Methods of preventing deep vein thrombosis in a subject, including.
(Item 52)
51. The method of item 51, wherein the subject is undergoing orthopedic surgery or knee or hip replacement surgery.
(Item 53)
A method for reducing the risk of recurrence of pulmonary embolism, wherein the compound according to any one of items 1 to 38 of an effective amount or a pharmaceutically acceptable compound thereof is pharmaceutically acceptable to a subject suffering from pulmonary embolism. A method comprising the step of administering the salt to be made or the composition according to any one of items 40-42.
(Item 54)
A method for reducing the risk of recurrence of pulmonary embolism, which is an effective amount for a subject suffering from deep vein thrombosis, according to any one of items 1 to 38 of the effective amount, or the compound according to the drug thereof. A method comprising the step of administering an acceptable salt or the composition according to any one of items 40-42.
(Item 55)
53. The method of item 53 or 54, wherein the administering step reduces the risk of recurrence of pulmonary embolism in the subject as compared to the subject not receiving the compound.
(Item 56)
A method for treating pulmonary embolism in a subject suffering from deep vein thrombosis, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutically acceptable compound thereof thereof is acceptable to the subject. A method comprising the step of administering a salt, or the composition according to any one of items 40-42.
(Item 57)
A method for preventing pulmonary embolism in a subject suffering from pulmonary embolism, wherein the compound according to any one of items 1 to 38 of an effective amount or a pharmaceutically acceptable compound thereof thereof is acceptable to the subject. A method comprising the step of administering a salt or the composition according to any one of items 40-42.
(Item 58)
A method for preventing pulmonary embolism in a subject suffering from pulmonary embolism, wherein the compound according to any one of items 1 to 38 of an effective amount or a pharmaceutically acceptable compound thereof thereof is acceptable to the subject. A method comprising the step of administering a salt or the composition according to any one of items 40-42.
(Item 59)
A method for preventing pulmonary embolism in a subject suffering from deep vein thrombosis, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutically acceptable compound thereof thereof is acceptable to the subject. A method comprising the step of administering a salt, or the composition according to any one of items 40-42.
(Item 60)
A method for treating a subject having an ischemic event, wherein the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or any one of items 40 to 42. To the subject, 12 hours or less, 10 hours or less, 9 hours or less, 8 hours or less, 7 hours or more after the onset of the ischemic event in the subject. A method comprising the steps of administration within less than, 6 hours or less, or 1 hour or less.
(Item 61)
A method for treating deep vein thrombosis to a subject previously administered with an anticoagulant, wherein the compound according to any one of items 1 to 38 in an effective amount or a compound thereof thereof is used for the subject. A method comprising the step of administering a pharmaceutically acceptable salt or the composition according to any one of items 40-42.
(Item 62)
A method for treating pulmonary embolism in a subject previously administered with an anticoagulant, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutical agent thereof is used for the subject. A method comprising the step of administering a pharmaceutically acceptable salt or the composition according to any one of items 40-42.
(Item 63)
61. The method of item 61 or 62, wherein the anticoagulant is administered parenterally for 5-10 days.
(Item 64)
A method for treating a subject having an ischemic event, wherein the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or any one of items 40 to 42. To the subject, more than 2 hours to 12 hours, for example, more than 2 hours to 10 hours or less, more than 2 hours to 8 hours or less after the onset of the ischemic event in the subject. A method comprising the step of administering within.
(Item 65)
A method for treating acute coronary syndrome in a subject, the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or item 40 to the subject in need thereof. 42. A method comprising the step of administering the composition according to any one of 42.
(Item 66)
For a subject suffering from ischemia, an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or any one of items 40 to 42. A method of inhibiting Factor XIa in a subject, comprising the step of administering the composition.
(Item 67)
66. The method of item 66, wherein the ischemia is coronary ischemia.
(Item 68)
A method for treating a subject having edema, wherein the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or the composition according to any one of items 40 to 42. A method comprising the step of administering a substance.
(Item 69)
A subject having edema is administered an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or the composition according to any one of items 40 to 42. A method of inhibiting kallikrein in a subject, comprising the steps of
(Item 70)
A method of treating thromboembolic consequences or complications in a subject, wherein the subject is given an effective amount of the compound according to any one of items 1-38 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. A method comprising the step of administering the composition according to any one of items 40-42.
(Item 71)
Larger of said thromboembolic consequences or complications used to treat peripheral vascular intervention, hemodialysis, catheter ablation, cerebrovascular intervention, organ transplantation, surgery, transcatheter aortic valve implantation, aneurysm. 70. The method of item 70, which is associated with oral intervention, percutaneous coronary intervention or treatment of hemophilia.
(Item 72)
The method of item 71, wherein the surgery is orthopedic surgery, lung surgery, abdominal surgery or cardiac surgery.
(Item 73)
A step of administering to a subject an effective amount of a compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or a composition according to any one of items 40 to 42. A method of treating restenosis following an arterial injury in a subject, including.
(Item 74)
73. The method of item 73, wherein the arterial injury occurs after indwelling a cranial artery stent.
(Item 75)
A method for treating hepatic vascular thrombosis in a subject, wherein the subject has an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or items 40 to 42. A method comprising the step of administering the composition according to any one of the above.
(Item 76)
A method for treating non-ST-segment elevation myocardial infarction or ST-segment elevation myocardial infarction, wherein the compound according to any one of items 1 to 38 of an effective amount or a pharmaceutically acceptable salt thereof is used for a subject. Alternatively, a method comprising the step of administering the composition according to any one of items 40-42.
(Item 77)
A step of administering to a subject an effective amount of a compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or a composition according to any one of items 40 to 42. Methods for maintaining vascular patency, including.
(Item 78)
77. The method of item 77, wherein the subject has an acute kidney injury.
(Item 79)
78. The method of item 78, wherein the subject further receives continuous renal replacement therapy.
(Item 80)
A method for treating hypertension in a subject, wherein an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or any of items 40 to 42 is given to the subject. A method comprising the step of administering the composition according to paragraph 1.
(Item 81)
The method according to item 80, wherein the hypertension is arterial hypertension.
(Item 82)
A method for reducing the risk of hypertension in a subject, wherein the subject has an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or items 40 to 40. 42. A method comprising the step of administering the composition according to any one of 42.
(Item 83)
82. The method of item 82, wherein the hypertension is arterial hypertension.
(Item 84)
A method for preventing hypertension in a subject, which is an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or any of items 40 to 42. A method comprising the step of administering the composition according to paragraph 1.
(Item 85)
84. The method of item 84, wherein the hypertension is arterial hypertension.
(Item 86)
A method for reducing inflammation in a subject, wherein an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or any of items 40 to 42 is given to the subject. A method comprising the step of administering the composition according to paragraph 1.
(Item 87)
86. The method of item 86, wherein the inflammation is vascular inflammation.
(Item 88)
87. The method of item 87, wherein the vascular inflammation is angiotensin II-induced vascular inflammation.
(Item 89)
A method for preventing leukocyte infiltration of blood vessels in a subject, wherein an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or item 40 to the subject is used. 42. A method comprising the step of administering the composition according to any one of 42.
(Item 90)
A method for preventing angiotensin II-induced endothelial dysfunction in a subject, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutically acceptable salt thereof, or an item thereof. A method comprising the step of administering the composition according to any one of 40-42.
(Item 91)
A method for preventing thrombin proliferation in a subject, wherein the subject has an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or items 40 to 42. A method comprising the step of administering the composition according to any one.
(Item 92)
A method for treating hypertension-related renal dysfunction in a subject, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutically acceptable salt thereof, or an item thereof. A method comprising the step of administering the composition according to any one of 40-42.
(Item 93)
A method for preventing hypertension-related renal dysfunction in a subject, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutically acceptable salt thereof, or an item thereof. A method comprising the step of administering the composition according to any one of 40-42.
(Item 94)
A method for reducing the risk of hypertension-related renal dysfunction in a subject, wherein the compound according to any one of items 1 to 38 of an effective amount or a pharmaceutically acceptable salt thereof is used for the subject. , Or a method comprising the step of administering the composition according to any one of items 40-42.
(Item 95)
A method for treating hypertension-related renal dysfunction in a subject, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutically acceptable salt thereof, or an item thereof. A method comprising the step of administering the composition according to any one of 40-42.
(Item 96)
A method for preventing hypertension-related renal dysfunction in a subject, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutically acceptable salt thereof, or an item thereof. A method comprising the step of administering the composition according to any one of 40-42.
(Item 97)
A method for reducing the risk of hypertension-related renal dysfunction in a subject, wherein the compound according to any one of items 1 to 38 of an effective amount or a pharmaceutically acceptable salt thereof is used for the subject. , Or a method comprising the step of administering the composition according to any one of items 40-42.
(Item 98)
A method for treating renal fibrosis in a subject, wherein the subject is given an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or items 40 to 42. A method comprising the step of administering the composition according to any one of the above.
(Item 99)
A method for preventing renal fibrosis in a subject, wherein an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or items 40 to 42 thereof is given to the subject. A method comprising the step of administering the composition according to any one of the above.
(Item 100)
A method for reducing the risk of renal fibrosis in a subject, the compound according to any one of items 1 to 38 in an effective amount, or a pharmaceutically acceptable salt thereof, or an item. A method comprising the step of administering the composition according to any one of 40-42.
(Item 101)
A method for treating a kidney injury in a subject, wherein the subject has an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or items 40 to 42. A method comprising the step of administering the composition according to any one.
(Item 102)
A method for preventing kidney injury in a subject, wherein the subject has an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or items 40 to 42. A method comprising the step of administering the composition according to any one.
(Item 103)
A method for reducing the risk of kidney injury in a subject, wherein the subject has an effective amount of the compound according to any one of items 1 to 38 or a pharmaceutically acceptable salt thereof, or item 40. 42. A method comprising the step of administering the composition according to any one of 42.
(Item 104)
A method of doing so in a subject in need of treatment for a thromboembolic disorder, wherein the subject is pharmaceutically acceptable for the compound according to any one of items 1-38 in an effective amount or pharmaceutically acceptable thereof. A method comprising the step of administering a salt or the composition according to any one of items 40-42, wherein the subject is exposed to an artificial surface.
(Item 105)
A method for doing so in a subject who needs to reduce the risk of thromboembolic disorder, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutically thereof thereof is used for the subject. A method comprising the step of administering an acceptable salt or the composition according to any one of items 40-42, wherein the subject is exposed to an artificial surface.
(Item 106)
A method of doing so in a subject in need of prevention of thromboembolic disorders, wherein the subject is pharmaceutically acceptable for the compound according to any one of items 1-38 of an effective amount or pharmaceutically acceptable thereof. A method comprising the step of administering a salt or the composition according to any one of items 40-42, wherein the subject is exposed to an artificial surface.
(Item 107)
A method of performing this in a subject in need of treatment for heparin-induced thrombocytopenia, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutically acceptable thereof thereof is acceptable to the subject. A method comprising the step of administering the salt to be added or the composition according to any one of items 40-42.
(Item 108)
A method for performing this in a subject who needs to reduce the risk of heparin-induced thrombocytopenia, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutical agent thereof is used for the subject. A method comprising the step of administering a pharmaceutically acceptable salt or the composition according to any one of items 40-42.
(Item 109)
A method of doing so in a subject in need of prevention of heparin-induced thrombocytopenia, wherein the compound according to any one of items 1 to 38 of an effective amount or a pharmaceutically acceptable thereof thereof is acceptable to the subject. A method comprising the step of administering the salt to be made or the composition according to any one of items 40-42.
(Item 110)
A method for performing this in a subject in need of treatment for heparin-induced thrombocytopenia thrombosis, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutical drug thereof is used for the subject. A method comprising the step of administering an acceptable salt to, or the composition according to any one of items 40-42.
(Item 111)
A method for performing this in a subject who needs to reduce the risk of heparin-induced thrombocytopenia thrombosis, wherein the compound according to any one of items 1 to 38 in an effective amount is used for the subject. A method comprising the step of administering the pharmaceutically acceptable salt or the composition according to any one of items 40-42.
(Item 112)
A method for performing this in a subject in need of prevention of heparin-induced thrombocytopenia thrombosis, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutical drug thereof is used for the subject. A method comprising the step of administering an acceptable salt to, or the composition according to any one of items 40-42.
(Item 113)
A method of doing so in a subject in need of prevention of thromboembolic disorders, wherein the compound according to any one of items 1 to 38 of an effective amount or a pharmaceutically acceptable thereof thereof is acceptable to the subject. A method comprising the step of administering a salt or the composition according to any one of items 40-42, wherein the subject has cancer.
(Item 114)
A method for performing this in a subject in need of treatment for thrombotic microangiosis, wherein the compound of formula (II) according to any one of items 1 to 38 in an effective amount or a compound thereof thereof is used for the subject. A method comprising the step of administering a pharmaceutically acceptable salt or the composition according to any one of items 40-42.
(Item 115)
A method for doing so in a subject who needs to reduce the risk of thrombotic microangiosis, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutical drug thereof is used for the subject. A method comprising the step of administering an acceptable salt, or the composition according to any one of items 40-42.
(Item 116)
A method for preventing thrombotic microangiopathy in a subject in need thereof, wherein the compound according to any one of items 1 to 38 in an effective amount or a pharmaceutically acceptable compound thereof thereof is acceptable to the subject. A method comprising the step of administering a salt or the composition according to any one of items 40-42.
(Item 117)
The method according to any one of items 43 to 116, wherein the subject is a subject having non-valvular atrial fibrillation.
(Item 118)
117. The method of item 117, wherein said subject has one or more of the following risk factors for stroke: past stroke, transient ischemic attack, or non-CNS systemic embolism.
(Item 119)
The method of item 118, wherein said subject has one or more of the following risk factors for stroke: age 75 or older, hypertension, heart failure or left ventricular ejection fraction, or diabetes.
(Item 120)
The method of item 117, wherein the compound is administered after an ischemic event.
(Item 121)
About 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days after the ischemic event. , Or the method of item 120, which is administered later.
(Item 122)
The item in which the compound is administered approximately 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or later of an ischemic event. The method according to 120.
(Item 123)
120. The method of item 120, wherein the compound is administered approximately 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or later of an ischemic event.
(Item 124)
The method of item 117, wherein the compound is administered in combination with an additional therapeutic agent.
(Item 125)
124. The method of item 124, wherein the additional therapeutic agent is administered after administration of the compound.
(Item 126)
124. The method of item 124, wherein the additional therapeutic agent is orally administered.
(Item 127)
The additional therapeutic agent is at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 after administration of the compound. The method of item 124, which is administered after hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, or later.
(Item 128)
The additional therapeutic agent is administered at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 28 days, or later after administration of the compound. , Item 124.
(Item 129)
Item 124, wherein the additional therapeutic agent is administered about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, or later after administration of the compound. The method described in.
(Item 130)
124. The method of item 124, wherein the additional therapeutic agent is administered for a long period of time after administration of the compound.
(Item 131)
The method of item 124, wherein the additional therapeutic agent is an NSAID, platelet aggregation inhibitor or anticoagulant.
(Item 132)
The method of item 124, wherein the additional therapeutic agent provides an additive therapeutic effect.
(Item 133)
The method of item 124, wherein the additional therapeutic agent provides a synergistic therapeutic effect.
(Item 134)
The method according to any one of items 43 to 133, wherein the compound is administered orally or parenterally.
(Item 135)
The method according to any one of items 43 to 133, wherein the compound is orally administered.
(Item 136)
The method according to any one of items 43 to 133, wherein the compound is administered parenterally.
(Item 137)
43-133, wherein the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered after the subject has directly discontinued the use of the oral anticoagulant. Method.
(Item 138)
137. The method of item 137, wherein the subject is a subject using the direct oral anticoagulant.
(Item 139)
The method according to any one of items 43 to 138, wherein the subject is a mammal.
(Item 140)
The method according to any one of items 43 to 139, wherein the mammal is a human.

Claims

Equation (II):

[During the ceremony,
R ¹ is hydrogen or -NR ⁸ R ⁹ ;
^Ra is C _1-6 alkyl, C _1-6 haloalkyl, halo, cyano or -OR ⁶ ;
R ^b is hydrogen or C _1-6 alkyl;
^R2 is a 5-membered heteroaryl or optionally substituted 5-membered heterocyclyl;
R ³ is hydrogen, C _1-6 alkyl or C _1-6 haloalkyl;
^R4 is C _1-6 alkyl, C _1-6 haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is halo, C _1-6 alkyl, C _1-6 haloalkyl, cyano or -OR ⁶ with one, two or three independent appearances substituted as needed;
R ⁵ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, cycloalkyl or aryl, wherein the cycloalkyl or aryl is halo, C _1-6 alkyl, C _1-6 haloalkyl, cyano or -Also substituted as needed with one, two or three independent appearances of OR ⁶ , or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a ring. Formed;
R ⁶ is hydrogen, C _1-6 alkyl or C _1-6 haloalkyl;
Each R ⁸ and R ⁹ are independently hydrogen, C _1-6 alkyl, -C (O) R ¹⁰ or -C (O) OR ¹⁰ ;
R ¹⁰ is C _1-6 alkyl or C _1-6 haloalkyl;
If R ^x is -O or absent, where R ^x is -O, then the nitrogen atom of the pyridyl ring is positively charged and R ^x is negatively charged. , Thereby forming pyridyl N-oxide;
m is 0, 1, 2 or 3;
n is 0 or 1, where n is 0, then R ⁵ is hydrogen and R ⁴ is absent]
Compound or pharmaceutically acceptable salt thereof.

Equation (I):

The compound according to claim 1, which is a compound of the above.

The compound according to claim 1, wherein R ^x does not exist.

The compound according to any one of claims 1 to 3, wherein R ⁶ is C _{1 to 6} alkyl or C ₁ to 6 halo alkyl.

The compound according to any one of claims 1 to 4, wherein R ⁶ is -CH ₃ or -CF ₃ .

The compound according to any one of claims 1 to 5, wherein R ¹ is hydrogen, -NH ₂ or -NHCH ₃ .

The compound according to any one of claims 1 to 6, wherein R ¹ is hydrogen.

The compound according to any one of claims 1 to 6, wherein R ¹ is -NH ₂ .

The compound according to any one of claims 1 to 6, wherein R ¹ is -NHCH ₃ .

The compound according to any one of claims 1 to 9, wherein R ² is a 5-membered heteroaryl optionally substituted with one or two independent appearances of C _1-6 alkyl.

^R2 is pyrazolyl, imidazolyl, thienyl, isothiazolyl, thiazolyl, oxadiazolyl or thiaziazolyl, wherein the imidazolyl, thienyl, isothiazolyl, thiazolyl, oxadiazolyl or thiaziazolyl is _one or two independent C1-6 alkyl. The compound according to any one of claims 1 to 10, which is optionally substituted at the time of appearance.

R ² is pyrazolyl, imidazolyl, thienyl, isothiazolyl, thiazolyl, oxadiazolyl or thiaziazolyl, wherein the imidazolyl, thienyl, isothiazolyl, thiazolyl, oxadiazolyl or thiaziazolyl is required in the appearance of one or two of -CH ₃ . The compound according to any one of claims 1 to 11, which is substituted accordingly.

R ² is

The compound according to any one of claims 1 to 12.

The compound according to any one of claims 1 to 9, wherein R ² is a 5-membered heterocyclyl in which one or two independent appearances of C _{1 to 6} alkyl are optionally substituted.

The compound according to any one of claims 1 to 14, wherein R ³ is C _{1 to 6} alkyl.

The compound according to any one of claims 1 to 15, wherein R ³ is −CH ₃ .

^R4 is C _1-6 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or heteroaryl is one, two or three of halo or C _1-6 alkyl. The compound according to any one of claims 1 to 16, which is optionally substituted with the independent appearance of.

^R4 is cyclohexyl, cyclopropyl, phenyl, tetrahydropyranyl, pyridyl, pyrazolyl, thienyl or C _1-6 alkyl, wherein the cyclohexyl, cyclopropyl, phenyl, tetrahydropyranyl, pyridyl, pyrazolyl or thienyl The compound according to any one of claims 1 to 17, which is optionally substituted with one, two or three independent appearances of halo or C _1-6 alkyl.

^R4 is cyclohexyl, phenyl, pyridyl, pyrazolyl or thienyl, wherein said cyclohexyl, phenyl, pyridyl, pyrazolyl or thienyl is one, two or three independent appearances of halo or C _1-6 alkyl. The compound according to any one of claims 1 to 18, which is optionally substituted in 1.

¹³ _. The compound described.

R ⁵ is hydrogen, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CF ₃ or unsubstituted cyclopropyl. The compound according to any one of claims 1 to 20.

The compound according to any one of claims 1 to 21, wherein R ⁵ is -CH ₂ CH ₃ , -CF ₃ or unsubstituted cyclopropyl.

Equation (Ia):

The compound according to any one of claims 1 to 22, which is the compound of the above.

Equation (I-b):

The compound according to any one of claims 1 to 23, which is the compound of the above.

Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ii) or Formula (Ij) :.

The compound according to any one of claims 1 to 24, which is the compound of the above.

Equation (Ic):

The compound according to any one of claims 1 to 25, which is the compound of the above.

Formula (Ie), formula (Ik), formula (Il), formula (Im), formula (Io), formula (Ip), formula (It), formula. (Iu) or formula (Iv):

[In the formula, each of R ^b2 is independently halo, C _1-6 alkyl, C _1-6 haloalkyl, cyano or -OR ⁶ ; p is 0, 1, 2 or 3].
The compound according to any one of claims 1 to 26, which is the compound of the above.

The compound according to any one of claims 1 to 22, wherein ^Ra is halo or -C _{1 to 6} alkyl.

The compound according to any one of claims 1 to 22 or 28, wherein ^Ra is F or -CH ₃ .

The compound according to any one of claims 1 to 22 or 28 to 29, wherein m is 1.

The compound according to any one of claims 1 to 22 or 28 to 30, wherein R ^a is −CH ₃ and m is 1.

Equation (Iq):

Equation (Ir):

The compound according to any one of claims 1 to 22 or 32, which is the compound of the above.

Equation (Is):

The compound according to any one of claims 1 to 22, 32 or 33, which is the compound of the above.

Equation (I-s1) or Equation (I-s2):

[In the formula, each of R ^b2 is independently halo, C _1-6 alkyl, C _1-6 haloalkyl, cyano or -OR ⁶ ; p is 0, 1, 2 or 3].
The compound according to any one of claims 1 to 22 or 32 to 34, which is the compound of the above.

The compound according to any one of claims 1 or 3 to 22, wherein R ^b is C _{1 to 6} alkyl.

The compound according to any one of claims 1, 3 to 22 or 36, wherein R ^b is -CH ₃ .

formula:

Compound.

A pharmaceutically acceptable salt of the compound according to any one of claims 1 to 38.

A pharmaceutical composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

The pharmaceutical composition according to claim 40, which is provided as a liquid preparation.

The pharmaceutical composition according to claim 40, which is provided as a solid preparation.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , for reducing the risk of stroke in a subject suffering from an ischemic event. The composition according to any one of claims 40 to 42 .

43. The composition of claim 43, wherein administration of the composition reduces the risk of stroke in the subject as compared to a subject to whom the composition is not administered.

A compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof for reducing the risk of stroke or systemic embolism in a subject suffering from atrial fibrillation . The composition comprising , or the composition according to any one of claims 40 to 42 .

The compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for reducing systemic embolism of the non-central nervous system in a subject suffering from an ischemic event . The composition comprising , or the composition according to any one of claims 40 to 42 .

46. The composition of claim 46, wherein administration of the composition reduces systemic embolism of the non-central nervous system in the subject as compared to a subject to which the composition is not administered.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for treating deep vein thrombosis, or any one of claims 40 to 42. The composition of the description, wherein the composition is administered to a subject suffering from an ischemic event .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, or a composition according to claims 40 to 42, for reducing the risk of recurrence of deep vein thrombosis. The composition according to any one of the above , which is administered to a subject suffering from deep vein thrombosis .

49. The composition of claim 49, wherein administration of the composition reduces the risk of recurrence of deep vein thrombosis in the subject as compared to a subject to which the composition is not administered.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , or any of claims 40 to 42 for the prevention of deep vein thrombosis in a subject. The composition according to one item .

51. The composition of claim 51, wherein the subject has undergone orthopedic surgery or knee or hip replacement surgery.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , or any of claims 40 to 42 for reducing the risk of recurrence of pulmonary embolism. The composition according to claim 1, wherein the composition is administered to a subject suffering from pulmonary embolism .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , or any of claims 40 to 42 for reducing the risk of recurrence of pulmonary embolism. The composition according to item 1, wherein the composition is administered to a subject suffering from deep vein thrombosis .

The composition according to claim 53 or 54, wherein administration of the composition reduces the risk of recurrence of pulmonary embolism in the subject as compared to a subject to which the composition is not administered.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for treating pulmonary embolism in a subject suffering from deep vein thrombosis. The composition according to any one of claims 40 to 42 .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for the prevention of pulmonary embolism in a subject suffering from pulmonary embolism, or a claim thereof. Item 2. The composition according to any one of Items 40 to 42 .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for the prevention of pulmonary embolism in a subject suffering from deep vein thrombosis. The composition according to any one of claims 40 to 42 .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for treating a subject having an ischemic event, or any of claims 40 to 42. The composition according to paragraph (1) , wherein the subject has 12 hours or less, 10 hours or less, 9 hours or less, 8 hours or more after the onset of the ischemic event in the subject. A composition, characterized in that it is administered within less than, 7 hours or less, 6 hours or less, or 1 hour or less.

Contains the compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof for treating deep vein thrombosis to a subject previously administered with an anticoagulant. The composition or the composition according to any one of claims 40 to 42 .

A composition comprising the compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof for treating pulmonary embolism in a subject previously administered with an anticoagulant. The product or the composition according to any one of claims 40 to 42 .

The composition according to claim 61 or 62, wherein the anticoagulant is administered parenterally for 5 to 10 days.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for treating a subject having an ischemic event, or any of claims 40 to 42. The composition according to claim 1 , wherein the subject has more than 2 hours to 12 hours, for example, more than 2 hours to 10 hours or less, more than 2 hours after the onset of the ischemic event in the subject. The composition, characterized in that it is administered within 8 hours or less.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for treating acute coronary syndrome in a subject, or any one of claims 40 to 42. The composition according to the section .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for inhibiting factor XIa in a subject , or any one of claims 40 to 42. The composition according to the section, wherein the composition is administered to a subject suffering from ischemia .

The composition according to claim 66, wherein the ischemia is coronary ischemia.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for treating a subject having edema, or any one of claims 40 to 42. The composition according to.

The composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for inhibiting kallikrein in a subject , or any one of claims 40 to 42. The composition of the description, wherein the composition is administered to a subject having edema .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for treating thromboembolic consequences or complications in a subject, or claims 40 to 40. 42. The composition according to any one of.

Larger of said thromboembolic consequences or complications used to treat peripheral vascular intervention, hemodialysis, catheter ablation, cerebrovascular intervention, organ transplantation, surgery, transcatheter aortic valve implantation, aneurysm. 70. The composition of claim 70, which is associated with caliber intervention, percutaneous coronary intervention or treatment of hemophilia.

The composition according to claim 71, wherein the surgery is an orthopedic surgery, a lung surgery, an abdominal surgery or a heart surgery.

A composition comprising the compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof for treating restenosis following an arterial injury in a subject , or claims 40-42. The composition according to any one of the above .

33. The composition of claim 73, wherein the arterial injury occurs after indwelling a cranial artery stent.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for treating hepatic vascular thrombosis in a subject, or any of claims 40 to 42. The composition according to one item .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for treating non-ST-segment elevation myocardial infarction or ST-segment elevation myocardial infarction, or claim 40. The composition according to any one of 42 .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for maintaining vascular patency , or any one of claims 40 to 42. The composition described .

17. The composition of claim 77, wherein the subject has an acute kidney injury.

28. The composition of claim 78, wherein the subject further receives continuous renal replacement therapy.

The composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for treating hypertension in a subject, or any one of claims 40 to 42. The composition described .

The composition according to claim 80, wherein the hypertension is arterial hypertension.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , or any of claims 40 to 42, for reducing the risk of hypertension in a subject. The composition according to one item .

82. The composition of claim 82, wherein the hypertension is arterial hypertension.

The composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for the prevention of hypertension in a subject, or any one of claims 40 to 42. The composition described .

The composition according to claim 84, wherein the hypertension is arterial hypertension.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , or any one of claims 40 to 42 for reducing inflammation in a subject. The composition described .

The composition according to claim 86, wherein the inflammation is vascular inflammation.

87. The composition of claim 87, wherein the vascular inflammation is angiotensin II-induced vascular inflammation.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , or any of claims 40 to 42 for preventing leukocyte infiltration of blood vessels in a subject. The composition according to one item .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for preventing angiotensin II-induced endothelial dysfunction in a subject, or claims 40 to 42. The composition according to any one .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for preventing thrombin proliferation in a subject, or any one of claims 40 to 42. The composition according to.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for treating hypertension-related renal dysfunction in a subject, or claims 40 to 42. The composition according to any one .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for the prevention of hypertension-related renal dysfunction in a subject, or claims 40 to 42. The composition according to any one .

40, or a composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , for reducing the risk of hypertension-related renal dysfunction in a subject. The composition according to any one of 42 .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for treating renal fibrosis in a subject, or any one of claims 40 to 42. The composition according to the section .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , or any one of claims 40 to 42 for the prevention of renal fibrosis in a subject. The composition according to the section .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, or a composition according to claims 40 to 42, for reducing the risk of renal fibrosis in a subject. The composition according to any one .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for treating a kidney injury in a subject, or any one of claims 40 to 42. The composition according to.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , or any one of claims 40 to 42 for preventing kidney injury in a subject. The composition according to.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , or any of claims 40 to 42, for reducing the risk of kidney injury in a subject. The composition according to one item .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , or a claim thereof, for performing the treatment in a subject in need of treatment for a thromboembolic disorder. A composition according to any one of 40 to 42, wherein the subject is exposed to an artificial surface.

A composition comprising the compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof for doing so in a subject who needs to reduce the risk of thromboembolic disorder. Alternatively, the composition according to any one of claims 40 to 42, wherein the subject is exposed to an artificial surface.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , or a claim thereof, for performing the same in a subject in need of prevention of thromboembolic disorder. A composition according to any one of 40 to 42, wherein the subject is exposed to an artificial surface.

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for performing it in a subject in need of treatment for heparin-induced thrombocytopenia. The composition according to any one of claims 40 to 42 .

A composition comprising the compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof for doing so in a subject in need of reduced risk of heparin-induced thrombocytopenia. The product or the composition according to any one of claims 40 to 42 .

A composition comprising the compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof , for performing the same in a subject in need of prevention of heparin-induced thrombocytopenia. The composition according to any one of claims 40 to 42 .

A composition comprising the compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof for performing it in a subject in need of treatment for heparin-induced thrombocytopenia thrombosis. , Or the composition according to any one of claims 40 to 42 .

The compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for doing so in a subject who needs to reduce the risk of heparin-induced thrombocytopenia thrombosis. The composition comprising , or the composition according to any one of claims 40 to 42 .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for performing it in a subject in need of prevention of heparin-induced thrombocytopenia thrombosis. , Or the composition according to any one of claims 40 to 42 .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof , or a claim thereof, for performing the same in a subject in need of prevention of thromboembolic disorder. The composition according to any one of 40 to 42 .

Contains the compound of formula (II) according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof for performing it in a subject in need of treatment for thrombotic microangiopathy. The composition or the composition according to any one of claims 40 to 42 .

A composition comprising the compound according to any one of claims 1-38 or a pharmaceutically acceptable salt thereof for doing so in a subject who needs to reduce the risk of thrombotic microangiosis. , Or the composition according to any one of claims 40 to 42 .

A composition comprising the compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof for performing prevention of thrombotic microangiopathy in a subject in need thereof , or a claim thereof. Item 2. The composition according to any one of Items 40 to 42 .

The composition according to any one of claims 43 to 116, wherein the subject is a subject having non-valvular atrial fibrillation.

17. The composition of claim 117, wherein said subject has one or more of the following risk factors for stroke: past stroke, transient ischemic attack, or non-CNS systemic embolism.

18. The composition of claim 118, wherein said subject has one or more of the following risk factors for stroke: age 75 or older, hypertension, heart failure or left ventricular ejection fraction, or diabetes.

17. The composition of claim 117, wherein the composition is administered after an ischemic event.

The composition is about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 after the ischemic event. The composition according to claim 120, which is administered after a day or later.

The composition is administered approximately 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or later of the ischemic event. The composition according to claim 120.

120. The composition of claim 120, wherein said composition is administered approximately 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or later of an ischemic event. ..

17. The composition of claim 117, wherein the composition is administered in combination with an additional therapeutic agent.

The composition of claim 124, wherein the additional therapeutic agent is administered after administration of the composition .

The composition of claim 124, wherein the additional therapeutic agent is orally administered.

The additional therapeutic agent is at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours after administration of the composition . The composition according to claim 124, which is administered after 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, or later.

The additional therapeutic agent is administered at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 28 days, or later after administration of the composition. The composition according to claim 124.

Claimed that the additional therapeutic agent is administered about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, or later after administration of the composition. Item 124 .

The composition of claim 124, wherein the additional therapeutic agent is administered for a long period of time after administration of the composition .

The composition of claim 124, wherein the additional therapeutic agent is an NSAID, platelet aggregation inhibitor or anticoagulant.

The composition of claim 124, wherein the additional therapeutic agent provides an additive therapeutic effect.

The composition of claim 124, wherein the additional therapeutic agent provides a synergistic therapeutic effect.

The composition according to any one of claims 43 to 133, wherein the composition is orally or parenterally administered.

The composition according to any one of claims 43 to 133, wherein the composition is orally administered.

The composition according to any one of claims 43 to 133, wherein the composition is administered parenterally.

The composition according to any one of claims 43 to 133, wherein the composition is administered after the subject has directly discontinued the use of the oral anticoagulant.

The composition according to claim 137, wherein the subject is a subject using the direct oral anticoagulant.

The composition according to any one of claims 43 to 138, wherein the subject is a mammal.

The composition according to any one of claims 43 to 139, wherein the mammal is a human.