JPWO2020247160A5

JPWO2020247160A5 -

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Publication number: JPWO2020247160A5
Application number: JP2021567819A
Authority: JP
Publication date: 2023-05-15

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他の実施形態
本開示は、本発明の単なる例示的な実施形態を提供する。当業者は、本開示ならびに添付の図面および特許請求の範囲から、以下の特許請求の範囲で定義される本発明の精神および範囲から逸脱することなく、種々の変更、改変、および変形を行うことができることを容易に認識するであろう。
本発明は、例えば、以下の項目を提供する。
（項目１）
式（Ｉ）の化合物、

その互変異性体、上述のいずれかの薬学的に許容される塩、および／または上述のいずれかの重水素化誘導体であって、
式中、
（ｉ）Ｒ ^０が、以下から選択され、
（ａ）Ｃ _１～Ｃ _８直鎖、分枝鎖、および環状アルキル基であって、前記アルキル基が、１～４個のＲ ^Ａで任意に置換される、Ｃ _１～Ｃ _８直鎖、分枝鎖、および環状アルキル基、ならびに
（ｂ）１～４個のＲ ^Ａで任意に置換された５～１４員の芳香族環であって、
各Ｒ ^Ａが、独立して、ハロゲン、シアノ、ヒドロキシ、チオール、スルホン酸、スルホンアミド、スルフィンアミド、アミノ、アミド、カルボン酸、５～１０員の芳香族環、ならびにＣ _１～Ｃ _６直鎖、分枝鎖、および環状基から選択され、
Ｒ ^Ａの前記アミド中のアミド窒素原子が、オキソで任意にさらに置換されたヘテロシクリル基で任意に置換され、
前記Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基が、アルキル、アルコキシ、チオアルキル、アルキルスルホキシド、アルキルスルホニル、アルキルスルホンアミド、アルキルスルフィンアミド、アミノアルキル、およびアルキルアミドから選択され、
前記５～１０員の芳香族環ならびにＣ _１～Ｃ _６直鎖、分枝鎖、および環状基が、ハロゲン、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基ならびにメトキシから１～４個の置換基で任意に置換され、
Ｒ ^Ａ基が、Ｒ ^２基上のＲ ^Ｂ基に任意に結合される、５～１４員の芳香族環、
（ｉｉ）Ｒ ^１が、以下から選択され、
（ａ）水素、
（ｂ）Ｃ _１～Ｃ _８直鎖、分枝鎖、および環状アルキル基であって、前記アルキル基が、
ハロゲン、
シアノ、
シアノアルキル、
ヒドロキシ、
アルキルスルホニル、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基、から独立して選択される１～４個の置換基で任意に置換され、前記Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基が、アルキル基およびアルキル基から独立して選択され、前記Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基が、
ハロゲン、
ヒドロキシ、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、から独立して選択される１～４個の置換基で任意に置換された、Ｃ _１～Ｃ _８直鎖、分枝鎖、および環状アルキル基、
（ｃ）
ハロゲン、
シアノ、
シアノアルキル、
スルホン、
スルホンアミド、
ヒドロキシ、ならびに
１～４個のハロゲンまたはアルコキシ基で任意に置換されたＣ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、から独立して選択される１～４個の置換基で任意に置換されたＣ _１～Ｃ _８直鎖、分枝鎖、および環状アルコキシ基または環状チオアルキル基、
（ｄ）Ｃ _１～Ｃ _６直鎖または分枝鎖アルキル基で任意に置換されたＣ _１～Ｃ _６直鎖、分枝鎖、および環状アルキルスルホニル基、
（ｅ）
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基から独立して選択される１個または２個の置換基で任意に置換された、アミノスルホニル基、
（ｆ）Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキルスルホニルアミノ基、ならびに
（ｇ）
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基から独立して選択される１または２個の置換基で任意に置換された、ホスフィンオキシド基、
（ｈ）Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状トリアルキルシリル基、
（ｉ）Ｃ _１～Ｃ _６アルキルアミド、
（ｉｉｉ）Ｒ ^２が、５員および６員の複素環（オキソおよび／またはＣ _１～Ｃ _６直鎖および分枝鎖アルキル基で任意に置換された）、ならびにＯ、ＮおよびＳから選択される０～４個のヘテロ原子を含む５～６員の芳香族環から選択され、前記５員の芳香族環が、１～４個のＲ ^Ｂ基で任意に置換され、前記６員の芳香族環が、１～５個のＲ ^Ｂ基で任意に置換され、前記Ｒ ^Ｂ基が、独立して、
アミドであって、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基（ヘテロアリールで任意に置換された）、４～６員ヘテロシクリル（オキソ、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ヒドロキシアルキル、アミド、アルキルスルホニル、およびアセトアミドで任意に置換された）から選択される１～３個の基で任意に置換されるか、または前記アミド窒素原子が、３～８員ヘテロシクリル環（アルキルスルホニルまたはＣ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基で任意に置換された）の一部を形成する、アミド、
イミダゾリジン－２，４－ジオン、
ヘテロシクリルであって、オキソ、アシル、ならびにＣ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基（オキソ、ヒドロキシ、およびアシルから独立して選択される１～３個の基で任意にさらに置換された）から独立して選択される１個以上の基で任意に置換された、ヘテロシクリル、
Ｃ _１～Ｃ _６直鎖、分枝鎖、または環状アルキル基で任意にエステル化された亜リン酸、
ジ（Ｃ _１～Ｃ _６）アルキルホスフィンオキシド、
Ｃ _１～Ｃ _６直鎖、分枝鎖、または環状アルキル基で任意にエステル化された（Ｃ _１～Ｃ _６）アルキルホスフィン酸、
ハロゲン、
シアノ、
ヒドロキシ、
ウロン酸またはＣ _１～Ｃ _６直鎖、分枝鎖、もしくは環状アルキル基で任意にエステル化されたカルボン酸、
オキソ、
ジヒドロキシルボリル、
Ｏ、Ｎ、およびＳから独立して選択される０～４個のヘテロ原子を含む５および６員の芳香族環であって、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、から独立して選択される１～２個の置換基で任意に置換され、これらが、
ヒドロキシ、
カルボン酸、
ピロリジン－２－オン、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキルスルホニル基、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、から独立して選択される１～４個の置換基で任意に置換された、５および６員の芳香族環、
スルホン酸、
アルキルスルホンアミド、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキルスルホニル基、
アミノスルホニル基であって、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基から独立して選択される１個または２個の置換基で任意に置換された、アミノスルホニル基、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基であって、
ハロゲン、
ヒドロキシ、
カルボン酸、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、
オキソで任意に置換されたヘテロシクリル、および
アミド、から独立して選択される１～４個の置換基で任意に置換された、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基であって、
ハロゲン、
ヒドロキシ、
カルボン酸、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、から独立して選択される１～４個の置換基で任意に置換された、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、ならびに
テトラゾリル基であって、
ハロゲン、
ヒドロキシ、
カルボン酸、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基から選択される置換基で任意に置換された、テトラゾリル基、から選択され、
前記５員または６員の芳香族環上の２つの隣接する水素が、Ｏ、Ｎ、およびＳから独立して選択される０～４個のヘテロ原子を含む第２の５員または６員の芳香族環への結合によって置き換えられて、１～６個のＲ ^Ｂ基で任意に置換された二環式Ｒ ^２基を形成することができ、
（ｉｖ）Ｘ ^１およびＸ ^２が、独立して、水素、ハロゲン、シアノ、ヒドロキシ、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基から選択され、前記Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基が、アルキル、アルコキシ、チオアルキル、およびアミノアルキル基から独立して選択され、前記Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基が、１～４個の独立して選択されるハロゲンによって任意に置換され、
（ｖ）Ｗ ^１およびＷ ^２の各々が、独立して、ＣおよびＮから選択され、
（ｖｉ）各

が、単結合または二重結合を表すが、但し、１つの

のみが二重結合であることを条件とし、
（ｖｉｉ）各Ｒ ^３が、独立して、水素、ハロゲン、シアノ、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびにＣ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基から選択され、前記Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびに前記Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基が、ハロゲン、ヒドロキシ基、およびカルボン酸から独立して選択される１～４個の置換基で任意に置換され、
（ｖｉｉｉ）ｎが、０、１、２、および３から選択される整数であり、
（ｉｘ）Ｚ ^１、Ｚ ^２、およびＺ ^３が、独立して、炭素、窒素、硫黄、および酸素から選択され、
Ｚ ^１、Ｚ ^２、および／またはＺ ^３が、炭素または窒素である場合、炭素または窒素の価電子が、水素原子、ハロゲン、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびにＣ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基で完了し、前記Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびに前記Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基が、ハロゲン、ヒドロキシ基、およびカルボン酸から独立して選択される１～４個の置換基で任意に置換されている、式（Ｉ）の化合物、その互変異性体、上述のいずれかの薬学的に許容される塩、および／または上述のいずれかの重水素化誘導体。
（項目２）
Ｒ ^０が、アリール環、ヘテロアリール環、およびＣ _１～Ｃ _８直鎖、分枝鎖、および環状アルキル基から選択され、これらの各々が、ハロゲン、カルボン酸、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、アリール環、ならびにヘテロアリール環から独立して選択される１～２個の置換基で任意に置換されている、項目１に記載の化合物、その互変異性体、前記化合物の薬学的に許容される塩、前記互変異性体の薬学的に許容される塩、前記化合物の重水素化誘導体、前記互変異性体の重水素化誘導体、および／または前記塩の重水素化誘導体。
（項目３）
Ｒ ^０が、

から選択される、項目１または２に記載の化合物、その互変異性体、前記化合物の薬学的に許容される塩、前記互変異性体の薬学的に許容される塩、前記化合物の重水素化誘導体、前記互変異性体の重水素化誘導体、および／または前記塩の重水素化誘導体。
（項目４）
Ｒ ^１が、
水素、メチル、トリメチルシリル、トリフルオロメチル、

から選択される、項目１～３のいずれか一項に記載の化合物、その互変異性体、前記化合物の薬学的に許容される塩、前記互変異性体の薬学的に許容される塩、前記化合物の重水素化誘導体、前記互変異性体の重水素化誘導体、および／または前記塩の重水素化誘導体。
（項目５）
Ｒ ^２が、

から選択される、項目１～４のいずれか一項に記載の化合物、その互変異性体、前記化合物の薬学的に許容される塩、前記互変異性体の薬学的に許容される塩、前記化合物の重水素化誘導体、前記互変異性体の重水素化誘導体、および／または前記塩の重水素化誘導体。
（項目６）
Ｚ ^１、Ｚ ^２、およびＺ ^３のうちの２つが、窒素であり、他方が、炭素および窒素から選択される、項目１～５のいずれか一項に記載の化合物、その互変異性体、前記化合物の薬学的に許容される塩、前記互変異性体の薬学的に許容される塩、前記化合物の重水素化誘導体、前記互変異性体の重水素化誘導体、および／または前記塩の重水素化誘導体。
（項目７）
各Ｒ ^３が、独立して、水素、重水素、ハロゲン、Ｃ _１～Ｃ _６直鎖アルキル基、およびヘテロシクリル基から選択される、項目１～６のいずれか一項に記載の化合物、その互変異性体、前記化合物の薬学的に許容される塩、前記互変異性体の薬学的に許容される塩、前記化合物の重水素化誘導体、前記互変異性体の重水素化誘導体、および／または前記塩の重水素化誘導体。
（項目８）
Ｘ ^１およびＸ ^２が、独立して、水素およびハロゲンから選択される、項目１～７のいずれか一項に記載の化合物、その互変異性体、前記化合物の薬学的に許容される塩、前記互変異性体の薬学的に許容される塩、前記化合物の重水素化誘導体、前記互変異性体の重水素化誘導体、および／または前記塩の重水素化誘導体。
（項目９）
式Ｉ－Ａ、Ｉ－Ｂ、Ｉ－Ｃ、Ｉ－Ｄ、Ｉ－Ｅ、Ｉ－Ｆ、Ｉ－Ｇ、およびＩ－Ｈの化合物から選択される、項目１に記載の化合物、

その互変異性体、前記化合物の薬学的に許容される塩、前記互変異性体の薬学的に許容される塩、前記化合物の重水素化誘導体、前記互変異性体の重水素化誘導体、および／または前記塩の重水素化誘導体であって、式中、
Ｒ ^０、Ｒ ^１、Ｒ ^２、Ｒ ^３、およびｎが、式（Ｉ）の化合物について定義され、
Ｘ ^１およびＸ ^２が、独立して、水素およびフッ素から選択されるか、またはＸ ^１が、フッ素であり、Ｘ ^２が、水素であるか、またはＸ ^２が、フッ素であり、Ｘ ^１が、水素であるか、またはＸ ^１およびＸ ^２が、各々水素であり、
Ｗ ^１およびＷ ^２の各々が、独立して、ＣおよびＮから選択され、
Ｙ ^１、Ｙ ^２、Ｙ ^３、およびＹ ^４が、独立して、
水素、
シアノ、
ハロゲン基、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基であって、
ヒドロキシ、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、から独立して選択される１～４個の置換基で任意に置換された、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、から選択され、
Ｙ ^５、Ｙ ^６、Ｙ ^７、およびＹ ^８が、独立して、
水素、
ハロゲン基、
ヒドロキシ、
１～４個の独立して選択されるハロゲン置換基で任意に置換された、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、から独立して選択され、
Ｙ ^９、Ｙ ^１０、Ｙ ^１１、Ｙ ^１２、Ｙ ^１３、Ｙ ^１４、Ｙ ^１５、およびＹ ^１６が、独立して、
カルボン酸、
水素、
ハロゲン基、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキルスルホニル基、
１～４個の独立して選択されるハロゲン置換基で任意に置換された、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、から独立して選択され、
Ｙ ^１７、Ｙ ^１８、Ｙ ^１９、Ｙ ^２０、およびＹ ^２１が、
水素、
カルボン酸、
ハロゲン基、
シアノ、
ヒドロキシ、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基であって、これらが、
ハロゲン、
ヒドロキシ、ならびに
カルボン酸、
カルボン酸基で任意に置換されたＣ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、
ジヒドロキシボリル、
スルホン酸、
ウロン酸で任意にエステル化されたカルボン酸、
テトラゾリル基、
アミノスルホニル基であって、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキルスルホニル基、から独立して選択される１個または２個の置換基で任意に置換された、アミノスルホニル基、から選択されるが、
但し、式Ｉ～Ｅにおいて、Ｙ ^１７、Ｙ ^１８、Ｙ ^１９、Ｙ ^２０、およびＹ ^２１のうちの少なくとも１つが、水素であることを条件とする、式Ｉ－Ａ、Ｉ－Ｂ、Ｉ－Ｃ、Ｉ－Ｄ、Ｉ－Ｅ、Ｉ－Ｆ、Ｉ－Ｇ、およびＩ－Ｈの化合物から選択される、項目１に記載の化合物、その互変異性体、前記化合物の薬学的に許容される塩、前記互変異性体の薬学的に許容される塩、前記化合物の重水素化誘導体、前記互変異性体の重水素化誘導体、および／または前記塩の重水素化誘導体。
（項目１０）
Ｙ ^１７、Ｙ ^１８、Ｙ ^１９、Ｙ ^２０、およびＹ ^２１のうちの１つ以上が、メチル、メトキシ、シアノ、フッ素、ヒドロキシ、－ＣＦ _３、－Ｂ（ＯＨ） _２、－ＳＯ _２ＮＨＭｅ、－ＳＯ _２Ｍｅ、－ＳＯ _２Ｈ、－ＣＨ _２ＣＯ _２Ｈ、

から選択される、項目９に記載の化合物、その互変異性体、前記化合物の薬学的に許容される塩、前記互変異性体の薬学的に許容される塩、前記化合物の重水素化誘導体、前記互変異性体の重水素化誘導体、および／または前記塩の重水素化誘導体。
（項目１１）
以下から選択される、化合物、

その互変異性体、前記化合物の薬学的に許容される塩、前記互変異性体の薬学的に許容される塩、前記化合物の重水素化誘導体、前記互変異性体の重水素化誘導体、および前記塩の重水素化誘導体。
（項目１２）
式（Ｉ’）の化合物、

その互変異性体、上述のいずれかの薬学的に許容される塩、および／または上述のいずれかの重水素化誘導体であって、
式中、
（ｉ）Ｒ ^０ ’が、以下から選択され、
（ａ）Ｃ _１～Ｃ _８直鎖、分枝鎖、および環状アルキル基であって、前記アルキル基が、１～４個のＲ ^Ａで任意に置換された、Ｃ _１～Ｃ _８直鎖、分枝鎖、および環状アルキル基、
（ｂ）１～４個のＲ ^Ａ ’で任意に置換された５～１４員の芳香族環であって、
各Ｒ ^Ａ ’が、独立して、ハロゲン、シアノ、ヒドロキシ、チオール、スルホン酸、スルホンアミド、スルフィンアミド、アミノ、アミド、５～１０員の芳香族環、ならびにＣ _１～Ｃ _６直鎖、分枝鎖、および環状基から選択され、前記Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基が、アルキル、アルコキシ、チオアルキル、アルキルスルホキシド、アルキルスルホニル、アルキルスルホンアミド、アルキルスルフィンアミド、アミノアルキル、およびアルキルアミドから選択され、前記５～１０員の芳香族環、ならびにＣ _１～Ｃ _６直鎖、分枝鎖、および環状基が、ハロゲンおよびメトキシから選択される１～４個の置換基で任意に置換され、
Ｒ ^Ａ ’基が、Ｒ ^２ ’基上のＲ ^Ｂ ’基に任意に結合される、１～４個のＲ ^Ａ ’で任意に置換された５～１４員の芳香族環、
（ｉｉ）Ｒ ^１ ’が、以下から選択され、
（ａ）水素、
（ｂ）Ｃ _１～Ｃ _８直鎖、分枝鎖、および環状アルキル基であって、前記アルキル基が、
ハロゲン、
シアノ、
ヒドロキシ、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基、から独立して選択される１～４個の置換基で任意に置換され、前記Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基が、独立して、アルキル基およびアルコキシ基から選択され、前記Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基が、
ハロゲン、
ヒドロキシ、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、から独立して選択される１～４個の置換基で任意に置換された、Ｃ _１～Ｃ _８直鎖、分枝鎖、および環状アルキル基、
（ｃ）
ハロゲン、
シアノ、
スルホン、
スルホンアミド、
ヒドロキシ、ならびに
１～４個のハロゲンで任意に置換されたＣ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、から独立して選択される１～４個の置換基で任意に置換されたＣ _１～Ｃ _８直鎖、分枝鎖、および環状アルコキシ基または環状チオアルキル基、
（ｄ）Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキルスルホニル基、
（ｅ）
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基から独立して選択される１個または２個の置換基で任意に置換された、アミノスルホニル基、
（ｆ）Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキルスルホニルアミノ基、ならびに
（ｇ）ホスフィンオキシド基であって、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基から独立して選択される１または２個の置換基で任意に置換された、ホスフィンオキシド基、
（ｈ）Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状トリアルキルシリル基、
（ｉｉｉ）Ｒ ^２ ’が、Ｏ、Ｎ、およびＳから選択される０～４個のヘテロ原子を含む５員および６員の芳香族環から選択され、前記５員環が、１～４個のＲ ^Ｂ ’基で任意に置換され、前記６員環が、１～５個のＲ ^Ｂ ’基で任意に置換され、前記Ｒ ^Ｂ ’基が、独立して、
任意に置換されたアミド、
イミダゾリジン－２，４－ジオン、
任意に置換されたヘテロシクリル、
Ｃ _１～Ｃ _６直鎖、分枝鎖、または環状アルキル基で任意にエステル化された亜リン酸、
ジ（Ｃ _１～Ｃ _６）アルキルホスフィンオキシド、
Ｃ _１～Ｃ _６直鎖、分枝鎖、または環状アルキル基で任意にエステル化された（Ｃ _１～Ｃ _６）アルキルホスフィン酸、
ハロゲン、
シアノ、
ヒドロキシ、
ウロン酸またはＣ _１～Ｃ _６直鎖、分枝鎖、もしくは環状アルキル基で任意にエステル化されたカルボン酸、
オキソ、
ジヒドロキシルボリル、
Ｏ、Ｎ、およびＳから独立して選択される０～４個のヘテロ原子を含む５および６員の芳香族環であって、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基から独立して選択される１または２個の置換基で任意に置換され、これらが、
ヒドロキシ、
カルボン酸、
ピロリジン－２－オン、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキルスルホニル基、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、から独立して選択される１～４個の置換基で任意に置換された、５および６員の芳香族環、
スルホン酸、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキルスルホニル基、
アミノスルホニル基であって、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基から独立して選択される１個または２個の置換基で任意に置換された、アミノスルホニル基、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基であって、
ハロゲン、
ヒドロキシ、
カルボン酸、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、から独立して選択される１～４個の置換基で任意に置換された、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基であって、
ハロゲン、
ヒドロキシ、
カルボン酸、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、から独立して選択される１～４個の置換基で任意に置換された、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、ならびに
テトラゾリル基であって、
ハロゲン、
ヒドロキシ、
カルボン酸、
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびに
Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基、から選択される置換基で任意に置換された、テトラゾリル基、から選択され、
前記５員または６員の芳香族環上の２つの隣接する水素が、Ｏ、Ｎ、およびＳから独立して選択される０～４個のヘテロ原子を含む第２の５員または６員の芳香族環への結合によって置き換えられて、１～６個のＲ ^Ｂ ’基で任意に置換された二環式Ｒ ^２ ’基を形成することができ、
（ｉｖ）Ｘ ^１ ’およびＸ ^２ ’が、独立して、水素、ハロゲン、シアノ、ヒドロキシ、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基から選択され、前記Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基が、独立して、アルキル、アルコキシ、チオアルキル、およびアミノアルキル基から選択され、前記Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状基が、１～４個の独立して選択されるハロゲンによって任意に置換され、
（ｖ）各

が、単結合または二重結合を表すが、但し、

の１つのみが二重結合であることを条件とし、
（ｖｉ）各Ｒ ^３が、独立して、水素、ハロゲン、シアノ、Ｃ _１～Ｃ _６直鎖、分枝鎖、および環状アルキル基、ならびにＣ _１～Ｃ _６直鎖、分枝鎖、および環状アルコキシ基から選択され、前記直鎖、分枝鎖、および環状アルキル基およびアルコキシ基が、１～４個の独立して選択されるハロゲンで任意に置換され、
（ｖｉｉ）ｎ’が、０、１、２、および３から選択される整数であり、
（ｖｉｉｉ）Ｚ ^１ ’、Ｚ ^２ ’、およびＺ ^３ ’が、独立して、炭素、窒素、硫黄、および酸素から選択され、Ｚ ^１ ’、Ｚ ^２ ’、および／またはＺ ^３ ’が、炭素または窒素である場合、炭素および窒素の価電子が、水素原子と共に完成する、式（Ｉ’）の化合物、その互変異性体、上述のいずれかの薬学的に許容される塩、および／または上述のいずれかの重水素化誘導体。
（項目１３）
結晶性化合物３３の形態Ａ。
（項目１４）
結晶性化合物３３の形態Ｂ。
（項目１５）
結晶性化合物３３のＤＣＭ溶媒和物形態Ａ。
（項目１６）
結晶性化合物３３の水和物形態Ａ。
（項目１７）
結晶性化合物３３のＭｅＯＨ／Ｈ _２Ｏ溶媒和物／水和物形態Ａ。
（項目１８）
結晶性化合物３３の形態Ｃ。
（項目１９）
結晶性化合物３３の形態Ｄ
（項目２０）
結晶性化合物３３の形態Ｅ。
（項目２１）
結晶性化合物３３の形態Ｆ。
（項目２２）
結晶性化合物３３の形態Ｇ。
（項目２３）
結晶性化合物３３の形態Ｈ。
（項目２４）
結晶性化合物３３の形態Ｉ
（項目２５）
結晶性化合物３３のＴＨＦ溶媒和物形態Ａ。
（項目２６）
結晶性化合物３３の形態Ｊ。
（項目２７）
結晶性化合物３３の形態Ｋ。
（項目２８）
結晶性化合物３３の形態Ｌ。
（項目２９）
結晶性化合物３３の２－ＭｅＴＨＦ溶媒和物形態Ａ。
（項目３０）
結晶性化合物３３の形態Ｍ。
（項目３１）
結晶性化合物３３の形態Ｎ。
（項目３２）
結晶性化合物３３の形態Ｏ。
（項目３３）
結晶性化合物３３のカリウム塩形態Ａ。
（項目３４）
結晶性化合物３３のカリウム塩形態Ｂ。
（項目３５）
結晶性化合物３３のカリウム塩形態Ｃ。
（項目３６）
実質的に非晶質の化合物３３。
（項目３７）
実質的に非晶質の化合物３３を含む、固体分散体。
（項目３８）
ポリマーをさらに含む、項目３７に記載の実質的に非晶質の化合物３３を含む、固体分散体。
（項目３９）
前記ポリマーが、ポリビニルピロリドン／酢酸ビニル（ＰＶＰＶＡ）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）、および酢酸コハク酸ヒドロキシプロピルメチルセルロース（ＨＰＭＣＡＳ）から選択される、項目３８に記載の実質的に非晶質の化合物３３を含む、固体分散体。
（項目４０）
実質的に非晶質の化合物３３が、３０～５０％の量で存在する、項目３８または項目３９に記載の実質的に非晶質の化合物３３を含む、固体分散体。
（項目４１）
実質的に非晶質の化合物３３が、５０～８０％の量で存在する、項目３８または項目３９に記載の実質的に非晶質の化合物３３を含む、固体分散体。
（項目４２）
噴霧乾燥分散体として調製された、項目３８～４１のいずれか一項に記載の実質的に非晶質の化合物３３を含む、固体分散体。
（項目４３）
項目１～１２のいずれか一項に記載の化合物、互変異性体、塩、もしくは重水素化誘導体、項目１３～３５のいずれか一項に記載の結晶性化合物３３、項目３６に記載の実質的に非晶質の化合物３３、または項目３７～４２のいずれか一項に記載の固体分散体と、薬学的に許容される担体と、を含む、薬学的組成物。
（項目４４）
α－１抗トリプシン欠損症を治療する方法であって、治療を必要とする患者に、項目１～１２のいずれか一項に記載の化合物、互変異性体、塩、および重水素化誘導体、項目１３～３５のいずれか一項に記載の結晶性化合物３３、項目３６に記載の実質的に非晶質の化合物３３、から選択される少なくとも１つの化合物、または項目３７～４２のいずれか一項に記載の固体分散体、または項目４３に記載の薬学的組成物を、治療を必要とする患者に投与することを含む、方法。
（項目４５）
前記患者が、α－１抗トリプシンにおいてＺ変異を有する、項目４４に記載の方法。
（項目４６）
前記患者が、α－１抗トリプシンにおいてＳＺ変異を有する、項目４５に記載の方法。
（項目４７）
前記患者が、α－１抗トリプシンにおいてＺ変異に対してホモ接合性である、項目４５に記載の方法。
（項目４８）
化合物４－［５－（４－フルオロフェニル）－６－テトラヒドロピラン－４－イル－１Ｈ－ピロロ［２，３－ｆ］インダゾール－７－イル］安息香酸を調製するための方法であって、
（ａ）メチル４－（５－（４－フルオロフェニル）－１－ピバロイル－６－（テトラヒドロ－２Ｈ－ピラン－４－イル）－１，５－ジヒドロピロロ［２，３－ｆ］インダゾール－７－イル）ベンゾエートを、第１の有機溶媒および第１の塩基と接触させて、第１の反応混合物を形成することと、
（ｂ）水および第１の酸を前記第１の反応混合物に添加することと、
（ｃ）ステップ（ｂ）からの有機部分を単離し、アルコールを添加し、水を前記有機部分に任意に添加し、蒸留によって前記混合物を濃縮することと、
（ｄ）前記化合物４－［５－（４－フルオロフェニル）－６－テトラヒドロピラン－４－イル－１Ｈ－ピロロ［２，３－ｆ］インダゾール－７－イル］安息香酸を、ステップ（ｃ）からの前記混合物から単離し、前記材料を乾燥させて、すべての水分含量を除去することと、を含む、方法。
（項目４９）
前記方法が、１－（５－（４－フルオロフェニル）－７－ヨード－６－（テトラヒドロ－２Ｈ－ピラン－４－イル）ピロロ［２，３－ｆ］インダゾール－１（５Ｈ）－イル）－２，２－ジメチルプロパン－１－オンを４－（メトキシカルボニル）フェニル）ボロン酸と反応させて、メチル４－（５－（４－フルオロフェニル）－１－ピバロイル－６－（テトラヒドロ－２Ｈ－ピラン－４－イル）－１，５－ジヒドロピロロ［２，３－ｆ］インダゾール－７－イル）ベンゾエートを形成することをさらに含む、項目４８に記載の方法。
（項目５０）
前記方法が、１－（５－（４－フルオロフクニル）－６－（テトラヒドロ－２Ｈ－ピラン－４－イル）ピロロ［２，３－ｆ］インダゾール－１（５Ｈ）－イル）－２，２－ジメチルプロパン－１－オンをＮ－ヨードスクシンイミドと反応させて、１－（５－（４－フルオロフェニル）－７－ヨード－６－（テトラヒドロ－２Ｈ－ピラン－４－イル）ピロロ［２，３－ｆ］インダゾール－１（５Ｈ）－イル）－２，２－ジメチルプロパン－１－オンを形成することをさらに含む、項目４９に記載の方法。
（項目５１）
前記方法が、５－（４－フルオロフェニル）－６－（テトラヒドロ－２Ｈ－ピラン－４－イル）－１，５－ジヒドロピロロ［２，３－ｆ］インダゾールを塩化トリメチルアセチルと反応させて、１－（５－（４－フルオロフェニル）－６－（テトラヒドロ－２Ｈ－ピラン－４－イル）ピロロ［２，３－ｆ］インダゾール－１（５Ｈ）－イル）－２，２－ジメチルプロパン－１－オンを形成することをさらに含む、項目５０に記載の方法。
（項目５２）
前記方法が、Ｎ－（４－フルオロフェニル）－６－（（テトラヒドロ－２Ｈ－ピラン－４－イル）エチニル）－１Ｈ－インダゾール－５－アミンを第２の酸と反応させて、５－（４－フルオロフェニル）－６－（テトラヒドロ－２Ｈ－ピラン－４－イル）－１，５－ジヒドロピロロ［２，３－ｆ］インダゾールを形成することをさらに含む、項目５１に記載の方法。
（項目５３）
前記方法が、５－ブロモ－６－ヨード－１Ｈ－インダゾールをトリメチル（（テトラヒドロ－２Ｈ－ピラン－４－イル）エチル）シランと反応させて、５－ブロモ－６－（（テトラヒドロ－２Ｈ－ピラン－４－イル）エチニル）－１Ｈ－インダゾールを形成することをさらに含む、項目５２に記載の方法。
（項目５４）
５－ブロモ－６－（（テトラヒドロ－２Ｈ－ピラン－４－イル）エチニル）－１Ｈ－インダゾール（Ｃ２）

Ｎ－（４－フルオロフェニル）－６－（（テトラヒドロ－２Ｈ－ピラン－４－イル）エチニル－１Ｈ－インダゾール－５－アミン（Ｃ１２）

５－（４－フルオロフェニル）－６－（テトラヒドロ－２Ｈ－ピラン－４－イル）－１，５－ジヒドロピロロ［２，３－ｆ］インダゾール（Ｃ１３）

１－（５－（４－フルオロフェニル）－６－（テトラヒドロ－２Ｈ－ピラン－４－イル）ピロロ［２，３－ｆ］インダゾール－１（５Ｈ）－イル）－２，２－ジメチルプロパン－１－オン（Ｃ１４）

１－（５－（４－フルオロフェニル）－７－ヨード－６－（テトラヒドロ－２Ｈ－ピラン－４－イル）ピロロ［２，３－ｆ］インダゾール－１（５Ｈ）－イル）－２，２－ジメチルプロパン－１－オン（Ｓ４）

メチル４－（５－（４－フルオロフェニル）－１－ピバロイル－６－（テトラヒドロ－２Ｈ－ピラン－４－イル）－１，５－ジヒドロピロロ［２，３－ｆ］インダゾール－７－イル）ベンゾエート（Ｃ５８）

から選択される化合物。
（項目５５）
噴霧乾燥した純粋な非晶質化合物３３。 Other embodiment
This disclosure provides merely exemplary embodiments of the present invention. One skilled in the art can make various changes, modifications and variations from this disclosure and the accompanying drawings and claims without departing from the spirit and scope of the invention as defined in the following claims. You will easily recognize what you can do.
The present invention provides, for example, the following items.
(Item 1)
a compound of formula (I),

a tautomer thereof, a pharmaceutically acceptable salt of any of the above, and/or a deuterated derivative of any of the above,
During the ceremony,
(i) R ⁰ is selected from
(a) C ₁ ～C ₈ straight-chain, branched-chain, and cyclic alkyl groups, wherein the alkyl groups are 1 to 4 R ^A. optionally replaced by C ₁ ～C ₈ straight-chain, branched-chain, and cyclic alkyl groups, and
(b) 1 to 4 R ^A. A 5- to 14-membered aromatic ring optionally substituted with
Each R ^A. are independently halogen, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, carboxylic acid, 5- to 10-membered aromatic rings, and C ₁ ～C ₆ selected from linear, branched and cyclic groups;
R. ^A. optionally substituted with a heterocyclyl group optionally further substituted with oxo, the amide nitrogen atom in said amide of
Said C ₁ ～C ₆ linear, branched and cyclic groups are selected from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamide, alkylsulfinamide, aminoalkyl and alkylamide;
the 5- to 10-membered aromatic ring and C ₁ ～C ₆ Straight-chain, branched-chain, and cyclic groups are halogen, C ₁ ～C ₆ optionally substituted with 1 to 4 substituents from linear, branched and cyclic groups and methoxy;
R. ^A. the group is R ² R on base ^B. a 5- to 14-membered aromatic ring optionally attached to a group;
(ii) R ¹ is selected from
(a) hydrogen,
(b) C ₁ ～C ₈ straight-chain, branched-chain, and cyclic alkyl groups, wherein the alkyl groups are
halogen,
cyano,
cyanoalkyl,
hydroxy,
alkylsulfonyl, and
C. ₁ ～C ₆ optionally substituted with 1 to 4 substituents independently selected from straight-chain, branched-chain, and cyclic groups; ₁ ～C ₆ Linear, branched and cyclic groups are independently selected from alkyl groups and alkyl groups, said C ₁ ～C ₆ Straight-chain, branched-chain, and cyclic groups are
halogen,
hydroxy, and
C. ₁ ～C ₆ optionally substituted with 1 to 4 substituents independently selected from straight-chain, branched-chain, and cyclic alkoxy groups, C ₁ ～C ₈ straight-chain, branched-chain, and cyclic alkyl groups,
(c)
halogen,
cyano,
cyanoalkyl,
sulfone,
sulfonamide,
hydroxy, and
C optionally substituted with 1-4 halogen or alkoxy groups ₁ ～C ₆ C optionally substituted with 1 to 4 substituents independently selected from straight-chain, branched-chain, and cyclic alkyl groups; ₁ ～C ₈ straight-chain, branched-chain, and cyclic alkoxy or cyclic thioalkyl groups,
(d)C ₁ ～C ₆ C optionally substituted with straight or branched chain alkyl groups ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkylsulfonyl groups,
(e)
C. ₁ ～C ₆ an aminosulfonyl group optionally substituted with one or two substituents independently selected from straight-chain, branched-chain, and cyclic alkyl groups;
(f) C ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkylsulfonylamino groups, and
(g)
C. ₁ ～C ₆ a phosphine oxide group optionally substituted with 1 or 2 substituents independently selected from linear, branched and cyclic alkyl groups;
(h)C ₁ ～C ₆ straight-chain, branched-chain, and cyclic trialkylsilyl groups,
(i) C ₁ ～C ₆ alkylamide,
(iii) R ² is a 5- and 6-membered heterocyclic ring (oxo and/or C ₁ ～C ₆ optionally substituted with straight and branched chain alkyl groups), and 5-6 membered aromatic rings containing 0-4 heteroatoms selected from O, N and S, said 5-membered has 1 to 4 R ^B. wherein said 6-membered aromatic ring is optionally substituted with 1-5 R ^B. optionally substituted with a group, said R ^B. The group independently
an amide, wherein C ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups (optionally substituted with heteroaryl), 4- to 6-membered heterocyclyl (oxo, C ₁ ～C ₆ optionally substituted with 1 to 3 groups selected from linear, branched and cyclic alkyl groups, hydroxyalkyl, amide, alkylsulfonyl, and acetamide) or said amide; The nitrogen atom is a 3- to 8-membered heterocyclyl ring (alkylsulfonyl or C ₁ ～C ₆ amides, optionally substituted with straight-chain, branched-chain, and cyclic alkyl groups, forming part of
imidazolidine-2,4-dione,
heterocyclyl, oxo, acyl, and C ₁ ～C ₆ one or more independently selected from straight-chain, branched-chain, and cyclic alkyl groups (optionally further substituted with 1 to 3 groups independently selected from oxo, hydroxy, and acyl) optionally substituted with groups, heterocyclyl,
C. ₁ ～C ₆ phosphorous acid optionally esterified with linear, branched, or cyclic alkyl groups;
Di (C ₁ ～C ₆ ) alkylphosphine oxide,
C. ₁ ～C ₆ optionally esterified with straight-chain, branched-chain, or cyclic alkyl groups (C ₁ ～C ₆ ) alkylphosphinic acid,
halogen,
cyano,
hydroxy,
Uronic acid or C ₁ ～C ₆ carboxylic acids optionally esterified with linear, branched, or cyclic alkyl groups;
Oxo,
dihydroxyboryl,
5- and 6-membered aromatic rings containing 0-4 heteroatoms independently selected from O, N, and S; ₁ ～C ₆ optionally substituted with 1 to 2 substituents independently selected from straight-chain, branched-chain, and cyclic alkoxy groups, which are
hydroxy,
carboxylic acid,
pyrrolidin-2-one,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkylsulfonyl groups, and
C. ₁ ～C ₆ 5- and 6-membered aromatic rings optionally substituted with 1 to 4 substituents independently selected from straight-chain, branched-chain, and cyclic alkoxy groups;
Sulfonic acid,
alkyl sulfonamide,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkylsulfonyl groups,
an aminosulfonyl group,
C. ₁ ～C ₆ an aminosulfonyl group optionally substituted with one or two substituents independently selected from straight-chain, branched-chain, and cyclic alkyl groups;
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups,
halogen,
hydroxy,
carboxylic acid,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkoxy groups,
heterocyclyl optionally substituted with oxo, and
C, optionally substituted with 1 to 4 substituents independently selected from amido, ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkoxy groups,
halogen,
hydroxy,
carboxylic acid,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and
C. ₁ ～C ₆ optionally substituted with 1 to 4 substituents independently selected from straight-chain, branched-chain, and cyclic alkoxy groups, C ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkoxy groups, and
a tetrazolyl group,
halogen,
hydroxy,
carboxylic acid,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and
C. ₁ ～C ₆ a tetrazolyl group optionally substituted with substituents selected from linear, branched and cyclic alkoxy groups;
a second 5- or 6-membered aromatic ring containing 0-4 heteroatoms in which two adjacent hydrogens on said 5- or 6-membered aromatic ring are independently selected from O, N, and S; 1-6 R, replaced by a bond to an aromatic ring ^B. bicyclic R optionally substituted with ² can form a group,
(iv) X ¹ and X ² is independently hydrogen, halogen, cyano, hydroxy, C ₁ ～C ₆ selected from linear, branched and cyclic groups, said C ₁ ～C ₆ Linear, branched and cyclic groups are independently selected from alkyl, alkoxy, thioalkyl and aminoalkyl groups, said C ₁ ～C ₆ linear, branched and cyclic groups are optionally substituted with 1 to 4 independently selected halogens;
(v) W ¹ and W ² is independently selected from C and N;
(vi) each

represents a single or double bond, provided that one

provided that only is a double bond,
(vii) each R ³ is independently hydrogen, halogen, cyano, C ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and C ₁ ～C ₆ selected from linear, branched and cyclic alkoxy groups, said C ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and said C ₁ ～C ₆ linear, branched, and cyclic alkoxy groups are optionally substituted with 1 to 4 substituents independently selected from halogens, hydroxy groups, and carboxylic acids;
(viii) n is an integer selected from 0, 1, 2, and 3;
(ix) Z ¹ , Z ² , and Z ³ is independently selected from carbon, nitrogen, sulfur, and oxygen;
Z. ¹ , Z ² , and/or Z ³ is carbon or nitrogen, the valence electrons of carbon or nitrogen are hydrogen atoms, halogens, C ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and C ₁ ～C ₆ complete with straight-chain, branched-chain, and cyclic alkoxy groups; ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and said C ₁ ～C ₆ compounds of formula (I), wherein the straight-chain, branched-chain, and cyclic alkoxy groups are optionally substituted with 1 to 4 substituents independently selected from halogens, hydroxy groups, and carboxylic acids; tautomers thereof, pharmaceutically acceptable salts of any of the above, and/or deuterated derivatives of any of the above.
(Item 2)
R. ⁰ is an aryl ring, a heteroaryl ring, and a C ₁ ～C ₈ selected from straight-chain, branched-chain and cyclic alkyl groups, each of which is selected from halogen, carboxylic acid, C ₁ ～C ₆ straight-chain, branched-chain and cyclic alkyl groups, C ₁ ～C ₆ A compound according to item 1, optionally substituted with 1 to 2 substituents independently selected from linear, branched, and cyclic alkoxy groups, aryl rings, and heteroaryl rings; variants, pharmaceutically acceptable salts of said compounds, pharmaceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and/or or deuterated derivatives of said salts.
(Item 3)
R. ⁰ but,

A compound according to item 1 or 2, a tautomer thereof, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer, deuterium of said compound selected from derivatives, deuterated derivatives of said tautomers, and/or deuterated derivatives of said salts.
(Item 4)
R. ¹ but,
hydrogen, methyl, trimethylsilyl, trifluoromethyl,

A compound according to any one of items 1 to 3, a tautomer thereof, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer, selected from A deuterated derivative of said compound, a deuterated derivative of said tautomer, and/or a deuterated derivative of said salt.
(Item 5)
R. ² but,

A compound according to any one of items 1 to 4, a tautomer thereof, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer, selected from A deuterated derivative of said compound, a deuterated derivative of said tautomer, and/or a deuterated derivative of said salt.
(Item 6)
Z. ¹ , Z ² , and Z ³ two of which are nitrogen and the other is selected from carbon and nitrogen, tautomers thereof, pharmaceutically acceptable compounds of said compounds A salt, a pharmaceutically acceptable salt of said tautomer, a deuterated derivative of said compound, a deuterated derivative of said tautomer, and/or a deuterated derivative of said salt.
(Item 7)
Each R ³ is independently hydrogen, deuterium, halogen, C ₁ ～C ₆ A compound according to any one of items 1 to 6, tautomers thereof, pharmaceutically acceptable salts of said compounds, said tautomers, selected from linear alkyl groups and heterocyclyl groups. A pharmaceutically acceptable salt, a deuterated derivative of said compound, a deuterated derivative of said tautomer, and/or a deuterated derivative of said salt.
(Item 8)
X ¹ and X ² is independently selected from hydrogen and halogen, a compound according to any one of items 1 to 7, a tautomer thereof, a pharmaceutically acceptable salt of said compound, said tautomer pharmaceutically acceptable salts of, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and/or deuterated derivatives of said salts.
(Item 9)
A compound according to item 1, selected from compounds of formulas IA, IB, IC, ID, IE, IF, IG, and IH;

tautomers thereof, pharmaceutically acceptable salts of said compounds, pharmaceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and/or a deuterated derivative of said salt, wherein
R. ⁰ , R ¹ , R ² , R ³ , and n are defined for compounds of formula (I),
X ¹ and X ² is independently selected from hydrogen and fluorine, or X ¹ is fluorine, and X ² is hydrogen or X ² is fluorine, and X ¹ is hydrogen or X ¹ and X ² are each hydrogen,
W. ¹ and W ² is independently selected from C and N;
Y. ¹ , Y ² , Y ³ , and Y ⁴ but independently
hydrogen,
cyano,
halogen group,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkoxy groups,
hydroxy,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and
C. ₁ ～C ₆ optionally substituted with 1 to 4 substituents independently selected from straight-chain, branched-chain, and cyclic alkoxy groups, C ₁ ～C ₆ selected from linear, branched and cyclic alkoxy groups,
Y. ⁵ , Y ⁶ , Y ⁷ , and Y ⁸ but independently
hydrogen,
halogen group,
hydroxy,
optionally substituted with 1 to 4 independently selected halogen substituents, C ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and
C. ₁ ～C ₆ independently selected from straight-chain, branched-chain, and cyclic alkoxy groups,
Y. ⁹ , Y ¹⁰ , Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ , and Y ¹⁶ but independently
carboxylic acid,
hydrogen,
halogen group,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkylsulfonyl groups,
optionally substituted with 1 to 4 independently selected halogen substituents, C ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and
C. ₁ ～C ₆ independently selected from straight-chain, branched-chain, and cyclic alkoxy groups,
Y. ¹⁷ , Y ¹⁸ , Y ¹⁹ , Y ²⁰ , and Y ²¹ but,
hydrogen,
carboxylic acid,
halogen group,
cyano,
hydroxy,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, which are
halogen,
hydroxy, and
carboxylic acid,
C optionally substituted with a carboxylic acid group ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkoxy groups,
dihydroxyboryl,
Sulfonic acid,
carboxylic acids optionally esterified with uronic acids,
a tetrazolyl group,
an aminosulfonyl group,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and
C. ₁ ～C ₆ aminosulfonyl groups optionally substituted with one or two substituents independently selected from linear, branched and cyclic alkylsulfonyl groups, but
However, in formulas I to E, Y ¹⁷ , Y ¹⁸ , Y ¹⁹ , Y ²⁰ , and Y ²¹ of formulas IA, IB, IC, ID, IE, IF, IG, and IH, with the proviso that at least one of Compound according to item 1, selected from compounds, tautomers thereof, pharmaceutically acceptable salts of said compounds, pharmaceutically acceptable salts of said tautomers, deuteration of said compounds derivatives, deuterated derivatives of said tautomers, and/or deuterated derivatives of said salts.
(Item 10)
Y. ¹⁷ , Y ¹⁸ , Y ¹⁹ , Y ²⁰ , and Y ²¹ one or more of is methyl, methoxy, cyano, fluorine, hydroxy, -CF ₃ , -B(OH) ₂ , -SO ₂ NHMe, -SO ₂ Me, -SO ₂ H, -CH ₂ CO ₂ H.

A compound according to item 9, a tautomer thereof, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer, a deuterated derivative of said compound selected from , deuterated derivatives of said tautomers, and/or deuterated derivatives of said salts.
(Item 11)
a compound selected from

tautomers thereof, pharmaceutically acceptable salts of said compounds, pharmaceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and deuterated derivatives of said salts.
(Item 12)
a compound of formula (I'),

a tautomer thereof, a pharmaceutically acceptable salt of any of the above, and/or a deuterated derivative of any of the above,
During the ceremony,
(i) R ⁰ ' is selected from
(a) C ₁ ～C ₈ straight-chain, branched-chain, and cyclic alkyl groups, wherein the alkyl groups are 1 to 4 R ^A. optionally substituted with C ₁ ～C ₈ straight-chain, branched-chain, and cyclic alkyl groups,
(b) 1 to 4 R ^A. a 5- to 14-membered aromatic ring optionally substituted with
Each R ^A. ' are independently halogen, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amido, 5-10 membered aromatic ring, and C ₁ ～C ₆ selected from linear, branched and cyclic groups, said C ₁ ～C ₆ linear, branched and cyclic groups are selected from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamide, alkylsulfinamide, aminoalkyl and alkylamide; ring, and C ₁ ～C ₆ linear, branched and cyclic groups are optionally substituted with 1 to 4 substituents selected from halogen and methoxy;
R. ^A. ' group is R ² 'R on the group ^B. 1 to 4 R optionally attached to the ' group ^A. 5-14 membered aromatic ring optionally substituted with ',
(ii) R ¹ ' is selected from
(a) hydrogen,
(b) C ₁ ～C ₈ straight-chain, branched-chain, and cyclic alkyl groups, wherein the alkyl groups are
halogen,
cyano,
hydroxy, and
C. ₁ ～C ₆ optionally substituted with 1 to 4 substituents independently selected from straight-chain, branched-chain, and cyclic groups; ₁ ～C ₆ Linear, branched and cyclic groups are independently selected from alkyl groups and alkoxy groups, said C ₁ ～C ₆ Straight-chain, branched-chain, and cyclic groups are
halogen,
hydroxy, and
C. ₁ ～C ₆ optionally substituted with 1 to 4 substituents independently selected from straight-chain, branched-chain, and cyclic alkoxy groups, C ₁ ～C ₈ straight-chain, branched-chain, and cyclic alkyl groups,
(c)
halogen,
cyano,
sulfone,
sulfonamide,
hydroxy, and
C optionally substituted with 1-4 halogens ₁ ～C ₆ C optionally substituted with 1 to 4 substituents independently selected from straight-chain, branched-chain, and cyclic alkyl groups; ₁ ～C ₈ straight-chain, branched-chain, and cyclic alkoxy or cyclic thioalkyl groups,
(d)C ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkylsulfonyl groups,
(e)
C. ₁ ～C ₆ an aminosulfonyl group optionally substituted with one or two substituents independently selected from straight-chain, branched-chain, and cyclic alkyl groups;
(f) C ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkylsulfonylamino groups, and
(g) a phosphine oxide group,
C. ₁ ～C ₆ a phosphine oxide group optionally substituted with 1 or 2 substituents independently selected from linear, branched and cyclic alkyl groups;
(h)C ₁ ～C ₆ straight-chain, branched-chain, and cyclic trialkylsilyl groups,
(iii) R ² ' is selected from 5- and 6-membered aromatic rings containing 0-4 heteroatoms selected from O, N, and S, said 5-membered ring containing 1-4 R ^B. ' group, said 6-membered ring is optionally substituted with 1-5 R ^B. ' group optionally substituted with said R ^B. ' groups are independently
optionally substituted amides,
imidazolidine-2,4-dione,
optionally substituted heterocyclyl,
C. ₁ ～C ₆ phosphorous acid optionally esterified with linear, branched, or cyclic alkyl groups;
Di (C ₁ ～C ₆ ) alkylphosphine oxide,
C. ₁ ～C ₆ optionally esterified with straight-chain, branched-chain, or cyclic alkyl groups (C ₁ ～C ₆ ) alkylphosphinic acid,
halogen,
cyano,
hydroxy,
Uronic acid or C ₁ ～C ₆ carboxylic acids optionally esterified with linear, branched, or cyclic alkyl groups;
Oxo,
dihydroxyboryl,
5- and 6-membered aromatic rings containing 0-4 heteroatoms independently selected from O, N, and S; ₁ ～C ₆ optionally substituted with 1 or 2 substituents independently selected from linear, branched and cyclic alkyl groups, which are
hydroxy,
carboxylic acid,
pyrrolidin-2-one,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkylsulfonyl groups, and
C. ₁ ～C ₆ 5- and 6-membered aromatic rings optionally substituted with 1 to 4 substituents independently selected from straight-chain, branched-chain, and cyclic alkoxy groups;
Sulfonic acid,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkylsulfonyl groups,
an aminosulfonyl group,
C. ₁ ～C ₆ an aminosulfonyl group optionally substituted with one or two substituents independently selected from straight-chain, branched-chain, and cyclic alkyl groups;
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups,
halogen,
hydroxy,
carboxylic acid, and
C. ₁ ～C ₆ optionally substituted with 1 to 4 substituents independently selected from straight-chain, branched-chain, and cyclic alkoxy groups, C ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkoxy groups,
halogen,
hydroxy,
carboxylic acid,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and
C. ₁ ～C ₆ optionally substituted with 1 to 4 substituents independently selected from straight-chain, branched-chain, and cyclic alkoxy groups, C ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkoxy groups, and
a tetrazolyl group,
halogen,
hydroxy,
carboxylic acid,
C. ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and
C. ₁ ～C ₆ a tetrazolyl group optionally substituted with a substituent selected from a straight-chain, branched-chain, and cyclic alkoxy group;
a second 5- or 6-membered aromatic ring containing 0-4 heteroatoms in which two adjacent hydrogens on said 5- or 6-membered aromatic ring are independently selected from O, N, and S; 1-6 R, replaced by a bond to an aromatic ring ^B. a bicyclic R optionally substituted with a ' group ² ' group can be formed,
(iv) X ¹ ' and X ² ' is independently hydrogen, halogen, cyano, hydroxy, C ₁ ～C ₆ selected from linear, branched and cyclic groups, said C ₁ ～C ₆ Linear, branched and cyclic groups are independently selected from alkyl, alkoxy, thioalkyl and aminoalkyl groups, said C ₁ ～C ₆ linear, branched and cyclic groups are optionally substituted with 1 to 4 independently selected halogens;
(v) each

represents a single or double bond, provided that

provided that only one of is a double bond,
(vi) each R ³ is independently hydrogen, halogen, cyano, C ₁ ～C ₆ straight-chain, branched-chain, and cyclic alkyl groups, and C ₁ ～C ₆ selected from linear, branched and cyclic alkoxy groups, wherein said linear, branched and cyclic alkyl and alkoxy groups are optionally substituted with 1 to 4 independently selected halogens;
(vii) n' is an integer selected from 0, 1, 2, and 3;
(viii) Z ¹ ', Z ² ', and Z ³ ' is independently selected from carbon, nitrogen, sulfur, and oxygen; ¹ ', Z ² ', and/or Z ³ When ' is carbon or nitrogen, compounds of formula (I'), tautomers thereof, pharmaceutically acceptable salts of any of the above, wherein the valence electrons of carbon and nitrogen are completed with a hydrogen atom , and/or deuterated derivatives of any of the above.
(Item 13)
Form A of crystalline compound 33.
(Item 14)
Form B of crystalline compound 33.
(Item 15)
DCM solvate form A of crystalline compound 33.
(Item 16)
Hydrate form A of crystalline compound 33.
(Item 17)
MeOH/H of crystalline compound 33 ₂ O solvate/hydrate form A.
(Item 18)
Form C of crystalline compound 33.
(Item 19)
Form D of Crystalline Compound 33
(Item 20)
Form E of crystalline compound 33.
(Item 21)
Form F of crystalline compound 33.
(Item 22)
Form G of crystalline compound 33.
(Item 23)
Form H of crystalline compound 33.
(Item 24)
Form I of Crystalline Compound 33
(Item 25)
THF solvate form A of crystalline compound 33.
(Item 26)
Form J of crystalline compound 33.
(Item 27)
Form K of crystalline compound 33.
(Item 28)
Form L of crystalline compound 33.
(Item 29)
2-MeTHF solvate form A of crystalline compound 33.
(Item 30)
Form M of crystalline compound 33.
(Item 31)
Form N of crystalline compound 33.
(Item 32)
Form O of crystalline compound 33.
(Item 33)
Potassium salt form A of crystalline compound 33.
(Item 34)
Potassium salt form B of crystalline compound 33.
(Item 35)
Potassium salt form C of crystalline compound 33.
(Item 36)
Compound 33, which is substantially amorphous.
(Item 37)
A solid dispersion comprising substantially amorphous compound 33.
(Item 38)
38. A solid dispersion comprising substantially amorphous compound 33 according to item 37, further comprising a polymer.
(Item 39)
substantially amorphous compound 33 according to item 38, wherein said polymer is selected from polyvinylpyrrolidone/vinyl acetate (PVPVA), hydroxypropylmethylcellulose (HPMC), and hydroxypropylmethylcellulose acetate succinate (HPMCAS); solid dispersions.
(Item 40)
A solid dispersion comprising the substantially amorphous compound 33 according to item 38 or item 39, wherein the substantially amorphous compound 33 is present in an amount of 30-50%.
(Item 41)
A solid dispersion comprising the substantially amorphous compound 33 according to item 38 or item 39, wherein the substantially amorphous compound 33 is present in an amount of 50-80%.
(Item 42)
42. A solid dispersion comprising substantially amorphous compound 33 according to any one of items 38-41, prepared as a spray-dried dispersion.
(Item 43)
The compound, tautomer, salt, or deuterated derivative of any one of items 1-12, the crystalline compound 33 of any one of items 13-35, the substance of item 36 A pharmaceutical composition comprising substantially amorphous compound 33, or a solid dispersion according to any one of items 37-42, and a pharmaceutically acceptable carrier.
(Item 44)
A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need of treatment a compound, tautomers, salts and deuterated derivatives of any one of items 1-12, at least one compound selected from the crystalline compound 33 according to any one of items 13 to 35, the substantially amorphous compound 33 according to item 36, or any one of items 37 to 42 44. A method comprising administering the solid dispersion of item 43 or the pharmaceutical composition of item 43 to a patient in need of treatment.
(Item 45)
45. The method of item 44, wherein said patient has a Z mutation in alpha-1 antitrypsin.
(Item 46)
46. The method of item 45, wherein said patient has an SZ mutation in alpha-1 antitrypsin.
(Item 47)
46. The method of item 45, wherein said patient is homozygous for the Z mutation in alpha-1 antitrypsin.
(Item 48)
A process for preparing the compound 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrrolo[2,3-f]indazol-7-yl]benzoic acid comprising:
(a) methyl 4-(5-(4-fluorophenyl)-1-pivaloyl-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazole-7 -yl)benzoate with a first organic solvent and a first base to form a first reaction mixture;
(b) adding water and a first acid to the first reaction mixture;
(c) isolating the organic portion from step (b), adding alcohol, optionally adding water to said organic portion, and concentrating said mixture by distillation;
(d) converting said compound 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrrolo[2,3-f]indazol-7-yl]benzoic acid to step (c) and drying the material to remove any moisture content.
(Item 49)
1-(5-(4-fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]indazol-1(5H)-yl) -2,2-dimethylpropan-1-one is reacted with 4-(methoxycarbonyl)phenyl)boronic acid to give methyl 4-(5-(4-fluorophenyl)-1-pivaloyl-6-(tetrahydro-2H) -pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate.
(Item 50)
1-(5-(4-fluorofukunyl)-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]indazol-1(5H)-yl)-2, 2-Dimethylpropan-1-one is reacted with N-iodosuccinimide to give 1-(5-(4-fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2 50. The method of item 49, further comprising forming ,3-f]indazol-1(5H)-yl)-2,2-dimethylpropan-1-one.
(Item 51)
The method comprises reacting 5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazole with trimethylacetyl chloride, 1-(5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]indazol-1(5H)-yl)-2,2-dimethylpropane- 51. The method of item 50, further comprising forming a 1-one.
(Item 52)
The method includes reacting N-(4-fluorophenyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-1H-indazol-5-amine with a second acid to give 5-( 52. The method of item 51, further comprising forming 4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazole.
(Item 53)
The method reacts 5-bromo-6-iodo-1H-indazole with trimethyl((tetrahydro-2H-pyran-4-yl)ethyl)silane to give 5-bromo-6-((tetrahydro-2H-pyran 53. The method of item 52, further comprising forming -4-yl)ethynyl)-1H-indazole.
(Item 54)
5-bromo-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-1H-indazole (C2)

N-(4-fluorophenyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl-1H-indazol-5-amine (C12)

5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazole (C13)

1-(5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]indazol-1(5H)-yl)-2,2-dimethylpropane- 1-on (C14)

1-(5-(4-fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]indazol-1(5H)-yl)-2,2 - dimethylpropan-1-one (S4)

Methyl 4-(5-(4-fluorophenyl)-1-pivaloyl-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl) Benzoate (C58)

A compound selected from
(Item 55)
Spray-dried pure amorphous compound 33.

Claims

a compound of formula (I),

a tautomer thereof, a pharmaceutically acceptable salt of any of the above, and/or a deuterated derivative of any of the above,
During the ceremony,
(i) R ⁰ is selected from
(a) C ₁ -C ₈ straight chain, branched chain, and cyclic alkyl groups, _wherein said alkyl groups are optionally substituted with _1-4 R ^A ; branched and cyclic alkyl groups, and (b) a 5-14 membered aromatic ring optionally substituted with 1-4 ^RA ,
Each R ^A is independently halogen, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, carboxylic acid, 5-10 membered aromatic ring, and C ₁ -C ₆ straight chain , branched chain, and cyclic groups;
the amide nitrogen atom in said amide of R ^A is optionally substituted with a heterocyclyl group optionally further substituted with oxo;
said C ₁ -C ₆ linear, branched and cyclic groups are selected from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamide, alkylsulfinamide, aminoalkyl and alkylamide;
wherein said 5-10 membered aromatic rings and C ₁ -C ₆ straight chain, branched chain and cyclic groups are independently from halogen, C ₁ -C ₆ straight chain, branched and cyclic groups and methoxy optionally substituted with 1 to 4 selected substituents;
a 5- to 14-membered aromatic ring in which the R ^A group is optionally attached to an R ^B group on the R ² group;
(ii) R ¹ is selected from
(a) hydrogen,
(b) C ₁ -C ₈ linear, branched and cyclic alkyl groups, wherein said alkyl groups are
halogen,
cyano,
cyanoalkyl,
hydroxy,
optionally substituted with ₁ to 4 substituents independently selected from alkylsulfonyl and C ₁ -C ₆ straight chain, branched chain and cyclic groups _; branched chain and cyclic groups are independently selected from alkyl groups and alkyl groups, and said C ₁ -C ₆ straight chain, branched chain and cyclic groups are
halogen,
C ₁ -C ₈ straight chain, branched, optionally substituted with 1 to 4 substituents independently selected from hydroxy, and C ₁ -C ₆ straight chain, branched and cyclic alkoxy groups; branched and cyclic alkyl groups,
(c)
halogen,
cyano,
cyanoalkyl,
sulfone,
sulfonamide,
with 1 to 4 substituents independently selected from hydroxy, and C ₁ to C ₆ linear, branched and cyclic alkyl groups optionally substituted with 1 to 4 halogen or alkoxy groups; optionally substituted C ₁ -C ₈ straight, branched and cyclic alkoxy or cyclic thioalkyl groups;
(d) C ₁ -C ₆ straight chain, branched chain, and cyclic alkylsulfonyl groups optionally substituted with C ₁ -C ₆ straight or branched chain alkyl groups;
(e)
an aminosulfonyl group optionally substituted with 1 or 2 substituents independently selected from C ₁ -C ₆ straight chain, branched chain and cyclic alkyl groups;
(f) C ₁ -C ₆ linear, branched and cyclic alkylsulfonylamino groups, and (g)
a phosphine oxide group optionally substituted with 1 or 2 substituents independently selected from C ₁ -C ₆ straight chain, branched chain, and cyclic alkyl groups;
(h) C ₁ -C ₆ straight chain, branched chain, and cyclic trialkylsilyl groups;
(i) C ₁ -C ₆ alkylamides,
(iii) R ² is independently from 5- and 6-membered heterocycles (optionally substituted with oxo and/or C ₁ -C ₆ straight and branched chain alkyl groups), and O, N and S; 5- to 6-membered aromatic ring containing 0-4 heteroatoms selected by , said 5-membered aromatic ring optionally substituted with 1-4 R ^B groups, said 6 The membered aromatic rings are optionally substituted with 1-5 R ^B groups, wherein said R ^B groups are independently
amido, C ₁ -C ₆ straight chain, branched chain and cyclic alkyl groups (optionally substituted with heteroaryl), 4-6 membered heterocyclyl (oxo, C ₁ -C ₆ straight chain, branched optionally substituted with 1 to 3 groups independently selected from cyclic alkyl groups, hydroxyalkyl, amido, alkylsulfonyl, and acetamide), or said amide nitrogen atom; forms part of a 3- to 8-membered heterocyclyl ring (optionally substituted with alkylsulfonyl or C ₁ -C ₆ straight, branched, and cyclic alkyl groups), an amide,
imidazolidine-2,4-dione,
heterocyclyl, oxo, acyl, and C ₁ -C ₆ straight, branched, and cyclic alkyl groups, optionally further with 1 to 3 groups independently selected from oxo, hydroxy, and acyl; heterocyclyl optionally substituted with one or more groups independently selected from
phosphorous acid optionally esterified with C ₁ -C ₆ straight chain, branched chain, or cyclic alkyl groups;
di(C ₁ -C ₆ )alkylphosphine oxide,
(C ₁ -C ₆ )alkylphosphinic acids optionally esterified with C ₁ -C ₆ linear, branched or cyclic alkyl groups;
halogen,
cyano,
hydroxy,
uronic acids or carboxylic acids optionally esterified with C ₁ -C ₆ linear, branched or cyclic alkyl groups;
Oxo,
dihydroxyboryl,
5- and 6-membered aromatic rings containing 0-4 heteroatoms independently selected from O, N, and S, and C ₁ -C ₆ straight, branched, and cyclic alkyls optionally substituted with 1 or 2 substituents independently selected from
hydroxy,
carboxylic acid,
pyrrolidin-2-one,
C ₁ -C ₆ straight, branched, and cyclic alkyl groups and C ₁ -C ₆ straight, branched, and cyclic alkylsulfonyl groups, and C ₁ -C ₆ straight, branched, and 5- and 6-membered aromatic rings optionally substituted with 1 to 4 substituents independently selected from cyclic alkoxy groups,
Sulfonic acid,
alkyl sulfonamide,
C ₁ -C ₆ straight chain, branched chain and cyclic alkylsulfonyl groups,
an aminosulfonyl group,
an aminosulfonyl group optionally substituted with 1 or 2 substituents independently selected from C ₁ -C ₆ straight chain, branched chain and cyclic alkyl groups;
C ₁ -C ₆ straight chain, branched chain and cyclic alkyl groups,
halogen,
hydroxy,
carboxylic acid,
C ₁ -C ₆ straight chain, branched chain and cyclic alkoxy groups,
C ₁ -C ₆ straight, branched and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from heterocyclyl optionally substituted with oxo, and amido;
C ₁ -C ₆ straight chain, branched chain and cyclic alkoxy groups,
halogen,
hydroxy,
carboxylic acid,
with 1 to 4 substituents independently selected from C ₁ to C ₆ straight chain, branched chain and cyclic alkyl groups and C ₁ to C ₆ straight chain, branched chain and cyclic alkoxy groups; optionally substituted C ₁ -C ₆ straight, branched and cyclic alkoxy groups and tetrazolyl groups, wherein
halogen,
hydroxy,
carboxylic acid,
a tetrazolyl group optionally substituted with substituents selected from C ₁ -C ₆ linear, branched and cyclic alkyl groups and C ₁ -C ₆ linear, branched and cyclic alkoxy groups; is selected from
a second 5- or 6-membered aromatic ring containing 0-4 heteroatoms in which two adjacent hydrogens on said 5- or 6-membered aromatic ring are independently selected from O, N, and S; can be replaced by a bond to an aromatic ring to form a bicyclic ^R2 group optionally substituted with 1 to 6 R ^B groups;
(iv) X ¹ and X ² are independently selected from hydrogen, halogen, cyano, hydroxy, C ₁ -C ₆ straight chain, branched chain, and cyclic groups, said C ₁ -C ₆ straight chain, Branched chain and cyclic groups are independently selected from alkyl, alkoxy, thioalkyl and aminoalkyl groups, and said C ₁ -C ₆ straight chain, branched chain and cyclic groups are independently selected from 1 to 4 optionally substituted by a halogen selected as
(v) each of W ¹ and W ² is independently selected from C and N;
(vi) each

represents a single or double bond, provided that one

provided that only is a double bond,
(vii) each R ³ is independently hydrogen, halogen, cyano, C ₁ -C ₆ straight chain, branched chain and cyclic alkyl groups, and C ₁ -C ₆ straight chain, branched chain and cyclic alkoxy groups wherein said C ₁ -C ₆ straight chain, branched chain and cyclic alkyl groups and said C ₁ -C ₆ straight chain, branched chain and cyclic alkoxy groups are selected from halogens, hydroxy groups and optionally substituted with 1 to 4 substituents independently selected from carboxylic acids;
(viii) n is an integer selected from 0, 1, 2, and 3;
(ix) Z ¹ , Z ² and Z ³ are independently selected from carbon, nitrogen, sulfur and oxygen;
when Z ¹ , Z ² , and/or Z ³ are carbon or nitrogen, the valence electrons of carbon or nitrogen are hydrogen atoms, halogens, C ₁ -C ₆ straight chain, branched chain, and cyclic alkyl groups; and complete with C ₁ -C ₆ straight chain, branched chain and cyclic alkoxy groups, said C ₁ -C ₆ straight chain, branched chain and cyclic alkyl groups and said C ₁ -C ₆ straight chain, branched chain Compounds of formula (I) wherein the branched and cyclic alkoxy groups are optionally substituted with 1 to 4 substituents independently selected from halogens, hydroxy groups and carboxylic acids, tautomerism thereof pharmaceutically acceptable salts of any of the above, and/or deuterated derivatives of any of the above.

R ⁰ is selected from aryl rings, heteroaryl rings, and C ₁ -C ₈ straight chain, branched chain and cyclic alkyl groups, each of which is selected from halogen, carboxylic acid, C ₁ -C ₆ straight chain, optionally with 1 to 2 substituents independently selected from branched and cyclic alkyl groups, C ₁ -C ₆ straight chain, branched and cyclic alkoxy groups, aryl rings, and heteroaryl rings; 3. The compound of claim 1, tautomers thereof, pharmaceutically acceptable salts of said compounds, pharmaceutically acceptable salts of said tautomers, deuteration of said compounds, which are substituted. derivatives, deuterated derivatives of said tautomers, and/or deuterated derivatives of said salts.

R ⁰ is

3. The compound of claim 1 or 2, a tautomer thereof, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer, a weight of said compound selected from hydrogenated derivatives, deuterated derivatives of said tautomers and/or deuterated derivatives of said salts.

R ¹ is
hydrogen, methyl, trimethylsilyl, trifluoromethyl,

A compound according to any one of claims 1 to 3, a tautomer thereof, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer selected from , deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and/or deuterated derivatives of said salts.

^R2 is

A compound according to any one of claims 1 to 4, a tautomer thereof, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer selected from , deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and/or deuterated derivatives of said salts.

A compound according to any one of claims 1 to 5, wherein two of Z ¹ , Z ² and Z ³ are nitrogen and the other is selected from carbon and nitrogen, tautomers thereof , a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer, a deuterated derivative of said compound, a deuterated derivative of said tautomer, and/or said salt deuterated derivatives of

A compound according to any one of claims 1 to 6, wherein each R ³ is independently selected from hydrogen, deuterium, halogen, C ₁ -C ₆ straight chain alkyl groups, and heterocyclyl groups, tautomers, pharmaceutically acceptable salts of said compounds, pharmaceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and /or deuterated derivatives of said salts.

A compound according to any one of claims 1 to 7, wherein X ¹ and X ² are independently selected from hydrogen and halogen, tautomers thereof, pharmaceutically acceptable salts of said compounds. , a pharmaceutically acceptable salt of said tautomer, a deuterated derivative of said compound, a deuterated derivative of said tautomer, and/or a deuterated derivative of said salt.

The compound of claim 1, selected from compounds of formulas IA, IB, IC, ID, IE, IF, IG, and IH;

tautomers thereof, pharmaceutically acceptable salts of said compounds, pharmaceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and/or a deuterated derivative of said salt, wherein
R ⁰ , R ¹ , R ² , R ³ , and n are defined for compounds of formula (I),
X ¹ and X ² are independently selected from hydrogen and fluorine, or X ¹ is fluorine and X ² is hydrogen, or X ² is fluorine and X ¹ is , is hydrogen, or X ¹ and X ² are each hydrogen,
each of W ¹ and W ² is independently selected from C and N;
Y ¹ , Y ² , Y ³ , and Y ⁴ are independently
hydrogen,
cyano,
halogen group,
C ₁ -C ₆ straight chain, branched chain and cyclic alkyl groups,
C ₁ -C ₆ straight chain, branched chain and cyclic alkoxy groups,
hydroxy,
with 1 to 4 substituents independently selected from C ₁ to C ₆ straight chain, branched chain and cyclic alkyl groups and C ₁ to C ₆ straight chain, branched chain and cyclic alkoxy groups; optionally substituted C ₁ -C ₆ straight chain, branched chain and cyclic alkoxy groups,
Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ are independently
hydrogen,
halogen group,
hydroxy,
C 1 -C 6 straight, branched _, and cyclic alkyl groups, and C ₁ -C ₆ straight, branched chain, optionally substituted with ₁ to 4 independently selected halogen substituents; , and a cyclic alkoxy group ,
Y ⁹ , Y ¹⁰ , Y ¹¹ , Y ¹² , Y ¹³ , Y ¹⁴ , Y ¹⁵ and Y ¹⁶ are independently
carboxylic acid,
hydrogen,
halogen group,
C ₁ -C ₆ straight chain, branched chain and cyclic alkylsulfonyl groups,
C 1 -C 6 straight, branched _, and cyclic alkyl groups, and C ₁ -C ₆ straight, branched chain, optionally substituted with ₁ to 4 independently selected halogen substituents; , and a cyclic alkoxy group ,
Y ¹⁷ , Y ¹⁸ , Y ¹⁹ , Y ²⁰ and Y ²¹ are independently
hydrogen,
carboxylic acid,
halogen group,
cyano,
hydroxy,
C ₁ -C ₆ straight chain, branched chain and cyclic alkyl groups, which are
halogen,
C ₁ -C ₆ straight chain, branched chain and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from hydroxy, and carboxylic acid;
C ₁ -C ₆ linear, branched and cyclic alkoxy groups optionally substituted with carboxylic acid groups;
dihydroxyboryl,
Sulfonic acid,
carboxylic acids optionally esterified with uronic acids,
a tetrazolyl group,
an aminosulfonyl group,
aminosulfonyl groups, and C ₁ -C ₆ straight chain , optionally substituted with 1 or 2 substituents independently selected from C ₁ -C ₆ straight chain, branched chain, and cyclic alkyl groups; chain, branched and cyclic alkylsulfonyl groups, but
with the proviso that in formulas IE, at least one of Y ¹⁷ , Y ¹⁸ , Y ¹⁹ , Y ²⁰ , and Y ²¹ is hydrogen; The compound of claim 1, selected from the compounds of C, ID, IE, IF, IG, and IH, tautomers thereof, pharmaceutically acceptable compounds of said compounds. pharmaceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and/or deuterated derivatives of said salts.

one or more of Y ¹⁷ , Y ¹⁸ , Y ¹⁹ , Y ²⁰ , and Y ²¹ is methyl, methoxy, cyano, fluorine, hydroxy, —CF ₃ , —B(OH) ₂ , —SO ₂ NHMe, — _SO2Me , _-SO2H , _-CH2CO2H _,

10. The compound of claim 9, a tautomer thereof, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer, deuteration of said compound, selected from derivatives, deuterated derivatives of said tautomers, and/or deuterated derivatives of said salts.

a compound selected from

tautomers thereof, pharmaceutically acceptable salts of said compounds, pharmaceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and deuterated derivatives of said salts.

a compound of formula (I'),

a tautomer thereof, a pharmaceutically acceptable salt of any of the above, and/or a deuterated derivative of any of the above,
During the ceremony,
(i) R ⁰ ' is selected from
(a) C ₁ -C ₈ straight chain, branched chain, and cyclic alkyl groups, _wherein said alkyl groups are optionally substituted with _1-4 R ^A ; branched and cyclic alkyl groups,
(b) a 5-14 membered aromatic ring optionally substituted with 1-4 R ^A ',
Each R ^A ′ is independently halogen, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amido, 5-10 membered aromatic ring, and C ₁ -C ₆ linear, branched selected from branched chain and cyclic groups, wherein said C ₁ -C ₆ straight chain, branched chain and cyclic groups are alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamide, alkylsulfinamide, aminoalkyl; , and alkylamides, and 1-4 of said 5-10 membered aromatic rings and C ₁ -C ₆ linear, branched and cyclic groups are independently selected from halogen and methoxy optionally substituted with the substituents of
a 5- to 14-membered aromatic ring optionally substituted with 1-4 R ^{A ', wherein the R A} ' group is optionally attached to ^an R ^B ' group on the R ² 'group;
(ii) R ¹ ' is selected from
(a) hydrogen,
(b) C ₁ -C ₈ linear, branched and cyclic alkyl groups, wherein said alkyl groups are
halogen,
cyano,
optionally substituted with 1 to 4 substituents independently selected from hydroxy and C ₁ -C ₆ straight chain, branched chain and cyclic groups, said C ₁ -C ₆ straight chain, branched chain chain and cyclic groups are independently selected from alkyl groups and alkoxy groups, and said C ₁ -C ₆ straight chain, branched chain and cyclic groups are
halogen,
C ₁ -C ₈ straight chain, branched, optionally substituted with 1 to 4 substituents independently selected from hydroxy, and C ₁ -C ₆ straight chain, branched and cyclic alkoxy groups; branched and cyclic alkyl groups,
(c)
halogen,
cyano,
sulfone,
sulfonamide,
optionally substituted with 1 to 4 substituents independently selected from hydroxy, and C ₁ -C ₆ linear, branched and cyclic alkyl groups optionally substituted with 1 to 4 halogens C ₁ -C ₈ linear, branched and cyclic alkoxy or cyclic thioalkyl groups,
(d) C ₁ -C ₆ straight, branched and cyclic alkylsulfonyl groups;
(e)
an aminosulfonyl group optionally substituted with 1 or 2 substituents independently selected from C ₁ -C ₆ straight chain, branched chain and cyclic alkyl groups;
(f) C ₁ -C ₆ straight, branched, and cyclic alkylsulfonylamino groups, and (g) phosphine oxide groups,
a phosphine oxide group optionally substituted with 1 or 2 substituents independently selected from C ₁ -C ₆ straight chain, branched chain, and cyclic alkyl groups;
(h) C ₁ -C ₆ straight chain, branched chain, and cyclic trialkylsilyl groups;
(iii) R ² ' is selected from 5- and 6-membered aromatic rings containing 0-4 heteroatoms independently selected from O, N, and S, wherein said 5-membered ring comprises 1 optionally substituted with up to 4 R ^B ' groups, said 6-membered ring optionally substituted with 1-5 R ^B ' groups, wherein said R ^B ' groups are independently
optionally substituted amides,
imidazolidine-2,4-dione,
optionally substituted heterocyclyl,
phosphorous acid optionally esterified with C ₁ -C ₆ straight chain, branched chain, or cyclic alkyl groups;
di(C ₁ -C ₆ )alkylphosphine oxide,
(C ₁ -C ₆ )alkylphosphinic acids optionally esterified with C ₁ -C ₆ linear, branched or cyclic alkyl groups;
halogen,
cyano,
hydroxy,
uronic acids or carboxylic acids optionally esterified with C ₁ -C ₆ linear, branched or cyclic alkyl groups;
Oxo,
dihydroxyboryl,
5- and 6-membered aromatic rings containing 0-4 heteroatoms independently selected from O, N, and S, and C ₁ -C ₆ straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 or 2 substituents independently selected from
hydroxy,
carboxylic acid,
pyrrolidin-2-one,
C ₁ -C ₆ straight, branched, and cyclic alkyl groups and C ₁ -C ₆ straight, branched, and cyclic alkylsulfonyl groups, and C ₁ -C ₆ straight, branched, and 5- and 6-membered aromatic rings optionally substituted with 1 to 4 substituents independently selected from cyclic alkoxy groups,
Sulfonic acid,
C ₁ -C ₆ straight chain, branched chain and cyclic alkylsulfonyl groups,
an aminosulfonyl group,
an aminosulfonyl group optionally substituted with 1 or 2 substituents independently selected from C ₁ -C ₆ straight chain, branched chain and cyclic alkyl groups;
C ₁ -C ₆ straight chain, branched chain and cyclic alkyl groups,
halogen,
hydroxy,
C ₁ -C ₆ straight chain, optionally substituted with 1 to 4 substituents independently selected from carboxylic acids and C ₁ -C ₆ straight chain, branched chain, and cyclic alkoxy groups; branched and cyclic alkyl groups,
C ₁ -C ₆ straight chain, branched chain and cyclic alkoxy groups,
halogen,
hydroxy,
carboxylic acid,
with 1 to 4 substituents independently selected from C ₁ to C ₆ straight chain, branched chain and cyclic alkyl groups and C ₁ to C ₆ straight chain, branched chain and cyclic alkoxy groups; optionally substituted C ₁ -C ₆ straight, branched and cyclic alkoxy groups and tetrazolyl groups, wherein
halogen,
hydroxy,
carboxylic acid,
a tetrazolyl group optionally substituted with substituents selected from C ₁ -C ₆ straight, branched and cyclic alkyl groups and C ₁ -C ₆ straight, branched and cyclic alkoxy groups; , selected from
a second 5- or 6-membered aromatic ring containing 0-4 heteroatoms in which two adjacent hydrogens on said 5- or 6-membered aromatic ring are independently selected from O, N, and S; can be replaced by a bond to an aromatic ring to form a bicyclic R ² ' group optionally substituted with 1 to 6 R ^B 'groups;
(iv) X ¹ ' and X ² ' are independently selected from hydrogen, halogen, cyano, _hydroxy , C ₁ _-C ₆ straight chain, branched chain, and cyclic groups; Chain, branched chain and cyclic groups are independently selected from alkyl, alkoxy, thioalkyl and aminoalkyl groups, and said C ₁ -C ₆ straight chain, branched chain and cyclic groups are from 1 to 4 optionally substituted by independently selected halogens,
(v) each

represents a single or double bond, provided that

provided that only one of is a double bond,
(vi) each R ³ is independently hydrogen, halogen, cyano, C ₁ -C ₆ straight chain, branched chain and cyclic alkyl groups, and C ₁ -C ₆ straight chain, branched chain and cyclic alkoxy groups, wherein said linear, branched and cyclic alkyl and alkoxy groups are optionally substituted with 1 to 4 independently selected halogens;
(vii) n' is an integer selected from 0, 1, 2, and 3;
(viii) Z ¹ ', Z ² ' and Z ³ ' are independently selected from carbon, nitrogen, sulfur and oxygen, Z ¹ ', Z ² ' and/or Z ³ ' are carbon or nitrogen, the compounds of formula (I'), tautomers thereof, pharmaceutically acceptable salts of any of the foregoing, and/or A deuterated derivative of any of the above.

Form A of crystalline compound 33.

Form B of crystalline compound 33.

DCM solvate form A of crystalline compound 33.

Hydrate form A of crystalline compound 33.

MeOH/ _H2O solvate/hydrate Form A of crystalline compound 33.

Form C of crystalline compound 33.

Form D of Crystalline Compound 33

Form E of crystalline compound 33.

Form F of crystalline compound 33.

Form G of crystalline compound 33.

Form H of crystalline compound 33.

Form I of Crystalline Compound 33

THF solvate form A of crystalline compound 33.

Form J of crystalline compound 33.

Form K of crystalline compound 33.

Form L of crystalline compound 33.

2-MeTHF solvate form A of crystalline compound 33.

Form M of crystalline compound 33.

Form N of crystalline compound 33.

Form O of crystalline compound 33.

Potassium salt form A of crystalline compound 33.

Potassium salt form B of crystalline compound 33.

Potassium salt form C of crystalline compound 33.

substantially amorphous compound 33;

A solid dispersion comprising substantially amorphous compound 33.

38. A solid dispersion comprising the substantially amorphous compound 33 of claim 37, further comprising a polymer.

39. The substantially amorphous compound 33 of claim 38, wherein said polymer is selected from polyvinylpyrrolidone/vinyl acetate (PVPVA), hydroxypropylmethylcellulose (HPMC), and hydroxypropylmethylcellulose acetate succinate (HPMCAS). A solid dispersion comprising:

A solid dispersion comprising the substantially amorphous compound 33 of claim 38 or claim 39, wherein the substantially amorphous compound 33 is present in an amount of 30-50%.

A solid dispersion comprising the substantially amorphous compound 33 of claim 38 or claim 39, wherein the substantially amorphous compound 33 is present in an amount of 50-80%.

A solid dispersion comprising the substantially amorphous compound 33 of any one of claims 38-40 prepared as a spray-dried dispersion.

A compound, tautomer, salt or deuterated derivative according to any one of claims 1 to 12, a crystalline compound 33 according to any one of claims 13 to 35, to claim 36 A pharmaceutical composition comprising the substantially amorphous compound 33 as described, or a solid dispersion according to any one of claims 37-42, and a pharmaceutically acceptable carrier.

A compound, tautomer, pharmacy according to any one of claims 1 to 12 for treating alpha-1 antitrypsin deficiency in a patient in need of treatment for alpha-1 antitrypsin deficiency. crystalline compound 33 according to any one of claims 13 to 35, substantially amorphous compound 33 according to claim 36, or a solid dispersion according to any one of claims 37 to 42, or a pharmaceutical composition according to claim 43 .

45. The pharmaceutical composition of claim 44, wherein said patient has a Z mutation in alpha-1 antitrypsin.

46. The pharmaceutical composition of claim 45, wherein said patient has an SZ mutation in alpha-1 antitrypsin.

46. The pharmaceutical composition of claim 45, wherein said patient is homozygous for the Z mutation in alpha-1 antitrypsin.

A process for preparing the compound 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrrolo[2,3-f]indazol-7-yl]benzoic acid comprising:
(a) methyl 4-(5-(4-fluorophenyl)-1-pivaloyl-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazole-7 -yl)benzoate with a first organic solvent and a first base to form a first reaction mixture;
(b) adding water and a first acid to the first reaction mixture;
(c) isolating the organic portion from step (b), adding alcohol, optionally adding water to said organic portion, and concentrating said mixture by distillation;
(d) converting said compound 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrrolo[2,3-f]indazol-7-yl]benzoic acid to step (c) and drying the material to remove any moisture content.

1-(5-(4-fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]indazol-1(5H)-yl) -2,2-dimethylpropan-1-one is reacted with 4-(methoxycarbonyl)phenyl)boronic acid to give methyl 4-(5-(4-fluorophenyl)-1-pivaloyl-6-(tetrahydro-2H) -pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate.

1-(5-(4-fluorofukunyl)-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]indazol-1(5H)-yl)-2, 2-Dimethylpropan-1-one is reacted with N-iodosuccinimide to give 1-(5-(4-fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2 50. The method of claim 49, further comprising forming ,3-f]indazol-1(5H)-yl)-2,2-dimethylpropan-1-one.

The method comprises reacting 5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazole with trimethylacetyl chloride, 1-(5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3-f]indazol-1(5H)-yl)-2,2-dimethylpropane- 51. The method of claim 50, further comprising forming a 1-one.

The method includes reacting N-(4-fluorophenyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-1H-indazol-5-amine with a second acid to give 5-( 52. The method of claim 51, further comprising forming 4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazole.

The method reacts 5-bromo-6-iodo-1H-indazole with trimethyl((tetrahydro-2H-pyran-4-yl)ethyl)silane to give 5-bromo-6-((tetrahydro-2H-pyran 53. The method of claim 52, further comprising forming -4-yl)ethynyl)-1H-indazole.

5-bromo-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-1H-indazole (C2)

A compound selected from

Spray-dried pure amorphous compound 33.