JPWO2021026451A5

JPWO2021026451A5 -

Info

Publication number: JPWO2021026451A5
Application number: JP2022507589A
Authority: JP
Publication date: 2023-08-15

Description

[本発明1001]
サイトカイン放出症候群（ＣＲＳ）を治療及び／又は予防するための方法であって、ＣＲＳに罹患しているか、又はＣＲＳを発症する危険性のある対象に、有効量の、キナーゼ阻害剤としての活性を有する化合物を投与する段階を含む、方法。
[本発明1002]
前記化合物が、ＪＡＫ阻害剤、ＩＲＡＫ阻害剤、又はこれらの組合せである、本発明1001の方法。
[本発明1003]
前記化合物が、式Ｉで表されるピリミジンジアミン化合物

（式中、
Ｘ及びＹはそれぞれ、独立に、Ｏ、Ｓ、Ｓ（Ｏ）、ＳＯ ₂ 又はＮＲ ¹ であり；
各Ｒ ¹ は、それぞれの出現時に独立に、Ｈ、Ｃ _1～6 アルキル、Ｃ（Ｏ）－Ｃ _1～6 アルキル、ＣＯ ₂ －Ｃ _1～6 アルキル又はＲ ⁵⁰ であり；
各Ｒ ⁵⁰ は、Ｃ（Ｒ ⁹ ） ₂ －Ｏ－Ｒ ¹⁰ 又はＣ（Ｒ ⁹ ） ₂ －Ｓ－Ｒ ¹⁰ であり；
各Ｒ ⁹ は、それぞれの出現時に独立に、Ｈ、Ｃ _1～6 アルキル、Ｃ _6～10 アリール又はＣ _7～16 アリールアルキルであり；又は代わりに、2個のＲ ⁹ は、それらが結合されている炭素と一緒に、Ｃ _3～8 シクロアルキル基又は3～8員複素脂環式を形成し；Ｒ ¹⁰ は、Ｒ ^ａ又は－Ｐ（Ｏ）（ＯＲ ¹¹ ） ₂ であり；各Ｒ ¹¹ は、それぞれの出現時に独立に、Ｒ ^ａ又は一価カチオン性基であり；又は2個のＲ ¹¹ は、それらが結合されている原子と一緒に、4～8員環状リン酸基を形成し、又は2個のＲ ¹¹ は、一緒に、二価カチオン性基を表し；
環Ａは、Ｃ _6～10 アリール又は5～10員ヘテロアリールであり；
各Ｒ ² は、それぞれの出現時に独立に、Ｈ、Ｒ ^ｅ、Ｒ ^ｂ、同一の又は異なるＲ ^ａ及び／又はＲ ^ｂの1つ以上で置換されたＲ ^ｅ、同一の又は異なるＲ ^ａ及び／又はＲ ^ｂの1つ以上で置換された－ＯＲ ^ｅ、同一の又は異なるＲ ^ａ及び／又はＲ ^ｂの1つ以上で置換された－ＳＲ ^ｅ、同一の又は異なるＲ ^ａ及び／又はＲ ^ｂの1つ以上で置換された－Ｃ（Ｏ）Ｒ ^ｅ、－Ｎ（Ｒ ^ａ）Ｒ ^ｅ（ここで、Ｒ ^ｅは、同一の又は異なるＲ ^ａ及び／又はＲ ^ｂの1つ以上で置換されている）、同一の又は異なるＲ ^ａ及び／又はＲ ^ｂの1つ以上で置換された－Ｓ（Ｏ） ₂ Ｒ ^ｅ、－Ｂ（ＯＲ ^ａ） ₂ 、－Ｂ（Ｎ（Ｒ ^ｃ） ₂ ） ₂ 、－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－Ｒ ^ｂ、－Ｏ－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－Ｒ ^ｂ、－Ｓ－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－Ｒ ^ｂ、－Ｏ－（Ｃ（Ｒ ^ｂ） ₂ ） _ｍ－Ｒ ^ａ、－Ｎ（Ｒ ^ａ）－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－Ｒ ^ｂ、－Ｏ－（ＣＨ ₂ ） _ｍ－ＣＨ（（ＣＨ ₂ ） _ｍＲ ^ｂ）Ｒ ^ｂ、－Ｃ（Ｏ）Ｎ（Ｒ ^ａ）－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－Ｒ ^ｂ、－Ｏ－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－Ｃ（Ｏ）Ｎ（Ｒ ^ａ）－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－Ｒ ^ｂ、－Ｎ（（Ｃ（Ｒ ^ａ） ₂ ） _ｍＲ ^ｂ） ₂ 、－Ｓ－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－Ｃ（Ｏ）Ｎ（Ｒ ^ａ）－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－Ｒ ^ｂ、－Ｎ（Ｒ ^ａ）－Ｃ（Ｏ）－Ｎ（Ｒ ^ａ）－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－Ｒ ^ｂ、－Ｎ（Ｒ ^ａ）－Ｃ（Ｏ）－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－Ｃ（Ｒ ^ａ）（Ｒ ^ｂ） ₂ 又は－Ｎ（Ｒ ^ａ）－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－Ｃ（Ｏ）－Ｎ（Ｒ ^ａ）－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－Ｒ ^ｂであり；
各Ｒ ^ａは、それぞれの出現時に独立に、Ｈ、重水素、Ｃ _1～6 アルキル、Ｃ _3～8 シクロアルキル、Ｃ _4～11 シクロアルキルアルキル、Ｃ _6～10 アリール、Ｃ _7～16 アリールアルキル、2～6員ヘテロアルキル、3～10員複素脂環式、4～11員複素脂環式アルキル、5～15員ヘテロアリール又は6～16員ヘテロアリールアルキルであり；
各Ｒ ^ｂは、それぞれの出現時に独立に、＝Ｏ、－ＯＲ ^ａ、－Ｏ－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－ＯＲ ^ａ、ハロＣ _1～3 アルキルオキシ、＝Ｓ、－ＳＲ ^ａ、＝ＮＲ ^ａ、＝ＮＯＲ ^ａ、－Ｎ（Ｒ ^ｃ） ₂ 、ハロ、－ＣＦ ₃ 、－ＣＮ、－ＮＣ、－ＯＣＮ、－ＳＣＮ、－ＮＯ、－ＮＯ ₂ 、＝Ｎ ₂ 、－Ｎ ₃ 、－Ｓ（Ｏ）Ｒ ^ａ、－Ｓ（Ｏ） ₂ Ｒ ^ａ、－ＳＯ ₃ Ｒ ^ａ、－Ｓ（Ｏ）Ｎ（Ｒ ^ｃ） ₂ 、－ＯＳ（Ｏ）Ｒ ^ａ、－ＯＳ（Ｏ） ₂ Ｒ ^ａ、－ＯＳＯ ₃ Ｒ ^ａ、－ＯＳ（Ｏ） ₂ Ｎ（Ｒ ^ｃ） ₂ 、－Ｃ（Ｏ）Ｒ ^ａ、－ＣＯ ₂ Ｒ ^ａ、－Ｃ（Ｏ）Ｎ（Ｒ ^ｃ） ₂ 、－Ｃ（ＮＲ ^ａ）－Ｎ（Ｒ ^ｃ） ₂ 、－Ｃ（ＮＯＨ）－Ｒ ^ａ、－Ｃ（ＮＯＨ）－Ｎ（Ｒ ^ｃ） ₂ 、－ＯＣ（Ｏ）Ｒ ^ａ、－ＯＣ（Ｏ）ＯＲ ^ａ、－ＯＣ（Ｏ）Ｎ（Ｒ ^ｃ） ₂ 、－ＯＣ（ＮＨ）－Ｎ（Ｒ ^ｃ） ₂ 、－ＯＣ（ＮＲ ^ａ）－Ｎ（Ｒ ^ｃ） ₂ 、－［Ｎ（Ｒ ^ａ）Ｃ（Ｏ）］ _ｎＲ ^ａ、－［Ｎ（Ｒ ^ａ）Ｃ（Ｏ）］ _ｎＯＲ ^ａ、－［Ｎ（Ｒ ^ａ）Ｃ（Ｏ）］ _ｎＮ（Ｒ ^ｃ） ₂ 又は－［Ｎ（Ｒ ^ａ）Ｃ（ＮＲ ^ａ）］ _ｎ－Ｎ（Ｒ ^ｃ） ₂ であり；
各Ｒ ^ｃは、それぞれの出現時に独立に、Ｒ ^ａであり、又は、代わりに、2個のＲ ^ｃは、それらが結合されている窒素原子と一緒になって、同一の又は異なる追加のヘテロ原子の1つ以上を含んでいてもよくかつ同一の又は異なるＲ ^ａ及び／又はＲ ^ｄ基の1つ以上で置換されていてもよい、3～10員複素脂環式又は5～10員ヘテロアリールを形成し；
各Ｒ ^ｄは、＝Ｏ、－ＯＲ ^ａ、ハロＣ _1～3 アルキルオキシ、Ｃ _1～6 アルキル、＝Ｓ、－ＳＲ ^ａ、＝ＮＲ ^ａ、＝ＮＯＲ ^ａ、－Ｎ（Ｒ ^ａ） ₂ 、ハロ、－ＣＦ ₃ 、－ＣＮ、－ＮＣ、－ＯＣＮ、－ＳＣＮ、－ＮＯ、－ＮＯ ₂ 、＝Ｎ ₂ 、－Ｎ ₃ 、－Ｓ（Ｏ）Ｒ ^ａ、－Ｓ（Ｏ ₂ ）Ｒ ^ａ、－ＳＯ ₃ Ｒ ^ａ、－Ｓ（Ｏ）Ｎ（Ｒ ^ａ） ₂ 、－Ｓ（Ｏ） ₂ Ｎ（Ｒ ^ａ） ₂ 、－ＯＳ（Ｏ）Ｒ ^ａ、－ＯＳ（Ｏ） ₂ Ｒ ^ａ、－ＯＳＯ ₃ Ｒ ^ａ、－ＯＳ（Ｏ） ₂ Ｎ（Ｒ ^ａ） ₂ 、－Ｃ（Ｏ）Ｒ ^ａ、－ＣＯ ₂ Ｒ ^ａ、－Ｃ（Ｏ）Ｎ（Ｒ ^ａ） ₂ 、－Ｃ（ＮＲ ^ａ）Ｎ（Ｒ ^ａ） ₂ 、－Ｃ（ＮＯＨ）Ｒ ^ａ、－Ｃ（ＮＯＨ）Ｎ（Ｒ ^ａ） ₂ 、－ＯＣＯ ₂ Ｒ ^ａ、－ＯＣ（Ｏ）Ｎ（Ｒ ^ａ） ₂ 、－ＯＣ（ＮＲ ^ａ）Ｎ（Ｒ ^ａ） ₂ 、－［Ｎ（Ｒ ^ａ）Ｃ（Ｏ）］ _ｎＲ ^ａ、－（Ｃ（Ｒ ^ａ） ₂ ） _ｎ－ＯＲ ^ａ、－Ｎ（Ｒ ^ａ）－Ｓ（Ｏ） ₂ Ｒ ^ａ、－Ｃ（Ｏ）－Ｃ _1～6 ハロアルキル、－Ｓ（Ｏ） ₂ Ｃ _1～6 ハロアルキル、－ＯＣ（Ｏ）Ｒ ^ａ、－Ｏ（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－ＯＲ ^ａ、－Ｓ（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－ＯＲ ^ａ、－Ｎ（Ｒ ^ａ）Ｃ _1～6 ハロアルキル、－Ｐ（Ｏ）（ＯＲ ^ａ） ₂ 、－Ｎ（Ｒ ^ａ）－（Ｃ（Ｒ ^ａ） ₂ ） _ｍ－ＯＲ ^ａ、－［Ｎ（Ｒ ^ａ）Ｃ（Ｏ）］ _ｎＯＲ ^ａ、－［Ｎ（Ｒ ^ａ）Ｃ（Ｏ）］ _ｎＮ（Ｒ ^ａ） ₂ 、－［Ｎ（Ｒ ^ａ）Ｃ（ＮＲ ^ａ）］ _ｎＮ（Ｒ ^ａ） ₂ 又は－Ｎ（Ｒ ^ａ）Ｃ（Ｏ）Ｃ _1～6 ハロアルキルであり；又は2個のＲ ^ｄは、それらが結合されている1つ又は複数の原子と一緒になって、組み合わされて、1個以上のヘテロ原子を含有していてもよくかつ1個以上のＲ ^ａで置換されていてもよい、3～10員の部分的に又は完全に飽和した単環式又は二環式環を形成し；
各Ｒ ^ｅは、それぞれの出現時に独立に、Ｃ _1～6 アルキル、Ｃ _3～8 シクロアルキル、Ｃ _4～11 シクロアルキルアルキル、Ｃ _6～10 アリール、Ｃ _7～16 アリールアルキル、2～6員ヘテロアルキル、3～10員複素脂環式、4～11員複素脂環式アルキル、5～15員ヘテロアリール又は6～16員ヘテロアリールアルキルであり；
ｐは、0、1、2、3又は4であり；
各ｍは、1、2又は3であり；
各ｎは、0、1、2又は3であり；
又は2個のＲ ² 基は、それらが結合されている1つ又は複数の原子と一緒になって、組み合わされて、1個以上のヘテロ原子を含有していてもよくかつ1個以上のＲ ^ａ及び／又はＲ ^ｂで置換されていてもよい、4～10員の部分的に又は完全に飽和した単環式又は二環式環を形成し；
Ｚ ¹ 及びＺ ² はそれぞれ、独立に、ＣＨ、ＣＲ ² 又はＮであり；
Ｒ ³ は、Ｈ、Ｃ _1～6 アルキル又はＲ ⁵⁰ であり；
Ｒ ⁴ は、Ｈ、Ｃ _1～6 アルキル又はＲ ⁵⁰ であり；
Ｒ ⁵ は、ハロ、－ＣＮ、Ｃ _1～6 アルキル、アルキニル、ヒドロキシ、Ｃ _1～6 アルコキシ、ニトロ、－Ｎ（Ｒ ^ａ） ₂ 、－Ｃ（Ｏ）Ｎ（Ｒ ^ａ） ₂ 、－ＣＯ ₂ Ｒ ^ａ又は－Ｃ（Ｏ）Ｒ ^ａである）
又はその塩、溶媒和物、若しくはＮ－オキシド
である、本発明1001又は本発明1002の方法。
[本発明1004]
前記化合物が、以下で表される式：
式IA：

又はその塩、溶媒和物、若しくはＮ－オキシド
（式中、Ｒ ^2ａ、Ｒ ^2ｂ、Ｒ ^2ｃ及びＲ ^2ｄのそれぞれは、それぞれの出現時に独立に、Ｒ ² について前に定義される通りである）；
式IA3：

又はその塩、溶媒和物、Ｎ－オキシド若しくはプロドラッグ
（式中、Ｒ ^ｂは、ＯＨ、Ｃ _1～6 アルキル、－ＣＯ ₂ Ｃ _1～6 アルキル、－Ｃ（Ｏ）Ｃ _1～6 アルキル又は－Ｓ（Ｏ） ₂ Ｃ _1～6 アルキルである）；
式IB：

又はその塩、溶媒和物、Ｎ－オキシド若しくはプロドラッグ
（式中、Ｑ ¹ 及びＱ ² はそれぞれ、独立に、Ｎ又はＣＨであり、ただし、Ｑ ¹ 及びＱ ² の少なくとも1つがＮである）；又は
式II：

又はその塩、溶媒和物、Ｎ－オキシド若しくはプロドラッグ
（式中、
環Ｂは、それが結合されている2個のフェニル環原子と一緒に、Ｎ（Ｒ ^ｃ）、Ｏ及びＳから独立に選択される1、2又は3個のヘテロ原子を含有していてもよい5、6又は7員環を形成し；
各Ｒ ^ａは、Ｃ _1～6 アルキルであり；
各Ｒ ^ｂは、それぞれの出現時に独立に、＝Ｏ、－ＯＲ ^ａ、ハロＣ _1～3 アルキルオキシ、－ＳＲ ^ａ、－Ｎ（Ｒ ^ｃ） ₂ 、ハロ、－ＣＦ ₃ 、－ＣＮ、－Ｓ（Ｏ） ₂ Ｎ（Ｒ ^ｃ） ₂ 、－Ｓ（Ｏ） ₂ Ｒ ^ａ、－Ｃ（Ｏ）Ｒ ^ａ、－ＣＯ ₂ Ｒ ^ａ、－Ｃ（Ｏ）Ｎ（Ｒ ^ｃ） ₂ 、－Ｎ（Ｒ ^ａ）－Ｓ（Ｏ） ₂ Ｒ ^ａ又は－Ｃ（Ｒ ^ａ） ₂ －Ｎ（Ｒ ^ｃ） ₂ である）
を有する、本発明1003の方法。
[本発明1005]
前記化合物が、
Ｎ2－（3，4，5－トリメチル）フェニル－5－メチル－Ｎ4－（2－オキソ－2，3－ジヒドロ－1，3－ベンゾオキサゾール－5－イル）－2，4－ピリミジンジアミン、又はその医薬的に許容される塩；
5－メチル－Ｎ4－［3－（ホスホノオキシ）メチル－2－オキソ－2，3－ジヒドロ－1，3－ベンゾオキサゾール－5－イル］－Ｎ2－（3，4，5－トリメチル）フェニル－2，4－ピリミジンジアミン、又はその医薬的に許容される塩；
5－メチル－Ｎ4－［3－（ホスホノオキシ）メチル－2－オキソ－2，3－ジヒドロ－1，3－ベンゾオキサゾール－5－イル］－Ｎ2－（3，4，5－トリメチル）フェニル－2，4－ピリミジンジアミンビス－ナトリウム塩；
Ｎ2－（3－メトキシ－5－トリフルオロメチル）フェニル－5－メチル－Ｎ4－［3－（ホスホノオキシ）メチル－2－オキソ－2，3－ジヒドロ－1，3－ベンゾオキサゾール－5－イル］－2，4－ピリミジンジアミン、又はその医薬的に許容される塩；
Ｎ2－（3－メトキシ－5－トリフルオロメチル）フェニル－5－メチル－Ｎ4－［3－（ホスホノオキシ）メチル－2－オキソ－2，3－ジヒドロ－1，3－ベンゾオキサゾール－5－イル］－2，4－ピリミジンジアミンビス－ナトリウム塩；
5－（2－（3－メトキシ－4，5－ジメチルフェニルアミノ）－5－メチルピリミジン－4－イルアミノ）ベンゾ［ｄ］オキサゾール－2（3Ｈ）－オン、又はその医薬的に許容される塩；
（5－（2－（4－フルオロ－3－メトキシ－5－メチルフェニルアミノ）－5－メチルピリミジン－4－イルアミノ）－2－オキソベンゾ［ｄ］オキサゾール－3（2Ｈ）－イル）メチル二水素ホスフェート；
5－（2－（4－フルオロ－3－メトキシ－5－メチルフェニルアミノ）－5－メチルピリミジン－4－イルアミノ）ベンゾ［ｄ］オキサゾール－2（3Ｈ）－オン、又はその医薬的に許容される塩；或いは
（5－（2－（4－フルオロ－3－メトキシ－5－メチルフェニルアミノ）－5－メチルピリミジン－4－イルアミノ）－2－オキソベンゾ［ｄ］オキサゾール－3（2Ｈ）－イル）メチルホスフェートナトリウム
である、本発明1001～1004のいずれかの方法。
[本発明1006]
前記化合物が、式ＩＩＩで表されるピリミジンジアミン化合物

（式中、
Ｘ ^Ｂは、アルキル、アルコキシ、アミノ、カルボキシル、カルボキシルエステル、シアノ、ハロ、ニトロ、アルケニル、又はアルキニルであり；
Ｒ ^Ｂは、水素、アルキル、アルケニル、アルキニル、又はシクロアルキルであり；
環Ａ ^Ｂは、アリール、ヘテロアリール、シクロアルキル、シクロアルケニル又は複素環式であり、ここで、環Ａは、インドリルでもベンズイミダゾリルでもなく；
ｒは、0、1、2又は3であり；
各Ｒ ^Ｂ2 は、独立に、アルキル、アルコキシ、アミノ、アリール、アリールオキシ（すなわち、アリール－Ｏ－）、シアノ、シクロアルキル、シクロアルコキシ、ヘテロアリール、ヘテロアリールオキシ、複素環式、ヘテロシクリルオキシ、アミノアシル、カルボキシル、カルボキシルエステル、炭酸エステル、スルホニル、オキソ、ニトロ又はハロ、好ましくは、アルコキシであり；
Ｚ ^Ｂ1 、Ｚ ^Ｂ2 、及びＺ ^Ｂ3 はそれぞれ、独立に、炭素又は窒素であり、ここで、Ｚ ^Ｂ1 が窒素である場合、Ｚ ^Ｂ2 及びＺ ^Ｂ3 は炭素であり、Ｚ ^Ｂ2 が窒素である場合、Ｚ ^Ｂ1 及びＺ ^Ｂ3 は炭素であり、Ｚ ^Ｂ3 が窒素である場合、Ｚ ^Ｂ1 及びＺ ^Ｂ2 は炭素であり、Ｚ ^Ｂ1 、Ｚ ^Ｂ2 、又はＺ ^Ｂ3 が窒素である場合、ＳＯ ₂ Ｒ ^Ｂ4 Ｒ ^Ｂ5 は、前記窒素に結合されず；
ｓは、0、1、2又は3であり；
各Ｒ ^Ｂ3 は、独立に、水素、アルキル、アルコキシ、又はシクロアルキル、ハロ、又は複素環式であり；
Ｒ ^Ｂ4 及びＲ ^Ｂ5 のそれぞれは、独立に、水素、アルキル、アシル又はＭ ^＋であり、ここで、Ｍ ^＋は、Ｋ ^＋、Ｎａ ^＋、Ｌｉ ^＋又は ^＋Ｎ（Ｒ ⁶ ） ₄ から選択される金属対イオンであり、ここで、Ｒ ^Ｂ6 は、水素又はアルキルであり、ＳＯ ₂ ＮＲ ^Ｂ4 Ｒ ^Ｂ5 の窒素はＮ ^－であり；
又はＲ ^Ｂ4 又はＲ ^Ｂ5 は、Ｃａ ^2＋、Ｍｇ ² ＋、及びＢａ ^2＋から選択される二価対イオンであり、ＳＯ ₂ ＮＲ ^Ｂ4 Ｒ ^Ｂ5 の窒素はＮ ^－である）
又はその塩、溶媒和物、Ｎ－オキシド若しくはプロドラッグ
である、本発明1001又は本発明1002の方法。
[本発明1007]
前記化合物が、

である、本発明1006の方法。
[本発明1008]
前記化合物が、式ＩＶで表されるピラゾール化合物

（式中、
Ｈｅｔ－1は、5員ヘテロアリールであり；
ｙは、1～2であり；
Ｒ ^Ｃ2 は、Ｈ、脂肪族、複素脂肪族、複素脂環式、アリール、アミド、ヘテロシクリル又は芳香脂肪族であり；
各Ｒ ^Ｃ3 は、独立に、Ｈ又は脂肪族であり；
Ｒ ^Ｃ4 、Ｒ ^Ｃ5 、Ｒ ^Ｃ6 及びＲ ^Ｃ7 はそれぞれ、独立に、Ｈ、脂肪族、複素脂肪族、アルコキシ、ヘテロシクリル、アリール、芳香脂肪族、－Ｏ－ヘテロシクリル、ヒドロキシル、ハロアルキル、ハロゲン、ニトロ、シアノ、カルボキシル、カルボキシルエステル、アシル、アミド、アミノ、スルホニル、スルホンアミド、スルファニル又はスルフィニルであり；
Ｒ ^Ｃ8 及びＲ ^Ｃ9 はそれぞれ、独立に、Ｈ、脂肪族、複素脂肪族、アリール、ヘテロシクリル、スルホニル、ニトロ、ハロゲン、ハロアルキル、カルボキシルエステル、シアノ又はアミノであり；
Ｒ ^Ｃ10 は、Ｈ、脂肪族、アルコキシ、複素脂肪族、カルボキシルエステル、芳香脂肪族、ＮＯ ₂ 、ＣＮ、ＯＨ、ハロアルキル、アシル、アルキルホスフェート又はアルキルホスホネートである）
又はその塩、溶媒和物及び／若しくはＮ－オキシド
である、本発明1001又は本発明1002の方法。
[本発明1009]
Ｈｅｔ－1が、チアゾリル又はフラニルであり；
Ｒ ^Ｃ10 が、Ｈ、アルキル、アルキルホスフェート又はアルキルホスホネートであり；
Ｒ ^Ｃ4 、Ｒ ^Ｃ6 、及びＲ ^Ｃ7 のそれぞれが、独立に、Ｈ、ハロ、アルキル又はハロアルキルであり；又は
これらの組合せ
である、本発明1008の方法。
[本発明1010]
Ｒ ^Ｃ4 、Ｒ ^Ｃ6 、及びＲ ^Ｃ7 のそれぞれが、独立に、Ｈ又はＦであり；
Ｒ ^Ｃ5 が、Ｈ、Ｆ、ＣＦ ₃ 、メトキシ、－Ｏ－ＣＨ ₂ Ｃ（ＣＨ ₃ ） ₂ ＯＨ、モルホリン－4－イル、1－メチルピペリジン－4－イル、又は－Ｏ－（オキセタン－3－イル）であり；又は
これらの組合せ
である、本発明1008又は本発明1009の方法。
[本発明1011]
前記化合物が、式Ｖ若しくは式ＶＩで表されるピラゾール化合物

（式中、
Ｒ ^Ｃ11 及びＲ ^Ｃ12 のそれぞれは、独立に、Ｈ又は脂肪族であり；
Ｒ ^Ｃ14 は、Ｈ又は脂肪族である）
又はその塩、溶媒和物及び／若しくはＮ－オキシド
である、本発明1008～1010のいずれかの方法。
[本発明1012]
前記ピラゾール化合物が、

又はその医薬的に許容される塩である、本発明1008～1011のいずれかの方法。
[本発明1013]
前記化合物が、リスト1又はリスト2から選択される、本発明1001又は本発明1002の方法。
[本発明1014]
前記化合物を投与する段階が、前記化合物の投与の前の兆候又は症状の重症度と比較して、ＣＲＳの兆候又は症状を改善する、本発明1001～1013のいずれかの方法。
[本発明1015]
前記兆候又は症状が、発熱である、本発明1014の方法。
[本発明1016]
投与する段階が、
ＣＲＳが既知の副作用、起こり得る副作用、又は潜在的な副作用である第1の治療を以前に施された対象に、投与すること；又は
ＣＲＳが既知の副作用、起こり得る副作用、又は潜在的な副作用である第1の治療を施される予定であるか、又は現在施されている対象に、投与すること
を含む、本発明1001～1015のいずれかの方法。
[本発明1017]
前記第1の治療が、細胞療法を含む、本発明1016の方法。
[本発明1018]
前記細胞療法が、キメラ抗原受容体（ＣＡＲ）発現療法、トランスジェニック受容体療法、又はこれらの組合せを含む、本発明1017の方法。
[本発明1019]
前記化合物を投与する段階が、第2の治療薬を投与することをさらに含む、本発明1001～1018のいずれかの方法。
[本発明1020]
前記第2の治療薬が、ステロイド、抗炎症剤、免疫抑制剤、又はこれらの組合せである、本発明1019の方法。
[本発明1021]
前記ステロイドが、アルクロメタゾン、アルゲストン、ベクロメタゾン、ベタメタゾン、ブデソニド、クロベタゾール、クロベタゾン、クロコルトロン、クロプレドノール、コルチコステロン、コルチゾン、コルチバゾール、デフラザコート、デソニド、デスオキシメタゾン、デキサメタゾン、ジフロラゾン、ジフルコルトロン、ジフルプレドナート、エノキソロン、フルアザコート、フルクロロニド、フルドロコルチゾン、フルメタゾン、フルニソリド、フルオシノロン、フルオシノニド、フルオコルチン、フルオコルトロン、フルオロメトロン、フルペロロン、フルプレドニデン、フルプレドニゾロン、フルランドレノリド、フルチカゾン、ホルモコータル、ハルシノニド、ハロベタゾール、ハロメタゾン、ハロプレドン、ハイドロコルタメート、ヒドロコルチゾン、エタボン酸ロテプレドノール、マジプレドン、メドリゾン、メプレドニゾン、メチルプレドニゾロン、モメタゾン、パラメタゾン、プレドニカルベート、プレドニゾロン、プレドニゾン、プレドニバール、プレドニリデン、リメキソロン、チキソコルトール、トリアムシノロン、又はこれらの任意の組合せであり；
前記抗炎症剤が、アミノサリチレート、シクロオキシゲナーゼ阻害剤、ジクロフェナク、エトドラク、ファモチジン、フェノプロフェン、フルルビプロフェン、ケトプロフェン、ケトロラク、イブプロフェン、インドメタシン、メクロフェナメート、メフェナム酸、メロキシカム、ナブメトン、ナプロキセン、オキサプロジン、ピロキシカム、サルサラート、スリンダク、トルメチン、又はこれらの組合せであり；又は
前記免疫抑制剤が、メルカプトプリン、コルチコステロイド、アルキル化剤、カルシニューリン阻害剤、イノシン一リン酸脱水素酵素（ＩＭＰＤＨ）の阻害剤、細胞性免疫を抑制しながらレシピエントの液性免疫応答を完全に保つように設計された剤、又はこれらの組合せである、本発明1020の方法。
[本発明1022]
前記第2の治療薬が、デキサメタゾン又はプレドニゾン、又はこれらの組合せである、本発明1020の方法。
本発明の上記及び他の目的、特徴及び利点は、以下の詳細な説明から一層明らかになるであろう。 [Invention 1001]
A method for treating and/or preventing cytokine release syndrome (CRS) comprising administering to a subject suffering from or at risk of developing CRS an effective amount of activity as a kinase inhibitor. administering a compound comprising:
[Invention 1002]
1001. The method of invention 1001, wherein said compound is a JAK inhibitor, an IRAK inhibitor, or a combination thereof.
[Invention 1003]
wherein said compound is a pyrimidinediamine compound represented by Formula I

(In the formula,
X and Y are each independently O, S, S(O), _SO2 or ^NR1 ;
each R ¹ is independently at each occurrence H, C _1-6 alkyl, C(O)—C _1-6 alkyl, CO ₂ —C _1-6 alkyl or R ⁵⁰ ;
each R ⁵⁰ is C(R ⁹ ) ₂ -OR ¹⁰ or C(R ⁹ ) ₂ -SR ¹⁰ ;
Each R ⁹ is independently at each occurrence H, C _1-6 alkyl, C ^6-10 _aryl or C _7-16 arylalkyl; together with the carbons to ^form a C _3-8 ^cycloalkyl _group or a ^3-8 membered heteroalicyclic group ^; is independently at each occurrence R ^a or a monovalent cationic group; or two R ¹¹ together with the atom to which they are attached form a 4- to 8-membered cyclic phosphate group , or two R ¹¹ together represent a divalent cationic group;
Ring A is C _6-10 aryl or 5-10 membered heteroaryl;
Each R ² is independently at each occurrence H, R ^e , R ^b , R ^e substituted with one or more of the same or different R ^a and/or R ^b , the same or different R ^a and/or or -OR ^e substituted with one or more of R ^b , -SR ^e substituted with one or more of the same or different R ^a and/or R ^b , the same or different R ^a and/or R ^b —C(O)R ^e , —N(R ^a )R ^e substituted with one or more, wherein R ^e is substituted with one or more of the same or different R ^a and/or R ^b -S(O) 2 R ^e , -B(OR a ) ₂ , -B(N(R c ) 2 ) ² substituted _with one _or more of the same or different R ^a and/or _R ^b ⁾ , -(C(R ^a ) ₂ ) _m -R ^b , -O-(C(R ^a ) ₂ ) _m -R ^b , -S-(C(R ^a ) ₂ ) _m -R ^b , -O- (C(R ^b ) ₂ ) _m —R ^a , —N(R ^a ) —(C(R ^a ) ₂ ) _m —R ^b , —O—(CH ₂ ) _m —CH((CH ₂ ) _m R ^b ) R ^b , —C(O)N(R ^a ) —(C(R ^a ) ₂ ) _m —R ^b , —O—(C(R ^a ) ₂ ) _m —C(O)N(R ^a )—(C(R ^a ) ₂ ) _m —R ^b , —N((C(R ^a ) ₂ ) _m R ^b ) ₂ , —S—(C(R ^a ) ₂ ) _m —C(O)N (R ^a )-(C(R ^a ) ₂ ) _m -R ^b ,-N(R ^a )-C(O)-N(R ^a )-(C(R ^a ) ₂ ) _m -R ^b ,- N(R ^a )—C(O)—(C(R ^a ) ₂ ) _m —C(R ^a )(R ^b ) ₂ or —N(R ^a )—(C(R ^a ) ₂ ) _m —C (O)-N(R ^a )-(C(R ^a ) ₂ ) _m -R ^b ;
Each R ^a is independently at each occurrence H, deuterium, C _1-6 alkyl, C _3-8 cycloalkyl, C _4-11 cycloalkylalkyl, C _6-10 aryl, C _7-16 arylalkyl , 2-6 membered heteroalkyl, 3-10 membered heteroalicyclic, 4-11 membered heteroalicyclic alkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;
Each R ^b is independently at each occurrence ═O, —OR ^a , —O—(C(R ^a ) ₂ ) _m —OR ^a , haloC _1-3 alkyloxy, ═S, —SR ^a , =NR ^a , =NOR ^a , -N(R ^c ) ₂ , halo, -CF ₃ , -CN, -NC, -OCN, -SCN, -NO, -NO ₂ , =N ₂ , -N ₃ , - S(O)R ^a , —S(O) ₂ R ^a , —SO ₃ R ^a , —S(O)N(R ^c ) ₂ , —OS(O)R ^a , —OS(O) ₂ R ^a , —OSO ₃ R ^a , —OS(O) ₂ N(R ^c ) ₂ , —C(O) R ^a , —CO ₂ R ^a , —C(O) N(R ^c ) ₂ , —C(NR ^a ) —N(R ^c ) ₂ , —C(NOH)—R ^a , —C(NOH)—N(R ^c ) ₂ , —OC(O)R ^a , —OC(O)OR ^a , —OC (O)N(R ^c ) ₂ , —OC(NH)—N(R ^c ) ₂ , —OC(NR ^a )—N(R ^c ) ₂ , —[N(R ^a )C(O)] _n R ^a , —[N(R ^a )C(O)] _n OR ^a , —[N(R ^a )C(O)] _n N(R ^c ) ₂ or —[N(R ^a )C(NR ^a )] _n —N(R ^c ) ₂ ;
Each R ^c is independently on each occurrence R ^a or, alternatively, two R ^c , together with the nitrogen atom to which they are attached, are the same or different additional hetero 3- to 10-membered heteroalicyclic or 5- to 10-membered heteroalicyclic, optionally containing one or more atoms and optionally substituted by one or more of the same or different R ^a and/or R ^d groups forming an aryl;
Each R ^d is ═O, —OR ^a , haloC _1-3 alkyloxy, C _1-6 alkyl, ═S, —SR ^a , ═NR ^a , ═NOR ^a , —N(R ^a ) ₂ , halo , -CF ₃ , -CN, -NC, -OCN, -SCN, -NO, -NO ₂ , =N ₂ , -N ₃ , -S(O) R ^a , -S(O ₂ )R ^a , - SO ₃ R ^a , —S(O)N(R ^a ) ₂ , —S(O) ₂ N(R ^a ) ₂ , —OS(O) R ^a , —OS(O) ₂ R ^a , —OSO ₃ R ^a , —OS(O) ₂ N(R ^a ) ₂ , —C(O)R ^a , —CO ₂ R ^a , —C(O)N(R ^a ) ₂ , —C(NR ^a )N( R ^a ) ₂ , —C(NOH)R ^a , —C(NOH)N(R ^a ) ₂ , —OCO ₂ R ^a , —OC(O)N(R ^a ) ₂ , —OC(NR ^a )N (R ^a ) ₂ , —[N(R ^a )C(O)] _n R ^a , —(C(R ^a ) ₂ ) _n —OR ^a , —N(R ^a ) —S(O) ₂ R ^a , —C(O)—C _1-6 haloalkyl, —S(O) ₂ C _1-6 haloalkyl, —OC(O)R ^a , —O(C(R ^a ) ₂ ) _m —OR ^a , —S (C(R ^a ) ₂ ) _m —OR ^a , —N(R ^a )C _1-6 haloalkyl, —P(O)(OR ^a ) ₂ , —N(R ^a )—(C(R ^a ) ₂ ) _m —OR ^a , —[N(R ^a )C(O)] _n OR ^a , —[N(R ^a )C(O)] _n N(R ^a ) ₂ , —[N(R ^a )C (NR ^a )] _n N(R ^a ) ₂ or —N(R ^a )C(O)C _1-6 haloalkyl; or two R ^d are one or more 3- to 10-membered, partially or fully, together with atoms, optionally containing one or more heteroatoms and optionally substituted with one or more R ^a forming a saturated monocyclic or bicyclic ring;
each R ^e is independently at each occurrence C _1-6 alkyl, C _3-8 cycloalkyl, C _4-11 cycloalkylalkyl, C _6-10 aryl, C _7-16 arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclic, 4-11 membered heteroalicyclic alkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;
p is 0, 1, 2, 3 or 4;
each m is 1, 2 or 3;
each n is 0, 1, 2 or 3;
or two R2 ^groups , together with the atom or atoms to which they are attached, in combination may contain one or more heteroatoms and one or more R forming a 4- to 10-membered partially or fully saturated monocyclic or bicyclic ring optionally substituted with a and/ ^or Rb ^;
Z ¹ and Z ² are each independently CH, CR ² or N;
R ³ is H, C _1-6 alkyl or R ⁵⁰ ;
R ⁴ is H, C _1-6 alkyl or R ⁵⁰ ;
R ⁵ is halo, —CN, C _1-6 alkyl, alkynyl, hydroxy, C _1-6 alkoxy, nitro, —N(R ^a ) ₂ , —C(O)N(R ^a ) ₂ , —CO ₂ R ^a or —C(O)R ^a )
or a salt, solvate, or N-oxide thereof
The method of the present invention 1001 or the present invention 1002 which is
[Invention 1004]
The compound is represented by the formula:
Formula IA:

or a salt, solvate, or N-oxide thereof
(wherein each of R ^2a , R ^2b , R ^2c and R ^2d is independently at each occurrence as defined above for R ² );
Formula IA3:

or a salt, solvate, N-oxide or prodrug thereof
(wherein R ^b is OH, C _1-6 alkyl, —CO ₂ C _1-6 alkyl, —C(O)C _1-6 alkyl or —S(O) ₂ C _1-6 alkyl) ;
Formula IB:

or a salt, solvate, N-oxide or prodrug thereof
(wherein Q ¹ and Q ² are each independently N or CH, provided that at least one of Q ¹ and Q ² is N); or
Formula II:

or a salt, solvate, N-oxide or prodrug thereof
(In the formula,
Ring B, together with the two phenyl ring atoms to which it is attached, may contain 1, 2 or 3 heteroatoms independently selected from N(R ^c ), O and S. forming a good 5-, 6- or 7-membered ring;
each R ^a is C _1-6 alkyl;
each R ^b is independently at each occurrence ═O, —OR ^a , haloC _1-3 alkyloxy, —SR ^a , —N(R ^c ) ₂ , halo, —CF ₃ , —CN, —S (O) ₂ N(R ^c ) ₂ , —S(O) ₂ R ^a , —C(O) R ^a , —CO ₂ R ^a , —C(O) N(R ^c ) ₂ , —N(R ^a ) —S(O) ₂ R ^a or —C(R ^a ) ₂ —N(R ^c ) ₂ )
The method of the present invention 1003, comprising:
[Invention 1005]
The compound is
N2-(3,4,5-trimethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine, or a pharmaceutically acceptable salt thereof;
5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N2-(3,4,5-trimethyl)phenyl-2 , 4-pyrimidinediamine, or a pharmaceutically acceptable salt thereof;
5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N2-(3,4,5-trimethyl)phenyl-2 , 4-pyrimidinediamine bis-sodium salt;
N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl] - 2,4-pyrimidinediamine, or a pharmaceutically acceptable salt thereof;
N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl] - 2,4-pyrimidinediamine bis-sodium salt;
5-(2-(3-methoxy-4,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one, or a pharmaceutically acceptable salt thereof ;
(5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl dihydrogen phosphate;
5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one, or a pharmaceutically acceptable salt;
(5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methylphosphate sodium
The method according to any one of the inventions 1001-1004.
[Invention 1006]
wherein the compound is a pyrimidinediamine compound represented by Formula III

(In the formula,
X ^B is alkyl, alkoxy, amino, carboxyl, carboxylester, cyano, halo, nitro, alkenyl, or alkynyl;
R ^B is hydrogen, alkyl, alkenyl, alkynyl, or cycloalkyl;
Ring A ^B is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocyclic, wherein Ring A is neither indolyl nor benzimidazolyl;
r is 0, 1, 2 or 3;
Each R ^B2 is independently alkyl, alkoxy, amino, aryl, aryloxy (ie, aryl-O-), cyano, cycloalkyl, cycloalkoxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclyloxy, aminoacyl , carboxyl, carboxyl ester, carbonate, sulfonyl, oxo, nitro or halo, preferably alkoxy;
ZB1 , ^ZB2 , and ^ZB3 are each independently carbon or nitrogen, wherein when ZB1 is ^nitrogen ^, ZB2 ^and ZB3 ^are carbon, when ^ZB2 is nitrogen, ZB1 and ^ZB3 are carbon; when ^ZB3 ^is nitrogen, ^ZB1 and ^ZB2 are carbon; when ^ZB1 , ^ZB2 ^, or ^ZB3 is ^nitrogen , _SO2RB4RB5 is , not bound to said nitrogen;
s is 0, 1, 2 or 3;
each R ^B3 is independently hydrogen, alkyl, alkoxy, or cycloalkyl, halo, or heterocyclic;
each of R ^B4 and R ^B5 is independently hydrogen, alkyl, acyl, or M ⁺ , where M ⁺ is selected from K ⁺ , Na ⁺ , Li ⁺ or ⁺ N(R ⁶ ) ₄ a metal counterion wherein R ^B6 is hydrogen or alkyl and the nitrogen of SO ₂ NR ^B4 R ^B5 is ^N- ;
or R ^B4 or R ^B5 is a divalent counterion selected from Ca ²⁺ , Mg ²⁺ and Ba ²⁺ and the nitrogen of SO ₂ NR ^B4 R ^B5 is N ⁻ )
or a salt, solvate, N-oxide or prodrug thereof
The method of the present invention 1001 or the present invention 1002 which is
[Invention 1007]
The compound is

The method of the present invention 1006, wherein
[Invention 1008]
wherein the compound is a pyrazole compound represented by Formula IV

(In the formula,
Het-1 is a 5-membered heteroaryl;
y is 1-2;
R ^C2 is H, aliphatic, heteroaliphatic, heteroalicyclic, aryl, amido, heterocyclyl or araliphatic;
each R ^C3 is independently H or aliphatic;
R ^C4 , R ^C5 , R ^C6 and R ^C7 are each independently H, aliphatic, heteroaliphatic, alkoxy, heterocyclyl, aryl, araliphatic, -O-heterocyclyl, hydroxyl, haloalkyl, halogen, nitro, cyano , carboxyl, carboxyl ester, acyl, amido, amino, sulfonyl, sulfonamide, sulfanyl or sulfinyl;
R ^C8 and R ^C9 are each independently H, aliphatic, heteroaliphatic, aryl, heterocyclyl, sulfonyl, nitro, halogen, haloalkyl, carboxylester, cyano or amino;
R ^C10 is H, aliphatic, alkoxy, heteroaliphatic, carboxylester, araliphatic, NO2 _, CN, OH, haloalkyl, acyl, alkylphosphate or alkylphosphonate)
or salts, solvates and/or N-oxides thereof
The method of the present invention 1001 or the present invention 1002 which is
[Invention 1009]
Het-1 is thiazolyl or furanyl;
R ^C10 is H, alkyl, alkylphosphate or alkylphosphonate;
each of R ^C4 , R ^C6 , and R ^C7 is independently H, halo, alkyl, or haloalkyl; or
a combination of these
The method of the present invention 1008, wherein
[Invention 1010]
each of R ^C4 , R ^C6 , and R ^C7 is independently H or F;
R ^C5 is H, F, CF ₃ , methoxy, —O—CH ₂ C(CH ₃ ) ₂ OH, morpholin-4-yl, 1-methylpiperidin-4-yl, or —O—(oxetane-3- or
a combination of these
The method of the present invention 1008 or the present invention 1009 which is
[Invention 1011]
wherein the compound is a pyrazole compound represented by formula V or formula VI

(In the formula,
each of R ^C11 and R ^C12 is independently H or aliphatic;
R ^C14 is H or aliphatic)
or salts, solvates and/or N-oxides thereof
The method of any one of the inventions 1008-1010, wherein
[Invention 1012]
The pyrazole compound is

or a pharmaceutically acceptable salt thereof.
[Invention 1013]
The method of Invention 1001 or Invention 1002, wherein said compound is selected from List 1 or List 2.
[Invention 1014]
1013. The method of any of inventions 1001-1013, wherein administering said compound ameliorates the signs or symptoms of CRS as compared to the severity of the signs or symptoms prior to administration of said compound.
[Invention 1015]
1015. The method of the present invention 1014, wherein said sign or symptom is fever.
[Invention 1016]
The step of administering
administering to a subject who has previously received a first therapy for which CRS is a known, possible, or potential side effect; or
Administering to a subject who will be or is currently on a first therapy for which CRS is a known, possible, or potential side effect
The method of any of the inventions 1001-1015, comprising:
[Invention 1017]
1016. The method of the invention 1016, wherein said first therapy comprises cell therapy.
[Invention 1018]
1017. The method of the invention 1017, wherein said cell therapy comprises chimeric antigen receptor (CAR) expression therapy, transgenic receptor therapy, or a combination thereof.
[Invention 1019]
The method of any of inventions 1001-1018, wherein administering said compound further comprises administering a second therapeutic agent.
[Invention 1020]
1019. The method of invention 1019, wherein said second therapeutic agent is a steroid, an anti-inflammatory agent, an immunosuppressive agent, or a combination thereof.
[Invention 1021]
The steroid is alclomethasone, algestone, beclomethasone, betamethasone, budesonide, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortibazole, deflazacort, desonide, desoxymethasone, dexamethasone, diflorazone, diflucortolone, diflu prednate, enoxolone, fluazacort, fluchloronide, fludrocortisone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene, fluprednisolone, flurandrenolide, fluticasone, hormonecortisone, halcinonide, halobetasol, Halomethasone, halopredone, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone, paramethasone, predniccarbate, prednisolone, prednisone, prednivar, prednilidene, rimexolone, thixocortol, triamcinolone, or any of these any combination of
The anti-inflammatory agent is aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof; or
wherein said immunosuppressive agent comprises a mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inhibitor of inosine monophosphate dehydrogenase (IMPDH), suppressing cell-mediated immunity while inhibiting the recipient's humoral immune response; The method of the invention 1020, which is an agent designed to preserve integrity, or a combination thereof.
[Invention 1022]
The method of invention 1020, wherein said second therapeutic agent is dexamethasone or prednisone, or a combination thereof.
The above and other objects, features and advantages of the present invention will become more apparent from the detailed description below.

Claims

A pharmaceutical composition for use in a method of treating and/or preventing CRS in a subject having or at risk of developing Cytokine Release Syndrome (CRS), the structure represented by Formula IV A compound having

(In the formula,
Het-1 is a 5-membered heteroaryl;
y is 1-2;
R ^C2 is H, aliphatic, heteroaliphatic, heteroalicyclic, aryl, amido, heterocyclyl or araliphatic;
each R ^C3 is independently H or aliphatic;
R ^C4 , R ^C5 , R ^C6 and R ^C7 are each independently H, aliphatic, heteroaliphatic, alkoxy, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, haloalkyl, halogen, nitro, cyano , carboxyl, carboxyl ester, acyl, amido, amino, sulfonyl, sulfonamide, sulfanyl or sulfinyl;
R ^C8 and R ^C9 are each independently H, aliphatic, heteroaliphatic, aryl, heterocyclyl, sulfonyl, nitro, halogen, haloalkyl, carboxylester, cyano, or amino;
R ^C10 is H, aliphatic, alkoxy, heteroaliphatic, carboxylester, araliphatic, NO ₂ , CN, OH, haloalkyl, acyl, alkylphosphate or alkylphosphonate)
or a pharmaceutical composition comprising a salt, solvate and/or N-oxide thereof.

whether Het-1 is thiazolyl or furanyl;
whether R ^C10 is H, alkyl, alkyl phosphate or alkyl phosphonate;
2. The pharmaceutical composition of claim 1 , wherein each of R ^<C4> , R ^<C6> , and R ^<C7> is independently H, halo, alkyl, or haloalkyl; or a combination thereof.

each of R ^C4 , R ^C6 , and R ^C7 is independently H or F;
R ^C5 is H, F, CF ₃ , methoxy, —O—CH ₂ C(CH ₃ ) ₂ OH, morpholin-4-yl, 1-methylpiperidin-4-yl, or —O—(oxetane-3- or a combination thereof .

The compound is a compound having a structure represented by formula V or formula VI , or a salt, solvate and/or N-oxide thereof

(In the formula,
each of R ^C11 and R ^C12 is independently H or aliphatic;
R ^C14 is H or aliphatic)
The pharmaceutical composition according to any one of claims 1 to 3 , which is

The compound is a compound having a structure represented by Formula VII, or a salt, solvate and/or N-oxide thereof

(In the formula,
R is an alkyl, acyl, carboxylester, amide, non-aromatic heterocyclyl, alkyl phosphoramidate, or alkyl phosphate; or
R is H and the compound is a salt)
The pharmaceutical composition according to claim 1, which is

wherein said compound is:
V-1: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazole- 4-yl)furan-2-carboxamide 2,2,2-trifluoroacetate;
V-2: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazole- 4-yl)furan-2-carboxamide;
V-3: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl) furan-2-carboxamide;
V-4: tert-butyl 4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)- 1H-pyrazole-1-carboxylate;
V-5: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2- carboxamide;
V-6: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl) furan-2-carboxamidoformic acid;
V-9: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl) furan-2-carboxamide;
V-10: di-tert-butyl ((4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl) furan-2 -yl)-1H-pyrazol-1-yl)methyl)phosphate;
V-11: tert-butyl ((4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl) furan-2-yl )-1H-pyrazol-1-yl)methyl)hydrogen phosphate;
V-12: (4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H- pyrazol-1-yl)methyl dihydrogen phosphate;
V-13: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazole- 4-yl)furan-2-carboxamide;
V-14: sodium (4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H -pyrazol-1-yl)methyl phosphate;
V-16: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl ) furan-2-carboxamide;
V-17: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl ) furan-2-carboxamide hydrochloride;
V-18: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazole -4-yl)furan-2-carboxamide;
V-19: 1-(isobutyryloxy)ethyl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan -2-yl)-1H-pyrazole-1-carboxylate;
V-20: tert-butyl (S)-(1-(4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl) ) furan-2-yl)-1H-pyrazol-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate;
V-21: 1-methylcyclopropyl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl )-1H-pyrazole-1-carboxylate;
V-22: 1-((4-methoxybenzyl)oxy)-2-methylpropan-2-yl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)- 1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate;
V-23: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl ) furan-2-carboxamide;
V-24: 5-(5-nitro-1H-pyrrol-3-yl)-N-(1-(propoxymethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan- 2-carboxamide;
V-25: N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2 - a carboxamide;
V-26: 5-(1-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl ) furan-2-carboxamide;
V-27: N-(1-((1,3-trans)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole -4-yl)furan-2-carboxamide;
V-28: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole -4-yl)furan-2-carboxamide;
V-29: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl -1H-pyrazol-4-yl)furan-2-carboxamide;
V-30: 5-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl ) furan-2-carboxamide;
V-31: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl -1H-pyrazol-4-yl)furan-2-carboxamide;
V-32: N-(1-((1,3-cis)-3-hydroxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole -4-yl)furan-2-carboxamide;
V-33: N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole -4-yl)furan-2-carboxamide;
V-34: N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole -4-yl)furan-2-carboxamide formate;
V-35: (4-(5-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl) furan-2-yl)-1H-pyrazol-1-yl)methylphosphate bis-sodium salt;
V-36: (4-(5-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan- 2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate;
V-37: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2- carboxamide formate;
V-38: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2- carboxamide;
V-39: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-ethyl-1H-pyrazol-4-yl) furan-2-carboxamide formate;
V-40: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-ethyl-1H-pyrazol-4-yl) furan-2-carboxamide;
V-41: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazole- 4-yl)furan-2-carboxamide formate;
V-42: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazole- 4-yl)furan-2-carboxamide;
V-43: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-isopentyl-1H-pyrazol-4-yl) furan-2-carboxamide formate;
V-44: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-isopentyl-1H-pyrazol-4-yl) furan-2-carboxamide;
V-45: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl) furan-2-carboxamide formate;
V-46: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl) furan-2-carboxamide;
V-47: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;
V-48: 5-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-N-(1-((3-methyloxetan-3-yl)methyl) -3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide formate;
V-49: 5-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-N-(1-((3-methyloxetan-3-yl)methyl) -3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;
V-52: 5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-( pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide formate;
V-53: 5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-( pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;
V-54: (4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H- pyrazol-1-yl)methyl dihydrogen phosphate;
V-55: Sodium (4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H -pyrazol-1-yl)methyl phosphate;
V-56: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl) furan-2-carboxamide formate;
V-57: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl) furan-2-carboxamide;
V-58: 5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazole-4- yl) furan-2-carboxamide formate;
V-59: 5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazole-4- yl)furan-2-carboxamide;
V-67: N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate;
V-68: 5-(1-methyl-1H-pyrazol-4-yl)-N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}furan-2-carboxamide ;
V-69: 5-(1-methyl-1H-pyrazol-4-yl)-N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}furan-2-carboxamide , formate;
V-70: tert-butyl-3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl] Azetidine-1-carboxylate, formate;
V-71: N-{1-(3-M ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan- 2-carboxamide, formate, cis isomer;
V-72: N-{1-(3-M ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan- 2-carboxamide, cis isomer;
V-73: N-{1-(3-benzyloxy)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan- 2-carboxamide, trans isomer;
V-74: tert-butyl-3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl] azetidine-1-carboxylate;
V-75: N-(1-((1s,3s)-3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4 -yl) furan-2-carboxamide formate;
V-76: N-(1-((1s,3s)-3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4 -yl)furan-2-carboxamide;
V-77: N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, free base;
V-78: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2 - carboxamides, TFA salts;
V-79: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2 - a carboxamide;
V-80: di-tert-butyl-[[4-{4-(5-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2- yl)-1H-pyrazol-1-yl}methyl]phosphate;
V-81: [4-{5-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2yl}-1H-pyrazol-1-yl] methyl dihydrogen phosphate;
V-82: sodium [4-{5-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl}-1H-pyrazole-1- yl]methyl phosphate;
V-83: N-{1-(1-acetylazetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl ) furan-2-carboxamide, free base;
V-84: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-( tert-butyl)azetidine-1-carboxamide, free base;
V-85: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-isopropyl Azetidine-1-carboxamide, free base;
V-86: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-propyl Azetidine-1-carboxamide, free base;
V-87: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-cyclo Propylazetidine-1-carboxamide, formate;
V-88: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-cyclo propylazetidine-1-carboxamide;
V-89: N-[1-{1-(cyclopropanecarbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazole- 4-yl)furan-2-carboxamide, formate;
V-90: N-[1-{1-(cyclopropanecarbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazole- 4-yl)furan-2-carboxamide;
V-91: N-[1-{1-pivaloylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazole-4 -yl)furan-2-carboxamide, formate;
V-92: N-[1-{1-pivaloylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazole-4 -yl)furan-2-carboxamide;
V-93: 5-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-(pyrrolidin-1-carbonyl)azetidin-3-yl}-1H-pyrazole-4 -yl)furan-2-carboxamide, formate;
V-94: 5-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-(pyrrolidin-1-carbonyl)azetidin-3-yl}-1H-pyrazole-4 -yl)furan-2-carboxamide;
V-95: N-[1-{1-isobutyrylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazole-4 -yl)furan-2-carboxamide, formate;
V-96: N-[1-{1-isobutyrylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazole-4 -yl)furan-2-carboxamide;
V-97: N-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-{1-(2,2,2-trifluoroethyl)azetidin-3-yl }-1H-pyrazol-4-yl}furan-2-carboxamide, TFA salt;
V-98: N-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-{1-(2,2,2-trifluoroethyl)azetidin-3-yl }-1H-pyrazol-4-yl}furan-2-carboxamide;
V-99: N-[1-{1-butyrylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazole-4- yl)furan-2-carboxamide, formate;
V-100: N-[1-{1-butyrylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazole-4- yl)furan-2-carboxamide;
V-101: N-{1-(1-methylazetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl ) furan-2-carboxamide, formate;
V-102: N-{1-(1-methylazetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl ) furan-2-carboxamide;
V-103: N-[1-{1-(2,2-difluorocyclopropane-1-carbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl] -5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate;
V-104: N-[1-{1-(2,2-difluorocyclopropane-1-carbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl] -5-(1H-pyrazol-4-yl)furan-2-carboxamide;
V-105: N-(1-methyl-3-(5-morpholinopyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
V-106: N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4 -yl)furan-2-carboxamide;
V-107: N-(3-(5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazole-4 -yl)furan-2-carboxamide;
V-108: N-(1-methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl) furan-2-carboxamide;
V-109: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
V-110: N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
V-111: N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2- carboxamide;
V-112: N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole -4-yl)furan-2-carboxamide;
V-113: 5-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H- pyrazol-4-yl)furan-2-carboxamide;
V-114: N-(1-((1s,3s)-3-isopropoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole- 4-yl)furan-2-carboxamide;
V-115: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
V-116: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-5 -(1H-pyrazol-4-yl)furan-2-carboxamide;
V-117: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl ) furan-2-carboxamide;
V-122: 5-(1-cyclobutyl-1H-pyrazol-4-yl)-N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide 2,2,2-trifluoroacetate;
V-123: 5-(1-cyclobutyl-1H-pyrazol-4-yl)-N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide ;
V-124: N-(1-((1s,4s)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4- yl) furan-2-carboxamide formate;
V-125: N-(1-((1s,4s)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4- yl)furan-2-carboxamide;
V-126: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4- yl) furan-2-carboxamide formate;
V-127: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4- yl)furan-2-carboxamide;
V-128: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazol-4-yl)furan-2-carboxamide formate;
V-129: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H- pyrazol-4-yl)furan-2-carboxamide;
V-130: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4- yl) furan-2-carboxamide formate;
V-131: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4- yl)furan-2-carboxamide;
V-132: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4- yl) furan-2-carboxamide formate;
V-133: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4- yl) furan-2-carboxamide;
V-134: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4- yl) furan-2-carboxamide formate;
V-135: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4- yl)furan-2-carboxamide;
V-136: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4- yl) furan-2-carboxamide formate;
V-137: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole-4- yl) furan-2-carboxamide;
V-138: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H- pyrazol-4-yl)furan-2-carboxamide formate;
V-139: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H- pyrazol-4-yl)furan-2-carboxamide;
V-140: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H -pyrazol-4-yl)furan-2-carboxamide formate;
V-141: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H -pyrazol-4-yl)furan-2-carboxamide;
V-142: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H- pyrazol-4-yl)furan-2-carboxamide formate;
V-143: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H- pyrazol-4-yl)furan-2-carboxamide;
V-144: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H- pyrazol-4-yl)furan-2-carboxamide formate;
V-145: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H- pyrazol-4-yl)furan-2-carboxamide;
V-146: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy ) cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide formate;
V-147: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy ) cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide;
V-148: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H- pyrazol-4-yl)furan-2-carboxamide formate;
V-149: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H- pyrazol-4-yl)furan-2-carboxamide;
V-150: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazole-4 -yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate;
V-151: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazole-4 -yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
V-152: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazole-4 -yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate;
V-153: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazole-4 -yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
V-154: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole -4-yl)furan-2-carboxamide formate;
V-155: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazole -4-yl)furan-2-carboxamide;
V-156: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-5-( 1H-pyrazol-4-yl)furan-2-carboxamide;
VI-1: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl) thiazole-4-carboxamide;
VI-2: 1-(isobutyryloxy)ethyl 4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl) -1H-pyrazole-1-carboxylate;
VI-3: tert-butyl (R)-(3-methyl-1-(4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl) Thiazol-2-yl)-1H-pyrazol-1-yl)-1-oxobutan-2-yl)carbamate;
VI-4: 2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazol-4-yl)-N-(1-methyl-3- (pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-5: 1-methylcyclopropyl 4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole -1-carboxylate;
VI-6: 1-((4-methoxybenzyl)oxy)-2-methylpropan-2-yl 4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazole-4 -yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;
VI-7: diethyl ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1 - yl)methyl)phosphonate;
VI-8: sodium ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1 - yl)methyl)phosphonate;
VI-9: ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1- yl)methyl)phosphonic acid;
VI-10: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl ) thiazole-4-carboxamide;
VI-11: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole -4-yl)thiazol-4-carboxamide;
VI-12: N-(1-((1,3-trans)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole -4-yl)thiazol-4-carboxamide;
VI-13: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-methyl -1H-pyrazol-4-yl)thiazol-4-carboxamide;
VI-14: N-(1-((1,3-cis)-3-hydroxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole -4-yl)thiazol-4-carboxamide;
VI-15: N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole -4-yl)thiazol-4-carboxamide;
VI-16: (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl) Thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate bis-sodium salt;
VI-17: (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazole- 2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate;
VI-18: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4- carboxamides, formates;
VI-19: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-(trifluoromethyl)-1H-pyrazole- 4-yl)thiazole-4-carboxamide, formate;
VI-20: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-(trifluoromethyl)-1H-pyrazole- 4-yl)thiazole-4-carboxamide;
VI-21: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl) Thiazole-4-carboxamide, formate;
VI-22: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide;
VI-23: 2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazole-4- yl) thiazole-4-carboxamide, formate;
VI-24: 2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazole-4- yl) thiazole-4-carboxamide;
VI-25: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4- carboxamide;
VI-26: N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-27: 2-(3-methyl-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide ;
VI-28: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4- carboxamide;
VI-29: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl) Thiazole-4-carboxamide, formate;
VI-30: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide;
VI-31: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl) thiazole-4-carboxamide;
VI-32: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate;
VI-33: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-34: N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4 - a carboxamide;
VI-35: (4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl ) methyl dihydrogen phosphate;
VI-36: sodium (4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1- yl) methyl phosphate;
VI-37: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl ) thiazole-4-carboxamide;
VI-38: potassium (4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1- yl) methyl phosphate;
VI-39: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazole -4-yl)thiazole-4-carboxamide formate;
VI-40: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazole -4-yl)thiazol-4-carboxamide;
VI-41: 2-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl ) thiazole-4-carboxamide, formate;
VI-42: 2-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl ) thiazole-4-carboxamide;
VI-43: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)thiazole-4 - a carboxamide formate;
VI-44: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)thiazole-4 - a carboxamide;
VI-45: 2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)- 1H-pyrazol-4-yl)thiazole-4-carboxamide formate;
VI-46: 2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)- 1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-47: N-(1-((3-(hydroxymethyl)oxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3- methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide formate;
VI-48: N-(1-((3-(hydroxymethyl)oxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3- methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-49: N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole- 4-carboxamide, formate;
VI-50: N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole- 4-carboxamide;
VI-51: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H- pyrazol-4-yl)thiazole-4-carboxamide;
VI-52: N-(1-(2-fluoroethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazole -4-yl)thiazol-4-carboxamide;
VI-53: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4- carboxamide;
VI-54: tert-butyl-3-[4-{2-(1H-pyrazol-4-yl)thiazol-2-carboxamide}-3-(pyridin-2-yl)-1H-pyrazol-1-yl] Azetidine-1-carboxylate, free base;
VI-55: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4 - carboxamides, TFA salts;
VI-56: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4 - a carboxamide;
VI-57: N-{1-(3-M ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole- 4-carboxamide, free base, cis isomer;
VI-58: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-59: N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-60: N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4- carboxamide;
VI-61: N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole -4-yl)thiazol-4-carboxamide;
VI-65: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H- pyrazol-4-yl)thiazole-4-carboxamide;
VI-66: 2-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H- pyrazol-4-yl)thiazole-4-carboxamide;
VI-71: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-72: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1H -pyrazol-4-yl)thiazole-4-carboxamide;
VI-73: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1H -pyrazol-4-yl)thiazole-4-carboxamide formate;
VI-76: N-(1-((1s,3s)-3-isopropoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole- 4-yl)thiazole-4-carboxamide;
VI-77: Potassium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazole) -2-yl)-1H-pyrazol-1-yl)methyl phosphate;
VI-78: Calcium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazole) -2-yl)-1H-pyrazol-1-yl)methyl phosphate;
VI-79: N-(1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide;
VI-80: ammonium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazole -2-yl)-1H-pyrazol-1-yl)methyl phosphate;
VI-81: 5-amino-5-carboxypentane-1-aminium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)- 1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate;
VI-82: 1-(4-amino-4-carboxybutyl)guanidinium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl) -1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate;
VI-83: (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazole- 2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate;
VI-84: 1,3-dihydroxy-2-(hydroxymethyl)propane-2-aminium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridine- 2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl hydrogen phosphate;
VI-85: triethylammonium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl) Thiazol-2-yl)-1H-pyrazol-1-yl)methyl hydrogen phosphate;
VI-86: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2 -(1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-87: N-(1-(3-hydroxy-3-methylcyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl ) thiazole-4-carboxamide;
VI-88: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-89: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2 -(1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-90: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2 -(1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-91: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-(trifluoro methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-92: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H -pyrazol-4-yl)thiazole-4-carboxamide;
VI-93: 2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl) -1H-pyrazol-4-yl)thiazol-4-carboxamide;
VI-94: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl ) thiazole-4-carboxamide;
VI-95: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)-1H-pyrazole-4- yl) thiazole-4-carboxamide;
VI-96: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole- 4-carboxamide;
VI-97: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(2,2,2-trifluoroethyl)- 1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-98: 2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl ) thiazole-4-carboxamide;
VI-99: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2 -(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-100: 2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole -4-yl)thiazol-4-carboxamide;
VI-103: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro- 2-hydroxypropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate;
VI-104: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro- 2-hydroxypropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-105: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazole-4 -yl) thiazole-4-carboxamide formate;
VI-106: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazole-4 -yl)thiazole-4-carboxamide;
VI-107: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro- 2-hydroxy-2-(trifluoromethyl)propyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate;
VI-108: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro- 2-hydroxy-2-(trifluoromethyl)propyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-117: N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole- 4-carboxamide;
VI-118: N-(1-(2-(2-fluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl ) thiazole-4-carboxamide formate;
VI-119: N-(1-(2-(2-fluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl ) thiazole-4-carboxamide;
VI-120: N-(1-benzyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-121: N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-122: N-(1-(2-(2,2-difluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole-4 -yl)thiazole-4-carboxamide;
VI-123: N-(1-(((1r,3r)-3-hydroxycyclobutyl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H- pyrazol-4-yl)thiazole-4-carboxamide formate;
VI-124: N-(1-(((1r,3r)-3-hydroxycyclobutyl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H- pyrazol-4-yl)thiazole-4-carboxamide;
VI-125: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide form Mate;
VI-126: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-127: N-(1-((1s,3s)-3-(ethoxy-d5)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H- pyrazol-4-yl)thiazole-4-carboxamide;
VI-128: N-(1-(diethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-129: N-(1-(morpholine-4-carbonyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4 - a carboxamide;
VI-130: N-(1-((1s,3s)-3-(2-fluoroethoxy)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide;
VI-131: N-(1-(morpholine-4-carbonyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4 - a carboxamide formate;
VI-132: N-(1-(3-fluorocyclobut-2-en-1-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole -4-yl)thiazol-4-carboxamide;
VI-133: N-(1-(3-fluorocyclobut-2-en-1-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole -4-yl)thiazole-4-carboxamide formate;
VI-134: N-(1-(3,3-difluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole -4-carboxamide formate;
VI-135: N-(1-(3,3-difluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole -4-carboxamide;
VI-140: N-(3-(3-fluoropyridin-2-yl)-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-2 -(1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-141: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy ) cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate;
VI-142: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy ) cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-143: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole-4- yl) thiazole-4-carboxamide formate;
VI-144: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole-4- yl) thiazole-4-carboxamide;
VI-145: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole-4- yl) thiazole-4-carboxamide formate;
VI-146: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole-4- yl) thiazole-4-carboxamide;
VI-147: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole-4- yl) thiazole-4-carboxamide formate;
VI-148: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole-4- yl) thiazole-4-carboxamide;
VI-149: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole-4- yl) thiazole-4-carboxamide formate;
VI-150: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole-4- yl) thiazole-4-carboxamide;
VI-151: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole-4- yl) thiazole-4-carboxamide formate;
VI-152: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole-4- yl) thiazole-4-carboxamide;
VI-153: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H- pyrazol-4-yl)thiazole-4-carboxamide formate;
VI-154: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H- pyrazol-4-yl)thiazole-4-carboxamide;
VI-155: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide formate;
VI-156: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide;
VI-157: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H- pyrazol-4-yl)thiazole-4-carboxamide;
VI-158: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H- pyrazol-4-yl)thiazole-4-carboxamide formate;
VI-159: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H- pyrazol-4-yl)thiazole-4-carboxamide;
VI-160: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H- pyrazol-4-yl)thiazole-4-carboxamide;
VI-161: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy ) cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate;
VI-162: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy ) cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-163: (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl) ) thiazol-2-yl)-1H-pyrazol-1-yl) methyl dihydrogen phosphate;
VI-164: sodium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate;
VI-165: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazole-4 -yl)-2-(1H-pyrazol-4-yl)thiazol-4-carboxamide formate;
VI-166: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazole-4 -yl)-2-(1H-pyrazol-4-yl)thiazol-4-carboxamide;
VI-167: N-(3-(3-fluoropyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazole-4 -yl)-2-(1H-pyrazol-4-yl)thiazol-4-carboxamide formate;
VI-168: N-(3-(3-fluoropyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazole-4 -yl)-2-(1H-pyrazol-4-yl)thiazol-4-carboxamide;
VI-169: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole -4-yl)thiazol-4-carboxamide;
VI-170: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazole-4 -yl)-2-(1H-pyrazol-4-yl)thiazol-4-carboxamide formate;
VI-171: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazole-4 -yl)-2-(1H-pyrazol-4-yl)thiazol-4-carboxamide;
VI-172: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H- pyrazol-4-yl)thiazole-4-carboxamide;
VI-173: (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl) ) thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate;
VI-174: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-( 1H-pyrazol-4-yl)thiazole-4-carboxamide;
VI-175: N-(1-((1s,4s)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazole -4-yl)thiazol-4-carboxamide;
VI-176: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide;
VI-177: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,4s)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide;
VI-180: N-(3-(3,5-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide;
VII-2: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate;
VII-3: di-tert-butyl ((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H- pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphate;
VII-4: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylphosphate disodium salt;
VII-5: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1 -methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VII-6: 2-(1-(acetyl-L-leucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r, 4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VII-7: 1-methylcyclopropyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole- 4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;
VII-8: 1-(isobutyryloxy)ethyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)- 1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;
VII-9: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1 -((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VII-10: 2-morpholinoethyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4 -yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;
VII-11: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide hemitartrate;
VII-12: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1 -(morpholine-4-carbonyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VII-13: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1 -((3-morpholinopropyl)carbamoyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VII-14: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1 -((3-(dimethylamino)propyl)carbamoyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VII-15: 3-morpholinopropyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4 -yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;
VII-16: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate hydrochloride;
VII-17: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-prolinate hydrochloride;
VII-18: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4- yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl dihydrogen phosphate;
VII-19: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylglycinate hydrochloride;
VII-20: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4- yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethylphosphate disodium salt;
VII-21: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate hydrochloride;
VII-22: 2-(1-acetyl-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxy cyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VII-23: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-amino-2-methylpropanoate hydrochloride;
VII-24: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4) -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid;
VII-25: Methyl 4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4) -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate;
VII-26: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1 -(2-morpholinoacetyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VII-27: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1 -(2-hydroxy-3-morpholinopropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VII-28: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-morpholinoacetate;
VII-29: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate;
VII-30: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate benzenesulfonate;
VII-31: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate mesylate;
VII-32: 2-(4-methylpiperazin-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r) -4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate;
VII-33: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4) -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl L-aspartate hydrochloride;
VII-34: methyl N-(2-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-) pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-2-oxoethyl)-N-methylglycinate;
VII-35: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate;
VII-36: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate benzenesulfonate;
VII-37: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-(morpholinomethyl)benzoate;
VII-38: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4) -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl L-aspartate hydrochloride;
VII-39: (1R,2R)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl) )-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid;
VII-40: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate mesylate;
VII-41: (S)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxy Cyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid hydrochloride;
VII-42: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4S)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1 -((2S,3S,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazole- 4-carboxamide;
VII-43: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4R)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1 -((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazole- 4-carboxamide;
VII-44: tert-butyl (1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H- Pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl)hydrogen phosphate acetic acid sodium salt;
VII-45: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylisopropyl carbonate;
VII-46: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl di(((isopropoxycarbonyl)oxy)methyl)phosphate;
VII-47: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4) -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl L-aspartate;
VII-48: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4) -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl L-aspartate benzenesulfonate;
VII-49: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4- yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl dihydrogen phosphate tris salt;
VII-50: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylglycinate benzenesulfonate;
VII-51: 2-(4-methylpiperazin-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r) -4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate benzenesulfonate;
VII-52: 2-(4-methylpiperazin-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r) -4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate succinate;
VII-53: (2R,3R)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r) -4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid;
VII-54: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl acetate;
VII-55: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4) -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl L-aspartate benzenesulfonate;
VII-56: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4) -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid tris salt;
VII-57: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-((S)-2-amino-3-methylbutanamido)butanoate hydrochloride;
VII-58: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1 -(2-hydroxyethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VII-59: 2-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4- yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)acetic acid;
VII-60: ((((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4 - yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(hydroxy)phosphoryl)oxy)methylisopropyl carbonate;
VII-61: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate hydrochloride;
VII-62: Isopropyl (((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4 -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate;
VII-63: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate tris salt;
VII-64: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide hydrochloride;
VII-65: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamidobenzenesulfonate;
VII-66: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide tartrate;
VII-67: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide sodium salt;
VII-68: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide hemicitrate;
VII-69: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate ditris salt;
VII-70: benzyl ((S)-1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)- 1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate;
VII-71: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-prolinate;
VII-72: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylglycinate;
VII-73: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (R)-2-amino-3,3-dimethylbutanoate;
VII-74: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-amino-2-methylpropanoate;
VII-75: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4) -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl L-aspartate;
VII-76: (S)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxy cyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid;
VII-77: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-((S)-2-amino-3-methylbutanamido)butanoate;
VII-78: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate;
VII-79: 2-(1-(acetyl-D-leucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r, 4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VII-80: 2-(1-(acetylleucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r) -4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
VII-81: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl D-valinate;
VII-82: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylvalinate;
VII-83: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl D-prolinate;
VII-84: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylprolinate;
VII-85: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-amino-3,3-dimethylbutanoate;
VII-86: (1S,2S)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl) )-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid;
VII-87: (1R,2S)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl) )-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid;
VII-88: (1S,2R)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl) )-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid;
VII-89: 2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole- 4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid;
VII-90: (R)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxy cyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid;
VII-91: 2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H) -pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid;
VII-92: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4) -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl D-aspartate;
VII-93: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4) -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methylaspartate;
VII-94: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4) -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl D-aspartate;
VII-95: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4) -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methylaspartate;
VII-96: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-((R)-2-amino-3-methylbutanamido)butanoate;
VII-97: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl) Carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-(2-amino-3-methylbutanamido)butanoate;
VII-98: isopropyl (((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4 -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate;
VII-99: Isopropyl (((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazole-4 -yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)alaninate;
VII-100: (2R,3S)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r) -4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid;
VII-101: (2S,3R)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r) -4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid;
VII-102: (2S,3S)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r) -4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid;
VII-103: 2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl) -1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid;
VII-104: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide phosphate;
VII-105: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide gentisate; or
VII-106: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H -pyrazol-4-yl)thiazole-4-carboxamide succinate
The pharmaceutical composition of claim 1, selected from.

The compound is

or a pharmaceutically acceptable salt thereof .

The pharmaceutical composition according to any one of claims 1 to 7 , which ameliorates signs or symptoms of CRS as compared to the severity of the signs or symptoms prior to administration of said pharmaceutical composition .

9. The pharmaceutical composition of claim 8 , wherein said sign or symptom is fever.

the subject is
The subject has previously received a first therapy for which CRS is a known, possible, or potential side effect; or a first therapy for which CRS is a known, potential, or potential side effect; a subject who is scheduled to receive or is currently receiving a treatment of 1;
The pharmaceutical composition according to any one of claims 1-9 .

11. The pharmaceutical composition of claim 10 , wherein said first therapy comprises cell therapy.

12. The pharmaceutical composition of Claim 11 , wherein said cell therapy comprises chimeric antigen receptor (CAR) expression therapy, transgenic receptor therapy, or a combination thereof.

13. The pharmaceutical composition according to any one of claims 1-12 , administered in combination with a second therapeutic agent.

14. The pharmaceutical composition of Claim 13 , wherein said second therapeutic agent is a steroid, an anti-inflammatory agent, an immunosuppressive agent, or a combination thereof.

The steroid is alclomethasone, algestone, beclomethasone, betamethasone, budesonide, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortibazole, deflazacort, desonide, desoxymethasone, dexamethasone, diflorazone, diflucortolone, diflu prednate, enoxolone, fluazacort, fluchloronide, fludrocortisone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene, fluprednisolone, flurandrenolide, fluticasone, hormonecortisone, halcinonide, halobetasol, Halomethasone, halopredone, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone, paramethasone, predniccarbate, prednisolone, prednisone, prednivar, prednilidene, rimexolone, thixocortol, triamcinolone, or any of these any combination of
The anti-inflammatory agent is aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or combinations thereof; ), or a combination thereof .

15. The pharmaceutical composition of Claim 14 , wherein said second therapeutic agent is dexamethasone or prednisone, or a combination thereof.