JP7495526B2 - P38アルファマイトジェン活性化プロテインキナーゼ阻害剤 - Google Patents
P38アルファマイトジェン活性化プロテインキナーゼ阻害剤 Download PDFInfo
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- JP7495526B2 JP7495526B2 JP2022570610A JP2022570610A JP7495526B2 JP 7495526 B2 JP7495526 B2 JP 7495526B2 JP 2022570610 A JP2022570610 A JP 2022570610A JP 2022570610 A JP2022570610 A JP 2022570610A JP 7495526 B2 JP7495526 B2 JP 7495526B2
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Description
又はその薬学的に許容される塩を有し、式中、
R1は、C1-4アルカンジイル、C1-4ヘテロアルカンジイル、置換C1-4アルカンジイル、及び置換C1-4ヘテロアルカンジイルから選択され、
R2は、式(2a)の部分、式(2b)の部分、式(2c)の部分、C8-16ヘテロビシクロアルキル、及び置換C8-16ヘテロビシクロアルキルから選択され、
式中、
B1、B2、B3、及びB4の各々は、独立して、-(CH(-R4))n-から選択され、式中、
各nは、独立して、0、1、2、3、及び4から選択され、
B1及びB2の両方は、0ではなく、
B3及びB4の両方は、0ではなく、
各R4は、独立して、水素、-OH、-NH2、-NO2、C1-3アルキル、C1-3ヘテロアルキル、置換C1-3アルキル、及び置換C1-3ヘテロアルキルから選択され、
Dは、メタン-ジイル及びエタン-ジイルから選択され、
Xは、-O-、-CH(-OH)-、-NR3-、及び-SO2-から選択され、R3は、水素、C1-6アルキル、C1-6シクロアルキル、C6アリール、C1-6ヘテロアルキル、C1-6ヘテロシクロアルキル、C5-6ヘテロアリール、置換C1-6アルキル、置換C1-6シクロアルキル、置換C6アリール、置換C1-6ヘテロアルキル、置換C1-6ヘテロシクロアルキル、及び置換C5-6ヘテロアリールから選択される。
又はその薬学的に許容される塩を有し、式中、
R1は、C1-4アルカンジイル、C1-4ヘテロアルカンジイル、置換C1-4アルカンジイル、及び置換C1-4ヘテロアルカンジイルから選択され、
R2は、式(2d)の部分であり、
式中、
各A1及びA2は、独立して、-CH2-、-CH(-R5)-、及び-C(=O)-から選択され、式中、各R5は、独立して、-OH、-NH2、-NO2、C1-6アルキル、C1-6シクロアルキル、C6アリール、C1-6ヘテロアルキル、C1-6ヘテロシクロアルキル、C5-6ヘテロアリール、置換C1-6アルキル、置換C1-6シクロアルキル、置換C6アリール、置換C1-6ヘテロアルキル、置換C1-6ヘテロシクロアルキル、及び置換C5-6ヘテロアリールから選択され、
A1及びA2のうちの1つ以上は、独立して、-CH(-R5)-及び-C(=O)-から選択され、
各nは、独立して、1、2、3、及び4から選択され、
Xは、-O-、-CH(-OH)-、-NR3-、及び-SO2-から選択され、R3は、水素、C1-6アルキル、C5-8シクロアルキル、C6アリール、C6-12シクロアルキルアルキル、C7-10アリールアルキル、C1-6ヘテロアルキル、C5-8ヘテロシクロアルキル、C5-6ヘテロアリール、C6-12ヘテロシクロアルキルアルキル、C7-10ヘテロアリールアルキル、置換C1-6アルキル、置換C5-8シクロアルキル、置換C6アリール、置換C6-12シクロアルキルアルキル、置換C7-10アリールアルキル、置換C1-6ヘテロアルキル、置換C5-8ヘテロシクロアルキル、置換C5-6ヘテロアリール、置換C6-12ヘテロシクロアルキルアルキル、及び置換C7-10ヘテロアリールアルキルから選択される。
又はその薬学的に許容される塩であって、式中、
R1は、C1-4アルカンジイル、C1-4ヘテロアルカンジイル、置換C1-4アルカンジイル、及び置換C1-4ヘテロアルカンジイルから選択され得、
R2は、式(2a)の部分、式(2b)の部分、式(2c)の部分、C8-16ヘテロビシクロアルキル、及び置換C8-16ヘテロビシクロアルキルから選択され得、
式中、
B1、B2、B3、及びB4の各々は、独立して、-(CH(-R4))n-から選択され得、式中、
各nは、独立して、0、1、2、3、及び4から選択され得、
B1及びB2の両方は、0ではなく、
B3及びB4の両方は、0ではなく、
各R4は、独立して、水素、-OH、-NH2、-NO2、C1-3アルキル、C1-3ヘテロアルキル、置換C1-3アルキル、及び置換C1-3ヘテロアルキルから選択され得、
Dは、メタン-ジイル及びエタン-ジイルから選択され得、
Xは、-O-、-CH(-OH)-、-NR3-、及び-SO2-から選択され得、R3は、水素、C1-6アルキル、C1-6シクロアルキル、C6アリール、C1-6ヘテロアルキル、C1-6ヘテロシクロアルキル、C5-6ヘテロアリール、置換C1-6アルキル、置換C1-6シクロアルキル、置換C6アリール、置換C1-6ヘテロアルキル、置換C1-6ヘテロシクロアルキル、及び置換C5-6ヘテロアリールから選択され得る。
式中、R5が、水素(非置換)、-OH、-NH2、-NR2から選択され、各Rが、独立して、水素及びC1-3アルキル、-NO2、=O、C1-3アルコキシ、及びC(=O)-Rから選択され、式中、Rが、C1-3アルキルである。
B1及びB2の各々におけるnは、1であり得、
B3及びB4の各々におけるnは、2であり得る。
B1及びB2の各々におけるnは、2であり得、
B3及びB4の各々におけるnは、1であり得る。
N-(4-((2-オキサ-6-アザスピロ[3.3]ヘプタン-6-イル)メチル)フェニル)-4-クロロベンズアミド(3)、
N-(4-((7-オキサ-2-アザスピロ[3.5]ノナン-2-イル)メチル)フェニル)-4-クロロベンズアミド(4)、
N-(4-((8-オキサ-2-アザスピロ[4.5]デカン-2-イル)メチル)フェニル)-4-クロロベンズアミド(5)、
N-(4-((1-オキサ-7-アザスピロ[4.4]ノナン-7-イル)メチル)フェニル)-4-クロロベンズアミド(6)、
N-(4-(((1R,5S)-3-オキサ-7-アザビシクロ[3.3.1]ノナン-7-イル)メチル)フェニル)-4-クロロベンズアミド(9)、及び
4-クロロ-N-(4-(((3aR,6aS)-テトラヒドロ-1H-フロ[3,4-c]ピロール-5(3H)-イル)メチル)フェニル)ベンズアミド(10)、
又は前述のいずれかの薬学的に許容される塩から選択され得る。
又はその薬学的に許容される塩であって、式中、
R1は、C1-4アルカンジイル、C1-4ヘテロアルカンジイル、置換C1-4アルカンジイル、及び置換C1-4ヘテロアルカンジイルから選択され得、
R2は、式(2d)の部分であり得、
式中、
各A1及びA2は、独立して、-CH2-、-CH(-R5)-、及び-C(=O)-から選択され得、式中、各R5は、独立して、-OH、-NH2、-NO2、C1-6アルキル、C1-6シクロアルキル、C6アリール、C1-6ヘテロアルキル、C1-6ヘテロシクロアルキル、C5-6ヘテロアリール、置換C1-6アルキル、置換C1-6シクロアルキル、置換C6アリール、置換C1-6ヘテロアルキル、置換C1-6ヘテロシクロアルキル、及び置換C5-6ヘテロアリールから選択され得、
A1及びA2のうちの1つ以上は、独立して、-CH(-R5)-及び-C(=O)-から選択され得、
各nは、独立して、1、2、3、及び4から選択され得、
Xは、-O-、-CH(-OH)-、-NR3-、及び-SO2-から選択され得、R3は、水素、C1-6アルキル、C5-8シクロアルキル、C6アリール、C6-12シクロアルキルアルキル、C7-10アリールアルキル、C1-6ヘテロアルキル、C5-8ヘテロシクロアルキル、C5-6ヘテロアリール、C6-12ヘテロシクロアルキルアルキル、C7-10ヘテロアリールアルキル、置換C1-6アルキル、置換C5-8シクロアルキル、置換C6アリール、置換C6-12シクロアルキルアルキル、置換C7-10アリールアルキル、置換C1-6ヘテロアルキル、置換C5-8ヘテロシクロアルキル、置換C5-6ヘテロアリール、置換C6-12ヘテロシクロアルキルアルキル、及び置換C7-10ヘテロアリールアルキルから選択され得る。
2-クロロ-N-(4-(モルホリノメチル)フェニル)ピリミジン-5-カルボキサミド(1)、
N-(4-((1,4-オキサゼパン-4-イル)メチル)フェニル)-4-クロロベンズアミド(2)、
4-クロロ-N-(4-(((2S,6R)-2,6-ジメチルモルホリノ)メチル)フェニル)ベンズアミド(7)、
4-クロロ-N-(4-(((2S,6S)-2,6-ジメチルモルホリノ)メチル)フェニル)ベンズアミド(8)、
4-クロロ-N-(4-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)ベンズアミド(11)、
4-クロロ-N-(4-((3-ヒドロキシピペリジン-1-イル)メチル)フェニル)ベンズアミド(12)、
4-クロロ-N-(4-((3-ヒドロキシピロリジン-1-イル)メチル)フェニル)ベンズアミド(13)、
N-(4-((4-アセチルピペラジン-1-イル)メチル)フェニル)-4-クロロベンズアミド(14)、
4-クロロ-N-(4-((3-オキソピペラジン-1-イル)メチル)フェニル)ベンズアミド(15)、
4-クロロ-N-(4-((4-メチル-3-オキソピペラジン-1-イル)メチル)フェニル)ベンズアミド(16)、及び
4-クロロ-N-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)ベンズアミド(17)、
又は前述のいずれかの薬学的に許容される塩から選択され得る。
式中、R5は、水素(非置換)、-OH、-NH2、-NR2から選択され、各Rは、独立して、水素及びC1-3アルキル、-NO2、=O、C1-3アルコキシ、及びC(=O)-Rから選択され、式中、Rは、C1-3アルキルである。
式中、
R5は、水素(非置換)、-OH、-NH2、-NR2から選択され、各Rは、独立して、水素及びC1-3アルキル、-NO2、=O、C1-3アルコキシ、及びC(=O)-Rから選択され、式中、Rは、C1-3アルキルであり、
R6は、C1-6アルキル及びC1-6アルコキシから選択される。
又はその薬学的に許容される塩であって、式中、
R1は、C1-4アルカンジイルから選択され得、
R2は、式(2a.1)~(2a.4)及び(2d.1)~(2d.5)のいずれか1つの置換又は非置換部分から選択され、
式中、
R5は、水素(非置換)、-OH、-NH2、-NR2から選択され、各Rは、独立して、水素及びC1-3アルキル、-NO2、=O、C1-3アルコキシ、及びC(=O)-Rから選択され、式中、Rは、C1-3アルキルであり、
R6は、C1-6アルキル及びC1-6アルコキシから選択される。
式中、
R5は、水素(非置換)、-OH、-NH2、-NR2から選択され、各Rは、独立して、水素及びC1-3アルキル、-NO2、=O、C1-3アルコキシ、及びC(=O)-Rから選択され、Rは、C1-3アルキルであり、
R6は、C1-6アルキル及びC1-6アルコキシから選択される。
Th発明は、以下の態様によって更に定義される。
又はその薬学的に許容される塩であって、式中、
R1が、C1-4アルカンジイル、C1-4ヘテロアルカンジイル、置換C1-4アルカンジイル、及び置換C1-4ヘテロアルカンジイルから選択され、
R2が、式(2a)の部分、式(2b)の部分、式(2c)の部分、C8-16ヘテロビシクロアルキル、及び置換C8-16ヘテロビシクロアルキルから選択され、
式中、
B1、B2、B3、及びB4の各々が、独立して、-(CH(-R4))n-から選択され、式中、
各nが、独立して、0、1、2、3、及び4から選択され、
B1及びB2の両方が、0ではなく、
B3及びB4の両方が、0ではなく、
各R4が、独立して、水素、-OH、-NH2、-NO2、C1-3アルキル、C1-3ヘテロアルキル、置換C1-3アルキル、及び置換C1-3ヘテロアルキルから選択され、
Dが、メタン-ジイル及びエタン-ジイルから選択され、
Xが、-O-、-CH(-OH)-、-NR3-、及び-SO2-から選択され、R3が、水素、C1-6アルキル、C1-6シクロアルキル、C6アリール、C1-6ヘテロアルキル、C1-6ヘテロシクロアルキル、C5-6ヘテロアリール、置換C1-6アルキル、置換C1-6シクロアルキル、置換C6アリール、置換C1-6ヘテロアルキル、置換C1-6ヘテロシクロアルキル、及び置換C5-6ヘテロアリールから選択される、化合物、又はその薬学的に許容される塩。
N-(4-((2-オキサ-6-アザスピロ[3.3]ヘプタン-6-イル)メチル)フェニル)-4-クロロベンズアミド(3)、
N-(4-((7-オキサ-2-アザスピロ[3.5]ノナン-2-イル)メチル)フェニル)-4-クロロベンズアミド(4)、
N-(4-((8-オキサ-2-アザスピロ[4.5]デカン-2-イル)メチル)フェニル)-4-クロロベンズアミド(5)、
N-(4-((1-オキサ-7-アザスピロ[4.4]ノナン-7-イル)メチル)フェニル)-4-クロロベンズアミド(6)、
N-(4-(((1R,5S)-3-オキサ-7-アザビシクロ[3.3.1]ノナン-7-イル)メチル)フェニル)-4-クロロベンズアミド(9)、及び
4-クロロ-N-(4-(((3aR,6aS)-テトラヒドロ-1H-フロ[3,4-c]ピロール-5(3H)-イル)メチル)フェニル)ベンズアミド(10)、
又は前述のいずれかの薬学的に許容される塩から選択される、態様53の化合物。
又はその薬学的に許容される塩であって、式中、
R1が、C1-4アルカンジイル、C1-4ヘテロアルカンジイル、置換C1-4アルカンジイル、及び置換C1-4ヘテロアルカンジイルから選択され、
R2が、式(2d)の部分であり、
式中、
各A1及びA2が、独立して、-CH2-、-CH(-R5)-、及び-C(=O)-から選択され、式中、各R5が、独立して、-OH、-NH2、-NO2、C1-6アルキル、C1-6シクロアルキル、C6アリール、C1-6ヘテロアルキル、C1-6ヘテロシクロアルキル、C5-6ヘテロアリール、置換C1-6アルキル、置換C1-6シクロアルキル、置換C6アリール、置換C1-6ヘテロアルキル、置換C1-6ヘテロシクロアルキル、及び置換C5-6ヘテロアリールから選択され、
A1及びA2のうちの1つ以上が、独立して、-CH(-R5)-及び-C(=O)-から選択され、
各nが、独立して、1、2、3、及び4から選択され、
Xが、-O-、-CH(-OH)-、-NR3-、及び-SO2-から選択され、R3が、水素、C1-6アルキル、C5-8シクロアルキル、C6アリール、C6-12シクロアルキルアルキル、C7-10アリールアルキル、C1-6ヘテロアルキル、C5-8ヘテロシクロアルキル、C5-6ヘテロアリール、C6-12ヘテロシクロアルキルアルキル、C7-10ヘテロアリールアルキル、置換C1-6アルキル、置換C5-8シクロアルキル、置換C6アリール、置換C6-12シクロアルキルアルキル、置換C7-10アリールアルキル、置換C1-6ヘテロアルキル、置換C5-8ヘテロシクロアルキル、置換C5-6ヘテロアリール、置換C6-12ヘテロシクロアルキルアルキル、及び置換C7-10ヘテロアリールアルキルから選択される、化合物、又はその薬学的に許容される塩。
2-クロロ-N-(4-(モルホリノメチル)フェニル)ピリミジン-5-カルボキサミド(1)、
N-(4-((1,4-オキサゼパン-4-イル)メチル)フェニル)-4-クロロベンズアミド(2)、
4-クロロ-N-(4-(((2S,6R)-2,6-ジメチルモルホリノ)メチル)フェニル)ベンズアミド(7)、
4-クロロ-N-(4-(((2S,6S)-2,6-ジメチルモルホリノ)メチル)フェニル)ベンズアミド(8)、
4-クロロ-N-(4-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)ベンズアミド(11)、
4-クロロ-N-(4-((3-ヒドロキシピペリジン-1-イル)メチル)フェニル)ベンズアミド(12)、
4-クロロ-N-(4-((3-ヒドロキシピロリジン-1-イル)メチル)フェニル)ベンズアミド(13)、
N-(4-((4-アセチルピペラジン-1-イル)メチル)フェニル)-4-クロロベンズアミド(14)、
4-クロロ-N-(4-((3-オキソピペラジン-1-イル)メチル)フェニル)ベンズアミド(15)、
4-クロロ-N-(4-((4-メチル-3-オキソピペラジン-1-イル)メチル)フェニル)ベンズアミド(16)、及び
4-クロロ-N-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)ベンズアミド(17)、
又は前述のいずれかの薬学的に許容される塩から選択される、態様78の化合物。
式中、R5が、水素(非置換)、-OH、-NH2、-NR2から選択され、各Rが、独立して、水素及びC1-3アルキル、-NO2、=O、C1-3アルコキシ、及びC(=O)-Rから選択され、式中、Rが、C1-3アルキルである、態様8の化合物。
式中、R5が、水素(非置換)、-OH、-NH2、-NR2から選択され、各Rが、独立して、水素及びC1-3アルキル、-NO2、=O、C1-3アルコキシ、及びC(=O)-Rから選択され、式中、Rが、C1-3アルキルである、態様78の化合物。
式中、
R5が、水素(非置換)、-OH、-NH2、-NR2から選択され、各Rが、独立して、水素及びC1-3アルキル、-NO2、=O、C1-3アルコキシ、及びC(=O)-Rから選択され、式中、Rが、C1-3アルキルであり、
R6が、C1-6アルキル及びC1-6アルコキシから選択される、態様78の化合物。
又はその薬学的に許容される塩であって、式中、
R1が、C1-4アルカンジイルから選択され、
R2が、式(2a.1)~(2a.4)及び(2d.1)~(2d.5)のいずれか1つの置換又は非置換部分から選択され、
式中、
R5が、水素(非置換)、-OH、-NH2、-NR2から選択され、各Rが、独立して、水素及びC1-3アルキル、-NO2、=O、C1-3アルコキシ、及びC(=O)-Rから選択され、式中、Rが、C1-3アルキルであり、
R6が、C1-6アルキル及びC1-6アルコキシから選択される、化合物、又はその薬学的に許容される塩。
式中、
R5が、-OH、-NH2、-NR2から選択され、各Rが、独立して、水素及びC1-3アルキル、-NO2、=O、C1-3アルコキシ、及びC(=O)-Rから選択され、式中、Rが、C1-3アルキルであり、
R6が、C1-6アルキル及びC1-6アルコキシから選択される、態様9A~11Aのいずれか1つの化合物。
4-クロロ-N-(4-(ヒドロキシメチル)フェニル)ベンズアミド(A)の合成
塩化4-クロロベンゾイル(15.63g、89.32mmol)を、THF(100mL)中の(4-アミノフェニル)メタノール(10g、81.2mmol)及び酢酸ナトリウム(10g、121.8mmol)の撹拌溶液に室温でゆっくりと加えた。添加の完了後、反応混合物を室温で1.5時間撹拌した。反応混合物を水(50mL)で希釈し、酢酸エチル(40mL×3)で抽出した。合わせた有機抽出物を水(100mL×2)及び飽和塩化ナトリウム溶液(100mL)で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮乾固した。得られた残渣をシリカゲルカラム(DCM:MeOH=50:1、v/v)によって精製し、4-クロロ-N-(4-(ヒドロキシメチル)フェニル)ベンズアミド(A)(19.53g、収率91.9%)を白色の固体として得た。LCMS(Agilent):Rt=1.47分、[M+H]+のm/z計算262.1、実測262.1。1H-NMR(400MHz、DMSO-d6) δ 10.27(s、1H)、7.99-7.96(m、2H)、7.70(d、J=8.4Hz、2H)、7.62-7.58(m、2H)、7.29(dd、J=6.4、2.0Hz、2H)、5.12(t、J=5.2Hz、1H)、4.46(d、J=5.2Hz、2H)。
4-クロロ-N-(4-(クロロメチル)フェニル)ベンズアミド(B)の合成
塩化メタンスルホニル(1.75g、15.28mmol)を、DCM(25mL)中の4-クロロ-N-(4-(ヒドロキシメチル)フェニル)ベンズアミド(A)(2.00g、7.64mmol)及びトリエチルアミン(1.53g、15.28mmol)の撹拌溶液に室温で滴下した。添加の完了後、反応混合物を室温で2時間撹拌した。反応混合物をH2O(20mL)で希釈し、DCM(20mL×3)で抽出した。合わせた有機抽出物をH2O(30mL)及び飽和塩化ナトリウム溶液(20mL)で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮乾固して、表題化合物(B)(627mg、収率29.3%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.4(シリカゲル、PE/EtOAc=3/1、v/v)。LCMS(Agilent):Rt=2.30分、[M+H]+のm/z計算280.0、実測280.0/282.1。1H-NMR(400MHz、DMSO-d6) δ 10.39(s、1H)、7.98(dd、J=6.4、2.0Hz、2H)、7.77(dd、J=6.4、2.0Hz、2H)、7.61(dd、J=6.8、2.0Hz、2H)、7.42(dd、J=6.8、2.0Hz、2H)、4.75(s、2H)。
N-(4-((1,4-オキサゼパン-4-イル)メチル)フェニル)-4-クロロベンズアミド(1)の合成
無水炭酸カリウム(99mg、0.71mmol)を1ロットでDMF(2mL)中の化合物(B)(100mg、0.36mmol)及び1,4-オキサゼパン(44mg、0.45mmol)の撹拌溶液に50℃で添加した。添加の完了後、反応混合物を50℃で1時間撹拌した。反応混合物をH2O(10mL)で希釈し、濾過した。得られた固体濾過ケーキを小体積のDCMで洗浄し、減圧下で乾燥させて、粗生成物を得た。粗生成物をその後0.5MのHCl(水性)で酸性化し、濃縮乾固して、表題化合物(1)(100mg、収率81.1%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.6(シリカゲル、DCM/MeOH=20/1、v/v)。LCMS(Agilent):Rt=0.86分、[M+H]+のm/z計算345.1、実測345.1。1H-NMR(400MHz、DMSO-d6) δ 10.95(s、1H)、10.51(s、1H)、8.1(d、J=8.4Hz、2H)、7.86(d、J=8.4Hz、2H)、7.63-7.60(m、4H)、4.33(d、J=5.2Hz、2H)、3.81-3.86(m、2H)、3.64-3.75(m、2H)、3.41-3.46(m、1H)、3.29-3.45(m、1H)、3.08-3.21(m、2H)、2.29-3.32(m、1H)、1.96-2.03(m、1H)。
N-(4-((2-オキサ-6-アザスピロ[3.3]ヘプタン-6-イル)メチル)フェニル)-4-クロロベンズアミド(2)の合成
無水炭酸カリウム(197.39mg、1.428mmol)を、1ロットでDMF(4mL)中の化合物(B)(200mg、0.714mmol)及び2-オキサ-6-アザスピロ[3.3]ヘプタン(84.95mg、0.857mmol)の撹拌混合物に室温で加え、50℃に加熱した。50℃で2時間撹拌した後、反応混合物をH2O(10mL)で希釈し、濾過した。収集された固体を分取C18逆相HPLC(10%~95%のMeCN/H2Oで溶出する)によって精製して、表題化合物(2)(109mg、収率44.5%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.2(シリカゲル、MeOH:DCM=1:10)。LCMS(Agilent):Rt=0.81分、[M+H]+のm/z計算343.1、実測343.1。1H-NMR(400MHz、DMSO-d6) δ 10.40(s、1H)、8.01-7.97(m、2H)、7.77(d、J=8.4Hz、2H)、7.63-7.59(m、2H)、7.35(d、J=8Hz、2H)、4.63(s、4H)、3.85(d、J=42.4Hz、4H)、3.33(s、2H)。
2-クロロ-N-(4-(モルホリノメチル)フェニル)ピリミジン-5-カルボキサミド(3)の合成
EEDQ(257mg、1.0mmol)を1ロットでDMF(4mL)中の4-(モルホリノメチル)アニリン(200mg、1.0mmol)及び2-クロロピリミジン-5-カルボン酸(164mg、1.0mmol)の撹拌溶液に室温で加えた。添加の完了後、反応混合物を室温で40時間撹拌し、H2O(10mL)で希釈した。得られたスラリーをEtOAc(30mL×3)で抽出し、減圧下で濃縮乾固した。得られた残渣を分取C18逆相HPLCによって精製して、表題化合物(3)(130mg、収率37.6%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.3(シリカゲル、MeOH/DCM=1/15、v/v)。LCMS(Agilent):Rt=0.49分、[M+Na]+のm/z計算333.1、実測333.0。1H-NMR(400MHz、DMSO-d6) δ 11.06(s、1H)、10.92(s、1H)、9.27(s、2H)、7.88-7.81(m、2H)、7.61(d、J=8.3Hz、2H)、4.30(d、J=5.1Hz、2H)、3.94(dd、J=13.0、3.3Hz、2H)、3.78(t、J=12.0Hz、2H)、3.22(d、J=12.4Hz、2H)、3.07(d、J=11.5Hz、2H)。
N-(4-((7-オキサ-2-アザスピロ[3.5]ノナン-2-イル)メチル)フェニル)-4-クロロベンズアミド(4)の合成
無水炭酸カリウム(621mg、4.49mmol)を、DMF(5mL)中の化合物(A)(430mg、1.5mmol)及び7-オキサ-2-アザスピロ[3.5]ノナン(191mg、1.5mmol)の撹拌溶液に室温で添加した。室温で6時間撹拌した後、反応混合物をH2O(10mL)で希釈し、濾過した。得られた固体を2NのHCl(2mL)及びDMSO(2mL)で溶解し、その後逆相Biotage(登録商標)カラムクロマトグラフィー(C18カラム、0.1%塩酸を含有する10%~95%のMeCN/H2Oで溶出する)によって精製して、表題化合物(4)(80mg、収率14.4%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.40(シリカゲル、PE:EtOAc=1:1、v/v)。LCMS(Agilent):Rt=2.00分、[M+H]+のm/z計算371.2、実測371.2。1H-NMR(400MHz、DMSO-d6) δ 10.43(s、1H)、7.99(d、J=8.6Hz、2H)、7.80(d、J=8.5Hz、2H)、7.62(d、J=8.6Hz、2H)、7.50(s、2H)、4.19(s、2H)、3.69(s、4H)、3.48(s、4H)、1.77(s、4H)。
N-(4-((8-オキサ-2-アザスピロ[4.5]デカン-2-イル)メチル)フェニル)-4-クロロベンズアミド(5)の合成
無水炭酸カリウム(230mg、1.66mmol)を1ロットでDMF(6mL)中の化合物(B)(280mg、0.83mmol)及び8-オキサ-2-アザスピロ[4.5]デカン(142mg、1.0mmol)の撹拌溶液に室温で加えた。室温で6時間撹拌した後、反応混合物をH2O(10mL)で希釈し、濾過した。得られた濾過ケーキを小体積のDCMで洗浄し、減圧下で乾燥させた。その後、残渣をシリカゲルカラム(DCM/MeOH=50/1、v/v)によって精製した。主要画分を減圧下で濃縮し、得られた固体を0.5NのHCl(水性)で処理し、減圧下で蒸発乾固して、表題化合物(5)(144.2mg、収率45.1%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.4シリカゲル、DCM:MeOH=20:1。LCMS(Agilent):Rt=1.96分、[M+H]+のm/z計算385.1、実測385.1。1H-NMR(400MHz、DMSO-d6) δ 11.37(s、1H)、10.51(s、1H)、8.01(d、J=8.4Hz、2H)、7.84(d、J=8.8Hz、2H)、7.63-7.60(m、4H)、4.35-4.25(m、2H)、3.58-3.47(m、4H)、4.45-3.37(m、1H)、3.25-3.14(m、2H)、2.95-2.89(m、1H)、2.01-1.95(m、1H)、1.91-1.84(m、1H)、1.67-1.80(m、3H)、1.55-1.50(m、1H)。
N-(4-((1-オキサ-7-アザスピロ[4.4]ノナン-7-イル)メチル)フェニル)-4-クロロベンズアミド(6)の合成
無水炭酸カリウム(444mg、3.21mmol)を、1ロットでDMF(5.6mL)中の化合物(B)(300mg、1.07mmol)及び1-オキサ-7-アザスピロ[4.4]ノナン(210mg、1.28mmol)の溶液に50℃で添加した。50℃で1時間撹拌した後、反応混合物をH2O(20mL)で希釈し、濾過した。得られた濾過ケーキを小体積のDCMで洗浄し、減圧下で乾燥させた。残渣をシリカゲルカラムクロマトグラフィー(DCM/MeOH=50/1、v/v)によって精製し、所望の画分を減圧下で蒸発させた。得られた残渣を0.5MのHCl(水性)で酸性化し、減圧下で濃縮して、表題化合物(6)(100mg、収率25.2%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。LCMS(Agilent):Rt=1.93分、m/z計算[M+H]+=371.1、実測[M+H]+=371.1。1H-NMR(400MHz、DMSO-d6) δ 10.55(d、J=13.6Hz、1H)、8.01-8.04(m、2H)、7.87-7.83(m、2H)、7.62-7.57(m、4H)、4.34-4.26(m、2H)、3.80-3.68(m、2H)、3.47-3.08(m、4H)、2.02-1.86(m、6H)。
4-クロロ-N-(4-(((2S,6R)-2,6-ジメチルモルホリノ)メチル)フェニル)ベンズアミド(7)の合成
4-クロロ-N-(4-(((2S,6S)-2,6-ジメチルモルホリノ)メチル)フェニル)ベンズアミド(8)の合成
無水炭酸カリウム(296mg、2.14mmol)を1ロットでDMF(5mL)中の化合物(B)(300mg、1.07mmol)及び2,6-ジメチルモルホリン(147mg、1.28mmol)の撹拌溶液に50℃で添加した。50℃で1時間撹拌した後、反応混合物をH2O(20mL)で希釈し、EtOAc(30mL×4)で抽出した。合わせた抽出物を濃縮乾固した。残渣をC18逆相分取HPLC(10%~95%のMeCN/H2Oで溶出する)によって精製した。主要画分を減圧下で濃縮し、得られた固体を0.5NのHCl(水性)で処理し、減圧下で蒸発乾固して、シス異性体(7)(105mg、27.3%)及びトランス異性体(8)(40mg、10.4%)を得た。構造は、LCMS及び1H-NMRによって確認した。
N-(4-(((1R,5S)-3-オキサ-7-アザビシクロ[3.3.1]ノナン-7-イル)メチル)フェニル)-4-クロロベンズアミド(9)の合成
無水炭酸カリウム(625mg、4.52mmol)を1ロットでDMF(6mL)中の化合物(B)(512mg、1.81mmol)及び3-オキサ-7-アザビシクロ[3.3.1]ノナン(230mg、1.81mmol)の撹拌溶液に室温で加えた。室温で7時間撹拌した後、反応混合物をH2O(30mL)で処理し、濾過した。得られた濾過ケーキを小体積のDCMで洗浄し、減圧下で乾燥させた。残渣を0.5NのHCl(水性)で酸性化し、濃縮乾固して、表題化合物(9)(437mg、収率78.2%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.4シリカゲル、PE:EtOAc=1:1。LCMS(Shimadzu):Rt=2.32分、m/z計算[M+H]+=371.2、実測[M+H]+=371.2。1H-NMR(400MHz、DMSO-d6) δ 10.58(s、1H)、8.65(s、1H)、8.04-8.00(m、2H)、7.92-7.88(m、2H)、7.64-7.57(m、4H)、4.22(d、J=5.3Hz、2H)、3.97(d、J=11.3Hz、2H)、3.69-3.64(m、2H)、3.48-3.42(m、2H)、3.27(t、J=11.2Hz、2H)、2.01(s、2H)、1.94-1.78(m、2H)。
4-クロロ-N-(4-(((3aR,6aS)-テトラヒドロ-1H-フロ[3,4-c]ピロール-5(3H)-イル)メチル)フェニル)ベンズアミド(10)の合成
無水炭酸カリウム(531mg、3.84mmol)を、1ロットでDMF(6.5mL)中の化合物(B)(435mg、1.28mmol)及び(3aR,6aS)-ヘキサヒドロ-1H-フロ[3,4-c]ピロール(230mg、1.54mmol)の撹拌溶液に室温で添加した。反応混合物を室温で7時間撹拌した。反応混合物をH2O(60mL)で処理し、濾過し、得られた固体を石油エーテル/酢酸エチル=3/1で洗浄し、C18逆相分取HPLC(10%~95%のMeCN/H2Oで溶出する)によって精製した。主要画分を減圧下で濃縮し、得られた固体を0.5NのHCl(水性)で処理し、減圧下で蒸発乾固して、表題化合物(10)(194.5mg、収率42.6%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.30(シリカゲル、DCM/MeOH=20/1、v/v)。LCMS(Shimadzu):Rt=2.25分、m/z計算[M+H]+=357.2、実測[M+H]+=357.2。1H-NMR(400MHz、DMSO-d6) δ 10.95(d、J=78.2Hz、1H)、10.51(d、J=6.3Hz、1H)、8.04-7.98(m、2H)、7.85(dd、J=8.5、6.2Hz、2H)、7.65-7.52(m、4H)、4.28(dd、J=21.3、5.6Hz、2H)、3.75(t、J=9.5Hz、2H)、3.67-3.55(m、2H)、3.37(ddd、J=38.9、11.0、5.8Hz、2H)、3.20-2.91(m、3H)、2.73-2.67(m、1H)。
4-クロロ-N-(4-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)ベンズアミド(11)の合成
無水炭酸カリウム(50.2mg、0.363mmol)を1ロットでDMF(2mL)中の化合物(B)(100.0mg、0.29mmol)及びピペリジン-4-オール(35.4mg、0.35mmol)の撹拌溶液に室温で加えた。室温で1時間撹拌した後、反応混合物をH2O(10mL)で希釈し、濾過した。得られた濾過ケーキを小体積のDCMで洗浄し、減圧下で乾燥させて、粗生成物を得た。粗生成物を0.5MのHClによって酸性化し、その後減圧下で濃縮して、表題化合物(11)(90mg、収率90.0%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.1シリカゲル、DCM:MeOH=10:1。LCMS(Agilent):Rt=1.72分、m/z計算[M+H]+=345.1、実測[M+H]+=345.1。1H-NMR(400MHz、DMSO-d6) δ 10.76(s、1H)、10.54(s、1H)、8.02(d、J=8.4Hz、2H)、7.84(d、1H-NMR=8.8Hz、2H)、7.60(m、J=4.5Hz、4H)、4.22(m、J=5.2Hz、2H)、3.92(s、1H)、3.61(m、J=5.6Hz、1H)、3.26(d、J=12.4Hz、1H)、3.08(m、J=6.8Hz、2H)、2.89(m、J=8.2Hz、1H)、1.95(m、J=14.0Hz、2H)、1.73(m、J=14.0Hz、2H)。
4-クロロ-N-(4-((3-ヒドロキシピペリジン-1-イル)メチル)フェニル)ベンズアミド(12)の合成
無水炭酸カリウム(160.4mg、1.16mmol)を1ロットでDMF(4mL)中の化合物(B)(200mg、0.58mmol)及びピペリジン-3-オール(70.8mg、0.70mmol)の撹拌溶液に室温で加えた。室温で1時間撹拌した後、反応混合物をH2O(20mL)で希釈し、濾過した。得られた濾過ケーキを小体積のDCMで洗浄し、減圧下で乾燥させて、粗生成物を得た。粗生成物を0.5MのHCl(水性)によって酸性化し、減圧下で濃縮乾固して、表題化合物(12)(122.5mg、収率61.25%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.2シリカゲル、DCM:MeOH=10:1。LCMS(Agilent):Rt=1.77分、m/z計算[M+H]+=345.1、実測[M+H]+=345.1。1H-NMR(400MHz、DMSO-d6) δ 10.99(s、0.57H)、10.55(d、J=11.6Hz、1H)、9.59(s、0.35H)、8.04-8.00(m、2H)、7.88-7.85(m、2H)、7.64-7.52(m、4H)、4.30-4.12(m、2H)、4.01(s、0.39H)、3.86(s、0.59H)、3.34-3.16(m、2H)、3.00 2.87(m、1H)、2.72(s、0.69H)、2.08-2.01(m、0.47H)、1.92-1.81(m、2H)、1.69-1.51(m、1H)、1.28-1.18(m、1H)。
4-クロロ-N-(4-((3-ヒドロキシピロリジン-1-イル)メチル)フェニル)ベンズアミド(13)の合成
無水炭酸カリウム(197.4mg、1.428mmol)を1ロットでDMF(4mL)中の化合物(B)(200mg、0.72mmol)及びピロリジン-3-オール(74.6mg、0.86mmol)の撹拌溶液に室温で加えた。50℃で6時間撹拌した後、反応混合物をH2O(20mL)で希釈し、濾過した。得られた濾過ケーキを小体積のDCMで洗浄し、減圧下で乾燥させて、粗生成物を得た。粗生成物を0.5MのHCl(水性)によって酸性化し、減圧下で濃縮乾固して、表題化合物(13)(230mg、収率87.71%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.25シリカゲル、DCM:MeOH=10:1。LCMS(Agilent):Rt=1.82分、m/z計算[M+H]+=333.1、実測[M+H]+=333.1。1H-NMR(400MHz、DMSO-d6) δ 11.79(s、0.45H)、10.78(s、0.40H)、10.51(d、J=7.6Hz、1H)、8.02-7.99(m、2H)、7.86-7.93(m、2H)、7.63-7.55(m、4H)、4.45-4.24(m、3H)、3.50-3.44(m、1H)、3.40-3.33(m、0.52H)、3.27-3.09(m、2H)、2.98-2.93(m、0.50H)、2.33-2.23(m、0.44H)、2.07-1.81(m、1.61H)。
N-(4-((4-アセチルピペラジン-1-イル)メチル)フェニル)-4-クロロベンズアミド(14)の合成
無水炭酸カリウム(414mg、2.99mmol)を1ロットでDMF(4mL)中の化合物(B)(340mg、1.0mmol)及び1-(ピペラジン-1-イル)エタン-1-オン(128mg、1.0mmol)の撹拌溶液に室温で加えた。室温で6時間撹拌した後、反応混合物をH2O(20mL)で希釈し、濾過した。得られた固体を2NのHCl(2mL)及びDMSO(2mL)によって溶解し、逆相Biotage(登録商標)クロマトグラフィー(C18カラム、0.1%塩酸を含有する10%~95%のMeCN/H2Oで溶出する)によって精製して、表題化合物(14)(130mg、収率35.0%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.4シリカゲル、DCM:MeOH=10:1。LCMS(Agilent):Rt=0.87分、m/z計算[M+H]+=372.0、実測[M+H]+=372.0。1H-NMR(400MHz、DMSO-d6) δ 11.58(s、1H)、10.55(s、1H)、8.05-7.98(m、2H)、7.87(d、J=8.5Hz、2H)、7.60(t、J=8.8Hz、4H)、4.41(d、J=14.1Hz、1H)、4.27(d、J=4.3Hz、2H)、3.98(d、J=14.4Hz、1H)、3.59(t、J=13.3Hz、1H)、3.28(d、J=12.1Hz、2H)、3.06(dt、J=20.9、12.0Hz、2H)、2.87(d、J=11.6Hz、1H)、2.03(s、3H)。
4-クロロ-N-(4-((3-オキソピペラジン-1-イル)メチル)フェニル)ベンズアミド(15)の合成
無水炭酸カリウム(414mg、2.88mmol)を1ロットでDMF(4mL)中の化合物(B)(280mg、1.0mmol)及びピペラジン-2-オン(100mg、1.0mmol)の撹拌溶液に室温で添加した。室温で6時間撹拌した後、反応混合物をH2O(20mL)で希釈し、濾過した。得られた固体を2NのHCl(2mL)及びDMSO(2mL)を用いて溶解し、その後Biotage(登録商標)逆相カラムクロマトグラフィー(C18カラム、0.1%塩酸を含有する10%~95%のMeCN/H2Oで溶出する)によって精製して、表題化合物(15)(108mg、収率31.5%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.3シリカゲル、PE:EtOAc=1:1。LCMS(Agilent):Rt=0.85分、m/z計算[M+H]+=344.1、実測[M+H]+=344.1。1H-NMR(400MHz、DMSO-d6) δ 11.93(s、1H)、10.55(s、1H)、8.39(s、1H)、8.06-7.98(m、2H)、7.92-7.83(m、2H)、7.61(dd、J=8.4、6.0Hz、4H)、4.34(s、2H)、3.78-3.40(m、5H)、3.19(d、J=21.8Hz、1H)。
4-クロロ-N-(4-((4-メチル-3-オキソピペラジン-1-イル)メチル)フェニル)ベンズアミド(16)の合成
無水カリウム(296mg、2.14mmol)を、1ロットでDMF(5mL)中の化合物(B)(300mg、1.07mmol)及び1-メチルピペラジン-2-オン(146mg、1.28mmol)の撹拌溶液に50℃で添加した。50℃で1時間撹拌した後、反応混合物をH2O(10mL)で希釈し、濾過した。得られた濾過ケーキを小体積のDCMで洗浄し、減圧下で乾燥させて、粗生成物を得た。粗生成物を0.5MのHClによって酸性化し、減圧下で濃縮乾固して、表題化合物(16)(121mg、収率31.6%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.4シリカゲル、DCM:MeOH=20:1。LCMS(Agilent):Rt=1.81分、m/z計算[M+H]+=358.1、実測[M+H]+=358.1。1H-NMR(400MHz、DMSO-d6) δ 10.36(s、1H)、8.01-7.99(m、2H)、7.75(d、J=8.0Hz、2H)、7.62-7.59(m、2H)、7.30-7.28(m、2H)、3.50(s、1H)、3.25(t、J=5.6Hz、2H)、2.94(s、2H)、2.81(s、3H)、2.83-2.62(m、2H)。
4-クロロ-N-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)ベンズアミド(17)の合成
無水炭酸カリウム(290mg、2.1mmol)を1ロットでDMF(4mL)中の化合物(B)(200mg、0.7mmol)及び1-メチルピペラジン(74mg、0.7mmol)の撹拌溶液に室温で加えた。室温で3時間撹拌した後、反応混合物をH2O(10mL)で希釈し、濾過した。得られた濾過ケーキをC18逆相分取HPLC(0.1%塩酸を含有する10%~95%MeCN/H2Oで溶出する)によって精製して、表題化合物(17)(110mg、収率43.4%)を白色の固体として得た。構造は、LCMS及び1H-NMRによって確認した。TLC:Rf=0.3シリカゲル、MeOH:DCM=1:15。LCMS(Agilent):Rt=0.83分、m/z計算[M+H]+=344.1、実測[M+H]+=344.1。1H-NMR(400MHz、DMSO-d6) δ 10.39(s、1H)、8.03-7.95(m、2H)、7.80(d、J=8.5Hz、2H)、7.66-7.56(m、2H)、7.38(d、J=8.3Hz、2H)、5.75(s、2H)、3.91(s、2H)、3.29(d、J=97.6Hz、6H)、2.80(s、3H)。
p38 MAPKタンパク質の発現及び精製
ヒトp38α及びβ MAPキナーゼアイソフォームは、E.coliにおいて発現され、Shah et al.,Journal of Immunology,2017,198,3296-3306に記載されるプロトコルを使用して精製されるであろう。
示差走査蛍光測定(DSF)アッセイ
式(1)の特定の化合物のp38α MAPK及びp38β MAPKアイソフォームへの結合を、試験化合物との相互作用に起因する標的タンパク質融解温度(ΔTm)の変化を評価する、示差走査蛍光測定(DSF)を使用して評価した。10mMのHEPES、150mMのNaCl(pH7.5)、及び1μMの非リン酸化組換えヒトp38α中で1:1000に希釈したSYPROオレンジ(Thermo Fischer Scientific)を、96ウェルPCRプレートに添加した。100%DMSO(2%最終DMSO濃度)に溶解した試験化合物(50nm~200nM)を添加し、プレートを混合し、封止し、1,000rpmで1分間遠心分離し、Applied Biosystems StepOne(商標)リアルタイムPCR機器を使用して融解曲線を決定した。融点は、第1の誘導曲線から決定される。
表面プラズモン共鳴(SPR)アッセイ
DSFアッセイにおいてp38αについて選択性を示した化合物を、Biacore T200機器を使用してSPRによって結合親和性について試験した。p38α又はp38βに対する結合親和性(KD)を、様々な用量の試験化合物(例えば、1、3、10、30、100μM)で生成された会合及び解離曲線から決定した。対照を使用して、ATP競合性p38阻害剤の結合を確認した。各実験を3回繰り返す。
血漿安定性アッセイ
ヒト、マウス、ラット、及びサル血漿(デフォルトではK2 EDTA)をBioreclamationから得た。10μMの各試験化合物を、血漿の存在下で37℃でインキュベートした。0、30、60、及び240分で、試料を有機溶媒でクエンチし、ボルテックスし、遠心分離した。上清を、Shimadzu LC-20AD LCポンプシステムに結合された、AB Sciex API 4000(商標)機器を使用して、LC/MS/MS分析のために新鮮なプレートに移した。分析試料を、Waters Atlantis T3 C18逆相HPLCカラム(20mm×2.1mm)を0.5mL/分の流量で使用して分離した。移動相は、水中0.1%ギ酸(溶媒A)及び100%アセトニトリル中0.1%ギ酸(溶媒B)を含んだ。
SARS-CoVID-19抗ウイルス有効性
A549-ACE2細胞を、10%FBSで補足されたDMEM中で培養し、37℃、5%CO2で維持した。HEK293T-ACE2細胞(ATCC、CRL-3216)を、10%FB(ピーク血清)及びペニシリン/ストレプトマイシン(Corning)で補足されたDMEM(Corning)中、37℃、及び5%CO2で維持した。hACE2異所的発現細胞を、ヒトACE2を発現するレンチウイルスベクターで形質導入することによって生成した。hACE2表面発現を有するピューロマイシン耐性細胞を、Alexa Fluor(登録商標)647コンジュゲートヤギ抗hACE2抗体で染色した後に選別した。次いで、細胞を単一細胞クローニングし、SARS-CoV-2複製を支持するそれらの能力についてスクリーニングした。この試験で使用される全ての細胞株を、Universal Detection Kit(ATCC、30-1012K)を使用してマイコプラズマ汚染について定期的にスクリーニングした。
また、本発明には以下の好ましい実施形態が含まれる。
[1]式(1)の構造を有する化合物、
又はその薬学的に許容される塩であって、式中、
R 1 が、C 1-4 アルカンジイル、C 1-4 ヘテロアルカンジイル、置換C 1-4 アルカンジイル、及び置換C 1-4 ヘテロアルカンジイルから選択され、
R 2 が、式(2a)の部分、式(2b)の部分、式(2c)の部分、C 8-16 ヘテロビシクロアルキル、及び置換C 8-16 ヘテロビシクロアルキルから選択され、
式中、
B 1 、B 2 、B 3 、及びB 4 の各々が、独立して、-(CH(-R 4 )) n -から選択され、式中、
各nが、独立して、0、1、2、3、及び4から選択され、
B 1 及びB 2 の両方が、0ではなく、
B 3 及びB 4 の両方が、0ではなく、
各R 4 が、独立して、水素、-OH、-NH 2 、-NO 2 、C 1-3 アルキル、C 1-3 ヘテロアルキル、置換C 1-3 アルキル、及び置換C 1-3 ヘテロアルキルから選択され、
Dが、メタン-ジイル及びエタン-ジイルから選択され、
Xが、-O-、-CH(-OH)-、-NR 3 -、及び-SO 2 -から選択され、R 3 が、水素、C 1-6 アルキル、C 1-6 シクロアルキル、C 6 アリール、C 1-6 ヘテロアルキル、C 1-6 ヘテロシクロアルキル、C 5-6 ヘテロアリール、置換C 1-6 アルキル、置換C 1-6 シクロアルキル、置換C 6 アリール、置換C 1-6 ヘテロアルキル、置換C 1-6 ヘテロシクロアルキル、及び置換C 5-6 ヘテロアリールから選択される、化合物、又はその薬学的に許容される塩。
[2]R 1 が、C 1-4 アルカンジイルであり、
R 2 が、式(2a.1)~(2a.4)及び(2d.1)~(2d.5)のいずれか1つの置換又は非置換部分から選択され、
式中、
R 5 が、水素(非置換)、-OH、-NH 2 、-NR 2 から選択され、各Rが、独立して、水素及びC 1-3 アルキル、-NO 2 、=O、C 1-3 アルコキシ、及びC(=O)-Rから選択され、式中、Rが、C 1-3 アルキルであり、
R 6 が、C 1-6 アルキル及びC 1-6 アルコキシから選択される、[1]に記載の化合物。
[3]R 1 が、メタン-ジイル、エタン-ジイル、及びn-プロパン-ジイルから選択される、[2]に記載の化合物。
[4][2]に記載の化合物であり、R 1 が、メタン-ジイルである、[2]に記載の化合物。
[5]R 2 が、式(2a.1)~(2a.4)及び(2d.1)~(2d.5)のいずれか1つの非置換部分から選択される、[2]に記載の化合物。
[6]R 2 が、式(2a.1)~(2a.4)及び(2d.1)~(2d.5)のいずれか1つの置換部分から選択される、[2]に記載の化合物。
[7]前記置換部分が、式(2a.1)~(2a.4)及び(2d.1)~(2d.5)のいずれか1つの構造を有し得、
式中、
R 5 が、-OH、-NH 2 、-NR 2 から選択され、各Rが、独立して、水素及びC 1-3 アルキル、-NO 2 、=O、C 1-3 アルコキシ、及びC(=O)-Rから選択され、式中、Rが、C 1-3 アルキルであり、
R 6 が、C 1-6 アルキル及びC 1-6 アルコキシから選択される、[2]に記載の化合物。
[8]B 1 が、-(CH 2 ) 2 -であり、B 2 が、-CH 2 -であり、B 3 が、-(CH 2 ) n -であり、nが、0、1、2、及び3から選択され、B 3 が、-(CH 2 ) 3n -であり、Xが、Oである、[2]に記載の化合物。
[9]式(2a)の前記部分が、式(2a.1)~(2a.4)の部分から選択され、
式中、R 5 が、水素(非置換)、-OH、-NH 2 、-NR 2 から選択され、各Rが、独立して、水素及びC 1-3 アルキル、-NO 2 、=O、C 1-3 アルコキシ、及びC(=O)-Rから選択され、式中、Rが、C 1-3 アルキルである、[2]に記載の化合物。
[10]A 1 が、-(CH 2 ) n -であり、nが、1~4の整数であり、A 2 が、-(CH 2 ) 5-n -であり、Xが、Oである、[2]に記載の化合物。
[11]式(2d)の前記部分が、式(2d.1)又は式(2d.2)の構造を有し、
式中、R 5 が、水素(非置換)、-OH、-NH 2 、-NR 2 から選択され、各Rが、独立して、水素及びC 1-3 アルキル、-NO 2 、=O、C 1-3 アルコキシ、及びC(=O)-Rから選択され、式中、Rが、C 1-3 アルキルである、[2]に記載の化合物。
[12]A 1 が、-(CH 2 ) n -であり、nが、1又は2であり、A 2 が、-(CH 2 ) 3-n -であり、Xが、-N(-C(=O)-R 6 )-であり、R 6 が、C 1-4 アルキル及びC 1-4 アルコキシから選択される、[2]に記載の化合物。
[13]式(2d)の前記部分が、式(2d.3)及び式(2d.4)の部分から選択され、
式中、
R 5 が、水素(非置換)、-OH、-NH 2 、-NR 2 から選択され、各Rが、独立して、水素及びC 1-3 アルキル、-NO 2 、=O、C 1-3 アルコキシ、及びC(=O)-Rから選択され、式中、Rが、C 1-3 アルキルであり、
R 6 が、C 1-6 アルキル及びC 1-6 アルコキシから選択される、[2]に記載の化合物。
[14]A 1 が、-(CH 2 ) n -であり、nが、1又は2であり、A 2 が、-(CH 2 ) 3-n -であり、Xが、Oであり、かつ1つ又は2つの-CH 3 置換基を含む、[2]に記載の化合物。
[15]式(2d)の前記部分が、式(2d.5)の構造を有し得る、[2]に記載の化合物。
[16]前記化合物が、
N-(4-((2-オキサ-6-アザスピロ[3.3]ヘプタン-6-イル)メチル)フェニル)-4-クロロベンズアミド(3)、
N-(4-((7-オキサ-2-アザスピロ[3.5]ノナン-2-イル)メチル)フェニル)-4-クロロベンズアミド(4)、
N-(4-((8-オキサ-2-アザスピロ[4.5]デカン-2-イル)メチル)フェニル)-4-クロロベンズアミド(5)、
N-(4-((1-オキサ-7-アザスピロ[4.4]ノナン-7-イル)メチル)フェニル)-4-クロロベンズアミド(6)、
N-(4-(((1R,5S)-3-オキサ-7-アザビシクロ[3.3.1]ノナン-7-イル)メチル)フェニル)-4-クロロベンズアミド(9)、及び
4-クロロ-N-(4-(((3aR,6aS)-テトラヒドロ-1H-フロ[3,4-c]ピロール-5(3H)-イル)メチル)フェニル)ベンズアミド(10)、
又は前述のいずれかの薬学的に許容される塩から選択される、[2]に記載の化合物。
[17]前記化合物が、
2-クロロ-N-(4-(モルホリノメチル)フェニル)ピリミジン-5-カルボキサミド(1)、
N-(4-((1,4-オキサゼパン-4-イル)メチル)フェニル)-4-クロロベンズアミド(2)、
4-クロロ-N-(4-(((2S,6R)-2,6-ジメチルモルホリノ)メチル)フェニル)ベンズアミド(7)、
4-クロロ-N-(4-(((2S,6S)-2,6-ジメチルモルホリノ)メチル)フェニル)ベンズアミド(8)、
4-クロロ-N-(4-((4-ヒドロキシピペリジン-1-イル)メチル)フェニル)ベンズアミド(10)、
4-クロロ-N-(4-((3-ヒドロキシピペリジン-1-イル)メチル)フェニル)ベンズアミド(11)、
4-クロロ-N-(4-((3-ヒドロキシシクロペンチル)メチル)フェニル)ベンズアミド(12)、
4-クロロ-N-(4-((3-ヒドロキシピロリジン-1-イル)メチル)フェニル)ベンズアミド(13)、
4-クロロ-N-(4-((3-オキソピペラジン-1-イル)メチル)フェニル)ベンズアミド(14)、
4-クロロ-N-(4-((4-メチル-3-オキソピペラジン-1-イル)メチル)フェニル)ベンズアミド(15)、及び
4-クロロ-N-(4-((4-メチルピペラジン-1-イル)メチル)フェニル)ベンズアミド(16)、
又は前述のいずれかの薬学的に許容される塩から選択される、[2]に記載の化合物。
[18]前記化合物が、前記p38α MAPK受容体を阻害する、[1]~[17]のいずれかに記載の化合物。
[19]前記化合物が、前記p38α MAPK受容体を選択的に阻害する、[1]~[17]のいずれかに記載の化合物。
[20]前記化合物が、前記p38β MAPKサブユニットに対してよりも前記p38α MAPKサブユニットに対してより高い結合親和性を有する、[1]~[17]のいずれかに記載の化合物。
[21]前記化合物が、p38α MAPKの選択的結合部位に結合し、前記結合ポケットが、ポケットによって定義され、少なくともp38α MAPKの残基R49、Hl07、Ll08、及びKl65によって定義される、[1]~[17]のいずれかに記載の化合物。
[22][1]~[21]のいずれかに記載の化合物又はその薬学的に許容される塩を含む、薬学的組成物。
[23]前記薬学的組成物が、患者において疾患を治療するための治療有効量の[1]~[22]のいずれかに記載の化合物又はその薬学的に許容される塩を含む、[22]に記載の薬学的組成物。
[24]前記疾患が、がん、炎症性疾患、及び自己免疫疾患、並びにウイルス性疾患から選択される、[23]に記載の薬学的組成物。
[25]前記疾患が、急性肺損傷、急性呼吸窮迫症候群(ARDS)、慢性閉塞性肺疾患(COPD)、筋萎縮性側索硬化症、及び嚢胞性線維症から選択される、[23]に記載の薬学的組成物。
[26]患者において疾患を治療する方法であって、その治療を必要とする患者に、治療有効量の[1]~[21]のいずれかに記載の化合物若しくはその薬学的に許容される塩、又は[22]及び[23]のいずれかに記載の薬学的組成物を投与することを含み、前記疾患が、がん、炎症性疾患、及び自己免疫疾患、並びにウイルス性疾患から選択される、方法。
Claims (12)
- N-(4-((1,4-オキサゼパン-4-イル)メチル)フェニル)-4-クロロベンズアミド(1)、
N-(4-((2-オキサ-6-アザスピロ[3.3]ヘプタン-6-イル)メチル)フェニル)-4-クロロベンズアミド(2)、
2-クロロ-N-(4-(モルホリノメチル)フェニル)ピリミジン-5-カルボキサミド(3)、
N-(4-((7-オキサ-2-アザスピロ[3.5]ノナン-2-イル)メチル)フェニル)-4-クロロベンズアミド(4)、
N-(4-((8-オキサ-2-アザスピロ[4.5]デカン-2-イル)メチル)フェニル)-4-クロロベンズアミド(5)、
N-(4-((1-オキサ-7-アザスピロ[4.4]ノナン-7-イル)メチル)フェニル)-4-クロロベンズアミド(6)、
4-クロロ-N-(4-(((2S,6R)-2,6-ジメチルモルホリノ)メチル)フェニル)ベンズアミド(7)、
4-クロロ-N-(4-(((2S,6S)-2,6-ジメチルモルホリノ)メチル)フェニル)ベンズアミド(8)、
N-(4-(((1R,5S)-3-オキサ-7-アザビシクロ[3.3.1]ノナン-7-イル)メチル)フェニル)-4-クロロベンズアミド(9)、
4-クロロ-N-(4-(((3aR,6aS)-テトラヒドロ-1H-フロ[3,4-c]ピロール-5(3H)-イル)メチル)フェニル)ベンズアミド(10)、
4-クロロ-N-(4-((3-ヒドロキシピペリジン-1-イル)メチル)フェニル)ベンズアミド(12)、
4-クロロ-N-(4-((3-ヒドロキシピロリジン-1-イル)メチル)フェニル)ベンズアミド(13)、
N-(4-((4-アセチルピペラジン-1-イル)メチル)フェニル)-4-クロロベンズアミド(14)、
4-クロロ-N-(4-((3-オキソピペラジン-1-イル)メチル)フェニル)ベンズアミド(15)、及び
4-クロロ-N-(4-((4-メチル-3-オキソピペラジン-1-イル)メチル)フェニル)ベンズアミド(16)
からなる群から選択される化合物、
又は前述のいずれかの薬学的に許容される塩。 - N-(4-((1,4-オキサゼパン-4-イル)メチル)フェニル)-4-クロロベンズアミド(1)、
N-(4-((1-オキサ-7-アザスピロ[4.4]ノナン-7-イル)メチル)フェニル)-4-クロロベンズアミド(6)、
4-クロロ-N-(4-(((2S,6S)-2,6-ジメチルモルホリノ)メチル)フェニル)ベンズアミド(8)、及び
N-(4-((4-アセチルピペラジン-1-イル)メチル)フェニル)-4-クロロベンズアミド(14)
からなる群から選択される化合物、又は前述のいずれかの薬学的に許容される塩である、
請求項1に記載の化合物。 - N-(4-((1,4-オキサゼパン-4-イル)メチル)フェニル)-4-クロロベンズアミド(1)、
N-(4-((2-オキサ-6-アザスピロ[3.3]ヘプタン-6-イル)メチル)フェニル)-4-クロロベンズアミド(2)、
2-クロロ-N-(4-(モルホリノメチル)フェニル)ピリミジン-5-カルボキサミド(3)、
N-(4-((7-オキサ-2-アザスピロ[3.5]ノナン-2-イル)メチル)フェニル)-4-クロロベンズアミド(4)、
N-(4-((1-オキサ-7-アザスピロ[4.4]ノナン-7-イル)メチル)フェニル)-4-クロロベンズアミド(6)、
4-クロロ-N-(4-(((2S,6S)-2,6-ジメチルモルホリノ)メチル)フェニル)ベンズアミド(8)、
4-クロロ-N-(4-(((3aR,6aS)-テトラヒドロ-1H-フロ[3,4-c]ピロール-5(3H)-イル)メチル)フェニル)ベンズアミド(10)、及び
4-クロロ-N-(4-((3-ヒドロキシピロリジン-1-イル)メチル)フェニル)ベンズアミド(13)
からなる群から選択される化合物、又は前述のいずれかの薬学的に許容される塩である、
請求項1に記載の化合物。 - 4-クロロ-N-(4-((3-ヒドロキシピペリジン-1-イル)メチル)フェニル)ベンズアミド(12)、及び
4-クロロ-N-(4-((3-ヒドロキシピロリジン-1-イル)メチル)フェニル)ベンズアミド(13)
からなる群から選択される化合物、又は前述のいずれかの薬学的に許容される塩である、
請求項1に記載の化合物。 - N-(4-((2-オキサ-6-アザスピロ[3.3]ヘプタン-6-イル)メチル)フェニル)-4-クロロベンズアミド(2)、又はその薬学的に許容される塩である、請求項1に記載の化合物。
- 請求項1~5のいずれか一項に記載の化合物又はその薬学的に許容される塩を含む、薬学的組成物。
- 前記薬学的組成物が治療有効量の請求項1~5のいずれか一項に記載の化合物又はその薬学的に許容される塩を含む、がん、炎症性疾患、自己免疫疾患、又はウイルス性疾患を治療するための、請求項6に記載の薬学的組成物。
- 前記ウイルス性疾患が、MERS-CoV感染症、SARS-CoV感染症、及びSARS-CoV-2感染症を含むコロナウイルス感染症、コロナウイルス感染症に関連する肺炎、並びにヒト呼吸器症候群感染症からなる群から選択され、
前記がんが、乳がん及び黒色腫からなる群から選択され、並びに
前記炎症性疾患が、急性呼吸窮迫症候群、巣状分節性糸球体腎炎、アテローム性動脈硬化症/急性冠動脈症候群、慢性閉塞性肺疾患、喘息、炎症性腸疾患、クローン病、乾癬、狼瘡、多発性硬化症、高コレステロール血症における炎症、疼痛、糖尿病、及びリウマチ性関節炎からなる群から選択される、請求項7に記載の薬学的組成物。 - 前記薬学的組成物が治療有効量の請求項1~5のいずれか一項に記載の化合物又はその薬学的に許容される塩を含む、急性肺損傷、急性呼吸窮迫症候群(ARDS)、慢性閉塞性肺疾患(COPD)、筋萎縮性側索硬化症、又は嚢胞性線維症を治療するための、請求項6に記載の薬学的組成物。
- がん、炎症性疾患、自己免疫疾患、又はウイルス性疾患を治療するための医薬の製造における、請求項1~5のいずれか一項に記載の化合物又はその薬学的に許容される塩の使用。
- 前記ウイルス性疾患が、MERS-CoV感染症、SARS-CoV感染症、及びSARS-CoV-2感染症を含むコロナウイルス感染症、コロナウイルス感染症に関連する肺炎、並びにヒト呼吸器症候群感染症からなる群から選択され、
前記がんが、乳がん及び黒色腫からなる群から選択され、並びに
前記炎症性疾患が、急性呼吸窮迫症候群、巣状分節性糸球体腎炎、アテローム性動脈硬化症/急性冠動脈症候群、慢性閉塞性肺疾患、喘息、炎症性腸疾患、クローン病、乾癬、狼瘡、多発性硬化症、高コレステロール血症における炎症、疼痛、糖尿病、及びリウマチ性関節炎からなる群から選択される、請求項10に記載の使用。 - 急性肺損傷、急性呼吸窮迫症候群(ARDS)、慢性閉塞性肺疾患(COPD)、筋萎縮性側索硬化症、又は嚢胞性線維症を治療するための医薬の製造における、請求項1~5のいずれか一項に記載の化合物又はその薬学的に許容される塩の使用。
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