JP2022521964A - 新型汎rafキナーゼ阻害剤及びその使用 - Google Patents
新型汎rafキナーゼ阻害剤及びその使用 Download PDFInfo
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Classifications
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Abstract
Description
Xは、
Y及びZの一方は炭素であり、他方は窒素であり、好ましくは、Yは窒素であり、Zは炭素であり、
A環は、
好ましくは、Aは、
R1、R2及びR3は、それぞれ独立してH、シアノ、C1~6アルキル、C1~6アルコキシ、C1~6ヒドロキシアルキル、C1~6ヒドロキシアルコキシ、C3~6シクロアルキルC1~6アルコキシ、C1~6アルコキシC1~6アルコキシ、フェニル、ピリジル、フェニルC1~6アルコキシ、フリルC1~6アルコキシ、R6で任意に置換されたヘテロシクロアルキル、R6で任意に置換されたヘテロシクロアルキルフェニル、R6で任意に置換されたヘテロシクロアルキルカルボニル、R6で任意に置換されたヘテロシクロアルキルオキシ、R6で任意に置換されたヘテロシクロアルキルC1~6アルコキシ、R6で任意に置換されたヘテロシクロアルキルC1~6アルカノイルアミノ、C3~6シクロアルキルC1~6アルカノイルアミノ、及びC1~6アルキルアミノカルボニルC1~6アルコキシからなる群から選択されるか、又はR1はR3と共に、
ここで、R1、R2及びR3は同時にHではなく、
R4及びR5は、それぞれ独立してH、C1~6アルキル、C1~6ハロアルキル、C1~6シアノアルキル、R6で任意に置換されたヘテロシクロアルキルC1~6アルキル、R6で任意に置換されたフェニル、R6で任意に置換されたヘテロアリール、及びアミノスルホニルから選択されるか、又はR4はR5と共に、
R6は、独立してオキソ、C1~6アルキル、C2~6アルカノイル、C1~6アルキルスルホニル、C1~6アルキルアミノC2~6アルカノイル、及びC1~6ハロアルキルからなる群から選択される)の化合物、又はその薬学的に許容可能な塩、溶媒和物、エステル、酸、代謝物若しくはプロドラッグを含む、選択的キナーゼ阻害剤を提供する。
R1は、H、ピリジル、ヘテロシクロアルキル、C1~6アルキルで任意に置換されたヘテロシクロアルキルフェニル、ヘテロシクロアルキルオキシ、ヘテロシクロアルキルC1~6アルコキシ、及びC1~6アルキルアミノカルボニルC1~6アルコキシからなる群から選択され、
R2は、H、C1~6アルキル、C1~6ヒドロキシアルコキシ、C1~6アルコキシC1~6アルコキシ、ヘテロシクロアルキルオキシ、及びヘテロシクロアルキルC1~6アルコキシからなる群から選択され、
R3は、H、及びC3~6シクロアルキルC1~6アルカノイルアミノからなる群から選択され、
ここで、R1、R2及びR3は同時にHではなく、
R4は、C1~6ハロアルキル及びC1~6シアノアルキルからなる群から選択され、
R5は、H、C1~6アルキル、及びC1~6アルキルで任意に置換されたヘテロシクロアルキルC1~6アルキルからなる群から選択される。
Xは、
Y及びZの一方は炭素であり、他方は窒素あり、
A環は、
R4及びR5は、それぞれ独立してH、C1~6アルキル、C1~6ハロアルキル、C1~6シアノアルキル、R6で任意に置換されたピペラジニルC1~6アルキル、R6で任意に置換されたフェニル、R6で任意に置換されたイミダゾリル、R6で任意に置換されたチエニル、R6で任意に置換されたピリジル、及びアミノスルホニルからなる群から選択されるか、又はR4はR5と共に、
R6は、独立してC1~6アルキル及びC1~6ハロアルキルからなる群から選択される)の化合物、又はその薬学的に許容可能な塩、溶媒和物、エステル、酸、代謝物若しくはプロドラッグを含む、選択的汎RAFキナーゼ阻害剤が提供される。
特段の規定がない限り、本明細書において使用される全ての技術用語及び科学用語は、特許請求の範囲に記載の主題が属する技術分野における当業者によって通常理解されるのと同じ意味を有する。
本発明は、式(I):
Xは、
Y及びZの一方は炭素であり、他方は窒素あり、
A環は、
R1、R2及びR3は、それぞれ独立してH、シアノ、C1~6アルキル、C1~6アルコキシ、C1~6ヒドロキシアルキル、C1~6ヒドロキシアルコキシ、C3~6シクロアルキルC1~6アルコキシ、C1~6アルコキシC1~6アルコキシ、フェニル、ピリジル、フェニルC1~6アルコキシ、フリルC1~6アルコキシ、R6で任意に置換されたヘテロシクロアルキル、R6で任意に置換されたヘテロシクロアルキルフェニル、R6で任意に置換されたヘテロシクロアルキルカルボニル、R6で任意に置換されたヘテロシクロアルキルオキシ、R6で任意に置換されたヘテロシクロアルキルC1~6アルコキシ、R6で任意に置換されたヘテロシクロアルキルC1~6アルカノイルアミノ、C3~6シクロアルキルC1~6アルカノイルアミノ、及びC1~6アルキルアミノカルボニルC1~6アルコキシからなる群から選択されるか、又はR1はR3と共に、
R4及びR5は、それぞれ独立してH、C1~6アルキル、C1~6ハロアルキル、C1~6シアノアルキル、R6で任意に置換されたヘテロシクロアルキルC1~6アルキル、R6で任意に置換されたフェニル、R6で任意に置換されたヘテロアリール、及びアミノスルホニルからなる群から選択されるか、又はR4はR5と共に、
R6は、独立してオキソ(=O)、C1~6アルキル、C2~6アルカノイル、C1~6アルキルスルホニル、C1~6アルキルアミノC2~6アルカノイル、及びC1~6ハロアルキルからなる群から選択される)の化合物、又は薬学的に許容可能な塩、溶媒和物、エステル、酸、代謝物若しくはプロドラッグを含む、選択的汎RAFキナーゼ阻害剤を提供する。
R1は、H、ピリジル(3-ピリジル、4-ピリジル等)、ヘテロシクロアルキル(N-モルホリニル、ピペラジン-1-イル等)、C1~6アルキルで任意に置換されたヘテロシクロアルキルフェニル(4-メチル-ピペラジン-イルフェニル等)、ヘテロシクロアルキルオキシ(テトラヒドロピラン-4-イルオキシ、オキセタン-3-イルオキシ等)、ヘテロシクロアルキルC1~6アルコキシ(2-モルホリノエトキシ、3-モルホリノプロポキシ、テトラヒドロフラン-3-イルメトキシ等)、及びC1~6アルキルアミノカルボニルC1~6アルコキシ(ジメチルアミノカルボニルメトキシ等)からなる群から選択され、
R2は、H、C1~6アルキル(メチル等)、C1~6ヒドロキシアルコキシ(2-ヒドロキシエトキシ、3-ヒドロキシプロポキシ、4-ヒドロキシブトキシ等)、C1~6アルコキシC1~6アルコキシ(2-メトキシエトキシ等)、ヘテロシクロアルキルオキシ(テトラヒドロピラン-4-イルオキシ、テトラヒドロフラン-3-イルオキシ、オキセタン-3-イルオキシ、アゼチジン-3-イルオキシ等)、及びヘテロシクロアルキルC1~6アルコキシ(2-モルホリノエトキシ、テトラヒドロフラン-2-イルメトキシ、テトラヒドロフラン-3-イルメトキシ、テトラヒドロピラン-4-イルメトキシ、オキセタン-3-イルメトキシ、ピロリジン-3-イルメトキシ等)からなる群から選択され、
R3は、H、及びC3~6シクロアルキルC1~6アルカノイルアミノ(シクロプロピルホルミルアミノ等)からなる群から選択され、
ここで、R1、R2、及びR3は同時にHではなく、
R4は、C1~6ハロアルキル(トリフルオロメチル等)、及びC1~6シアノアルキル(2-シアノ-エト-2-イル)、2-シアノ-プロプ-2-イル等)からなる群から選択され、
R5は、H、C1~6アルキル(メチル等)、及びC1~6アルキルで任意に置換されたヘテロシクロアルキルC1~6アルキル(4-メチル-ピペラジン-1-イルメチル等)からなる群から選択される。
Xは、
Y及びZの一方は炭素であり、他方は窒素あり、
A環は、
R4及びR5は、それぞれ独立してH、C1~6アルキル(メチル、エチル、n-プロピル、イソプロピル、n-ブチル、tert-ブチル等)、C1~6ハロアルキル(トリフルオロメチル等)、C1~6シアノアルキル(2-シアノ-エト-2-イル、2-シアノ-プロプ-2-イル等)、R6で任意に置換されたピペラジニルC1~6アルキル(ピペラジン-1-イルメチル等)、R6で任意に置換されたフェニル、R6で任意に置換されたイミダゾリル、R6で任意に置換されたチエニル、R6で任意に置換されたピリジル、及びアミノスルホニルからなる群から選択されるか、又はR4はR5と共に、
R6は、独立してC1~6アルキル(メチル、エチル、n-プロピル、イソプロピル、n-ブチル、tert-ブチル等)及びC1~6ハロアルキル(トリフルオロメチル等)からなる群から選択される)の化合物、又はその薬学的に許容可能な塩、溶媒和物、エステル、酸、代謝物若しくはプロドラッグを含む、選択的汎RAFキナーゼ阻害剤が提供される。
本出願はまた、少なくとも1つの式(I)若しくは式(Ia)の化合物、又は該化合物の薬学的に許容可能な塩、溶媒和物、エステル、酸、薬学的に活性な代謝物若しくはプロドラッグと、薬学的に許容可能な担体又は賦形剤と、任意に他の治療剤とを含む医薬組成物を提供する。
本発明の化合物(その薬学的に許容可能な塩、溶媒和物、エステル、酸、代謝物又はプロドラッグを含む)、又は医薬組成物は、チロシンキナーゼRAF(野生型若しくは様々な変異体、又はそれらの組合せ)及び/又はRAS(野生型若しくは様々な変異体、又はそれらの組合せ)の活性を阻害するために使用され得る。本発明の化合物、又はその薬学的に許容可能な塩、溶媒和物、エステル、酸、代謝物若しくはプロドラッグ、又は医薬組成物は、固形腫瘍(良性又は特に悪性のタイプを含む)、特に肉腫、消化管間質腫瘍(GIST)、結腸直腸癌、急性骨髄芽球性白血病(AML)、慢性骨髄性白血病(CML)、新生物、甲状腺癌、全身性肥満細胞症、好酸球増多症候群、線維症、エリテマトーデス、移植片対宿主病、神経線維腫症、肺高血圧症、アルツハイマー病、精上皮腫、未分化胚細胞腫、肥満細胞腫、肺癌、気管支癌、精巣上皮内腫瘍、黒色腫、乳癌、神経芽細胞腫、甲状腺乳頭癌/甲状腺濾胞癌、悪性リンパ腫、非ホジキンリンパ腫、多発性内分泌腫瘍症2型、褐色細胞腫、甲状腺癌、副甲状腺過形成/副甲状腺腫、結腸癌、結腸直腸腺腫、卵巣癌、前立腺癌、神経膠芽細胞腫、脳腫瘍、悪性神経膠腫、膵臓癌、悪性胸膜内皮腫、血管芽細胞腫、血管腫、腎臓癌、肝臓癌、副腎癌、膀胱癌、胃癌、直腸癌、膣癌、子宮頸癌、子宮内膜癌、多発性骨髄腫、頭頸部腫瘍、並びに他の増殖性の疾病等、又はそれらの組合せからなる群から選択される1つ以上の疾患の治療、予防又は改善のために使用され得る。頭頸部癌、甲状腺癌、黒色腫、結腸直腸癌、肺癌、乳癌、膵臓癌、食道癌、肝臓癌、白血病、新生物等、又はそれらの組合せの治療に特に好ましい。
本発明の化合物は、当業者に既知の標準的な合成技術を使用して、又は本明細書に記載される方法と組み合わせて当該技術分野で知られる方法を使用して合成することができる。さらに、本明細書において表記される溶媒、温度及び他の反応条件は当該技術分野における技術により変動し得る。更なる手引きとして、以下の合成方法も利用することができる。
4-ブロモピラゾール(5g、1当量)、2-フルオロ-1-メチル-4-ニトロベンゼン(5.5g、1.05当量)及び炭酸カリウム(13.1、3当量)の化合物をDMF(50ml)中で混合した。混合物を窒素雰囲気中、120℃で一晩撹拌し、次いで冷却して濃縮した。酢酸エチル(200ml)を濃縮物に加えた。その後、得られた混合物を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮し、次いでカラムクロマトグラフィーにより分離して、黄色の生成物a(5.2g)を得た。
化合物a(5g、1当量)、ビス(ピナコラト)ジボロン(5.8g、1.3当量)、酢酸カリウム(3.5g、2当量)、及び[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウムジクロリド(0.72g、0.05当量)を1,4-ジオキサン(50ml)中で混合した。混合物を窒素雰囲気中、100℃で一晩撹拌し、次いで濃縮した。濃縮物をカラムクロマトグラフィーにより分離し、黄色の生成物b(4.0g)を得た。
化合物b(4.0g、1.1当量)、5-ブロモ-3,3’-ビピリジル(2.6g、1当量)、炭酸カリウム(3.0g、2当量)及びテトラキス(トリフェニルホスフィン)パラジウム(0.6g、0.05当量)を、1,4-ジオキサン(40ml)及び水(4ml)中で混合した。混合物を窒素雰囲気中、90℃で一晩撹拌し、次いで濃縮した。濃縮物をカラムクロマトグラフィーにより分離し、黄色の生成物c(2.8g)を得た。
化合物c(2.8g、1当量)及びパラジウム炭素(0.5g)をメタノール(30ml)中で混合した。混合物を水素雰囲気中、室温で2時間撹拌した。その後、ジクロロメタン(100ml)を加えて混合物を希釈した。得られた混合物を濾過し、濃縮して、淡緑色の生成物d(2.1g)を得た。
化合物d(0.05g、1当量)、4-メチル-3-(トリフルオロメチル)安息香酸(0.031g、1当量)、HATU(0.064、1.1当量)、及びジイソプロピルエチルアミン(0.020g、1当量)をDMF(2ml)中で混合した。混合物を室温で0.5時間撹拌した。その後、酢酸エチル(50ml)を加えて混合物を希釈した。該混合物を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮し、HPLCにより分離して、生成物1(0.07g)を得た。正確な質量(計算値):513.17;MS(ESI)m/z(M+1)+:514.17。
5-(tert-ブチル)イソキサゾール-3-アミン(5g、1当量)、DIEPA(5.1g、1.1当量)及びTHF(20ml)を窒素雰囲気中、0℃で混合した。混合物にクロロギ酸フェニル(5.9g、1.05当量)を加えた。この温度で0.5時間反応させた。その後、反応混合物を酢酸エチル(120ml)で希釈し、水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥して、濾過し、濃縮した。得られた固体をn-ヘキサンで洗浄し、濾過して、白色の固体e(7g)を得た。
実施例1に記載されたものと同様の工程を使用することによって、化合物fを合成した。化合物e(0.05g、1当量)、化合物f(0.055g、1当量)及びDMSO(2ml)を混合した。混合物を80℃で4時間撹拌した。その後、酢酸エチル(50ml)を加えた。得られた混合物を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥して、濾過し、濃縮した。濃縮物をHPLCによって分離して、化合物12(0.06g)を得た。正確な質量(計算値):493.22;MS(ESI)m/z(M+1)+:494.22。
2-モルホリノエタノール(3g、1当量)、DIEPA(3.2g、1.1当量)、THF(15ml)を混合した。該混合物にメチルスルホニルクロリド(2.7g、1.1当量)を0℃で滴加した。得られた混合物をその温度で6時間撹拌した。反応液を濃縮し、酢酸エチル(100ml)で溶出し、水及び飽和食塩水で順次洗浄して、無水硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮して、生成物2-モルホリノエチルメタンスルホネート(3.8g、1当量)を得た。生成物を5-ブロモピリド-3-オール(2.8g、0.9当量)、炭酸カリウム(3.7g、2当量)と混合した。混合物をDMF(30ml)中、70℃で5時間撹拌した。その後、得られた混合物を濃縮し、酢酸エチル(150ml)で溶出し、水及び飽和食塩水で順次洗浄して、無水硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮して、生成物4-(2-((5-ブロモピリド-3-イル)オキシ)エチル)モルホリンg(3.2g)を得た。
3-ブロモピリド-4-イルアミン(1.0g、1当量)、テトラヒドロ-2H-ピラン-4-カルボン酸(0.75g、1当量)、HATU(2.4g、1.1当量)、DIPEA(0.75)、及びDMF(5mL)を混合し、室温で0.5時間撹拌した。その後、得られた混合物を酢酸エチル(150mL)で溶出し、水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥して、濾過した。濾液を濃縮して、次の工程で直接使用するための生成物h(1.3g)を得た。
4-ブロモピラゾール(5g、1当量)、2-フルオロ-1-メチル-4-ニトロベンゼン(5.5g、1.05当量)、炭酸カリウム(13.1、3当量)をDMF(50ml)中で混合し、窒素雰囲気中、100℃で一晩撹拌し、次いで冷却して濃縮した。濃縮物に酢酸エチル(200ml)を加えた。得られた混合物を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮し、次いでカラムクロマトグラフィーにより分離して、黄色の生成物i(5.2g)を得た。
化合物i(5g、1当量)、ビス(ピナコラト)ジボロン(5.8g、1.3当量)、酢酸カリウム(3.5g、2当量)、及び[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウムジクロリド(0.72g、0.05当量)を1,4-ジオキサン(50ml)中で混合した。混合物を窒素雰囲気中、100℃で一晩撹拌し、次いで濃縮した。濃縮物をカラムクロマトグラフィーにより分離し、黄色の生成物j(4.0g)を得た。
化合物j(4.0g、1.1当量)、5-ブロモ-1H-ピロロ[2,3-b]ピリジン(2.2g、1当量)、炭酸カリウム(3.0g、2当量)及びテトラキス(トリフェニルホスフィン)パラジウム(0.6g、0.05当量)を1,4-ジオキサン(40ml)及び水(4ml)中で混合した。混合物を窒素雰囲気中90℃で一晩撹拌し、次いで濃縮した。濃縮物をカラムクロマトグラフィーにより分離して、黄色の生成物k(2.8g)を得た。
化合物k(2.8g、1当量)及びパラジウム炭素(0.5g)をメタノール(30ml)中で混合した。混合物を水素雰囲気中、室温で2時間撹拌した。その後、ジクロロメタン(100ml)を加えて混合物を希釈した。得られた混合物を濾過し、濃縮して、淡緑色の生成物l(2.1g)を得た。
化合物l(0.05g、1当量)、3-(4-メチル-1H-イミダゾール-1-イル)-5-(トリフルオロメチル)安息香酸(0.46g、1当量)、HATU(0.072、1.1当量)、及びジイソプロピルエチレンジアミン(0.22g、1当量)をDMF(2ml)中で混合した。混合物を室温で1時間撹拌した。その後、酢酸エチル(50ml)を加えて混合物を希釈した。混合物を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮し、HPLCによって分離して、化合物167(0.07g)を得た。正確な質量(計算値):541.18;MS(ESI)m/z(M+1)+:542.19。
本発明の化合物を、癌細胞の成長に対するそれらの効果について試験し(表2)、癌細胞の増殖に対するそれらの阻害効果及び癌細胞の増殖を阻害する際のそれらの選択性について本明細書の化合物を更に評価した。
BRAF、BRAF V599E及びRAF1(cRAF)Y340の標的部位に対する化合物16及び対照化合物PLX4032(中国のMedChem Express社)の活性を、Invitrogen社(米国カールスバッド)によって試験した。
この実施例では、SDラット(180g~220g、雄性)(中国の安徽医科大学の実験動物センターから購入)を使用した。動物を、1ケージ当たり6匹のラットで、独立して換気されたケージにおいて飼育した。給餌を温度20℃~26℃、湿度35%~75%で行った。光条件は12時間の明期/12時間の暗期であった。トウモロコシの穂軸の寝床を週1回新しくした。ラットには自由に餌及び飲料水を与えた。ラットの尾に数字で印を付けた。実験中、動物の繁殖及び使用は、国際実験動物管理公認協会の規制に厳密に従った。
本実施例では、ヒト変性肺癌細胞Calu-6(KRAS Q61K変異キナーゼを発現、中国南京市のCobioer Biosciences Co., Ltd.社から購入)、黒色腫細胞A375(BRAF-V600E変異キナーゼを発現、中国南京市のCobioer Biosciences Co., Ltd.社から購入)、膵臓癌細胞BxPC3(KRAS野生型、BRAF V487-P492>A欠失変異キナーゼを発現、中国南京市のCobioer Biosciences Co., Ltd.社から購入)、結腸直腸癌細胞HCT116(KRAS G13D変異キナーゼを発現、米国のATCC社から購入)、結腸直腸癌細胞COLO205(BRAF-V600E変異キナーゼを発現、米国のATCC社から購入)のマウスモデルにおける、化合物16、比較化合物1、及び対照化合物LY30019120(中国のMedChemExpress社から購入)、PLX4032(中国のMedChemExpress社から購入)、RAF709(中国のMedChemExpress社から購入)、RAF265(中国のMedChemExpress社から購入)、及びPLX8394(中国のMedChemExpress社から購入)の実験結果を、それぞれ試験した。
(1)Beijing Vital River Laboratory Animal Technology Co., Ltd.社から購入した4週齢~6週齢の雌性SCIDマウス(A375/COLO205)及びヌードマウス(HCT116/Calu-6/BxPC3)を実験室においてSPFレベルで飼育した。飲料水及び寝床はオートクレーブ滅菌されていた。マウスに対する全ての手術を無菌条件下で行った。
(2)0日目に、約5×106個の非小細胞肺癌Calu-6細胞、結腸直腸癌HCT116細胞、結腸直腸癌COLO205細胞、黒色腫A375細胞及び膵臓癌BxPC3細胞をマウスの左背部に皮下注射した。
(3)14日目から、ヒマシ油:エタノール:水(1:1:6)の溶媒と共に、A375移植腫瘍の場合、50mg/kg、100mg/kgの用量の化合物16及び100mg/kgの用量のPLX4032;Calu-6移植腫瘍の場合、50mg/kg、100mg/kg及び200mg/kgの用量の化合物16、100mg/kgの用量のRAF709、60mg/kgの用量のLY30019120、並びに100mg/kgの用量の比較化合物1;HCT116移植腫瘍の場合、50mg/kg、100mg/kgの用量の化合物16、100mg/kgの用量のRAF709、及び60mg/kgの用量のLY30019120;COLO205移植腫瘍の場合、25mg/kg、50mg/kg、100mg/kgの用量の化合物16、100mg/kgの用量のPLX4032;BxPC3移植腫瘍の場合、50mg/kg、100mg/kg、200mg/kgの用量の化合物16、100mg/kgの用量のLY3009120、100mg/kgの用量のRAF265、及び100mg/kgのPLX8394を、それぞれのマウスに毎日経口投与した(マウス5匹)。15日目から、それぞれのマウスにヒマシ油:エタノール:水(1:1:6)の溶媒を毎日経口投与した。
(4)15日目から毎日ノギスで皮下腫瘍の長さ/幅を測定し、マウスの体重を毎日記録して、マウスの体重に対する化合物16の効果を判定した。
(5)各モデル群について、36日目、42日目、26日目、35日目、又は42日目にマウスを屠殺した。
(6)内皮下腫瘍の成長傾向を統計的に分析した。腫瘍体積を次のように計算した:長さ×幅×幅/2mm3。
Claims (17)
- キナーゼ阻害剤であって、式(I):
Xは、
Y及びZの一方は炭素であり、他方は窒素であり、
A環は、
R1、R2及びR3は、それぞれ独立してH、シアノ、C1~6アルキル、C1~6アルコキシ、C1~6ヒドロキシアルキル、C1~6ヒドロキシアルコキシ、C3~6シクロアルキルC1~6アルコキシ、C1~6アルコキシC1~6アルコキシ、フェニル、ピリジル、フェニルC1~6アルコキシ、フリルC1~6アルコキシ、R6で任意に置換されたヘテロシクロアルキル、R6で任意に置換されたヘテロシクロアルキルフェニル、R6で任意に置換されたヘテロシクロアルキルカルボニル、R6で任意に置換されたヘテロシクロアルキルオキシ、R6で任意に置換されたヘテロシクロアルキルC1~6アルコキシ、R6で任意に置換されたヘテロシクロアルキルC1~6アルカノイルアミノ、C3~6シクロアルキルC1~6アルカノイルアミノ、及びC1~6アルキルアミノカルボニルC1~6アルコキシからなる群から選択されるか、又はR1はR3と共に、
R4及びR5は、それぞれ独立してH、C1~6アルキル、C1~6ハロアルキル、C1~6シアノアルキル、R6で任意に置換されたヘテロシクロアルキルC1~6アルキル、R6で任意に置換されたフェニル、R6で任意に置換されたヘテロアリール、及びアミノスルホニルからなる群から選択されるか、又はR4はR5と共に、
R6は、独立してオキソ、C1~6アルキル、C2~6アルカノイル、C1~6アルキルスルホニル、C1~6アルキルアミノC2~6アルカノイル、及びC1~6ハロアルキルからなる群から選択される)の化合物、又はその薬学的に許容可能な塩、溶媒和物、エステル、酸、代謝物若しくはプロドラッグを含む、キナーゼ阻害剤。 - Yが窒素であり、Zが炭素である、請求項1に記載のキナーゼ阻害剤。
- R2及びR3がHであり、R1がフェニル、ピリジル、C1~6アルキルで任意に置換されたヘテロシクロアルキル、C1~6アルキルで任意に置換されたヘテロシクロアルキルフェニル、C1~6アルキルで任意に置換されたヘテロシクロアルキルカルボニル、ヘテロシクロアルキルオキシ、ヘテロシクロアルキルC1~6アルコキシ、及びC1~6アルキルアミノカルボニルC1~6アルコキシからなる群から選択される、請求項1に記載のキナーゼ阻害剤。
- R1がHであり、R2がH、シアノ、C1~6アルキル、C1~6ヒドロキシアルコキシ、C3~6シクロアルキルC1~6アルコキシ、C1~6アルコキシC1~6アルコキシ、フェニルC1~6アルコキシ、フリルC1~6アルコキシ、R6基で任意に置換されたヘテロシクロアルキルオキシ、R6基で任意に置換されたヘテロシクロアルキルC1~6アルコキシ、C1~6アルキルで任意に置換されたヘテロシクロアルキルC1~6アルカノイルアミノ、及びC1~6アルキルアミノカルボニルC1~6アルコキシからなる群から選択され、R6が、独立してオキソ、C2~6アルカノイル、C1~6アルキルスルホニル、C1~6アルキルアミノC2~6アルカノイルからなる群から選択され、R3がH及びC3~6シクロアルキルC1~6アルカノイルアミノからなる群から選択され、R2及びR3は同時にHではない、請求項1に記載のキナーゼ阻害剤。
- R1が、H、ピリジル、ヘテロシクロアルキル、C1~6アルキルで任意に置換されたヘテロシクロアルキルフェニル、ヘテロシクロアルキルオキシ、ヘテロシクロアルキルC1~6アルコキシ、及びC1~6アルキルアミノカルボニルC1~6アルコキシからなる群から選択され、
R2が、H、C1~6アルキル、C1~6ヒドロキシアルコキシ、C1~6アルコキシC1~6アルコキシ、ヘテロシクロアルキルオキシ、及びヘテロシクロアルキルC1~6アルコキシからなる群から選択され、
R3が、H、及びC3~6シクロアルキルC1~6アルカノイルアミノからなる群から選択され、
ここで、R1、R2、及びR3は同時にHではなく、
R4が、C1~6ハロアルキル、及びC1~6シアノアルキルからなる群から選択され、
R5は、H、C1~6アルキル、及びC1~6アルキルで任意に置換されたヘテロシクロアルキルC1~6アルキルからなる群から選択される、請求項6に記載のキナーゼ阻害剤。 - R1が、H、3-ピリジル、4-ピリジル、N-モルホリニル、ピペラジン-1-イル、4-メチル-ピペラジン-1-イルフェニル、テトラヒドロピラン-4-イルオキシ、オキセタン-3-イルオキシ、2-モルホリノエトキシ、3-モルホリノプロポキシ、テトラヒドロフラン-3-イルメトキシ、及びジメチルアミノカルボニルメトキシからなる群から選択され、
R2が、H、メチル、2-ヒドロキシエトキシ、3-ヒドロキシプロポキシ、4-ヒドロキシブトキシ、2-メトキシエトキシ、テトラヒドロピラン-4-イルオキシ、テトラヒドロフラン-3-イルオキシ、オキセタン-3-イルオキシ、アゼチジン-3-イルオキシ、2-モルホリノエトキシ、テトラヒドロフラン-2-イルメトキシ、テトラヒドロフラン-3-イルメトキシ、テトラヒドロフラン-4-イルメトキシ、オキセタン-3-イルメトキシ、及びピロリジン-3-イルメトキシからなる群から選択され、
R3がH及びシクロプロピルホルムアミドからなる群から選択され、
ここで、R1、R2、及びR3は同時にHではなく、
R4が、トリフルオロメチル、2-シアノエタン-2-イル、及び2-シアノプロプ-2-イルからなる群から選択され、
R5が、H、メチル、及び4-メチル-ピペラジン-1-イルメチルからなる群から選択される、請求項6に記載のキナーゼ阻害剤。 - R1が、3-ピリジル、4-ピリジル、N-モルホリニル、ヘテロシクロアルキルオキシ、ヘテロシクロアルキルC1~6アルコキシ、及びC1~6アルキルアミノカルボニルC1~6アルコキシからなる群から選択され、R4が、C1~6ハロアルキル及びC1~6シアノアルキルからなる群から選択され、R2、R3及びR5がそれぞれHである、請求項6に記載のキナーゼ阻害剤。
- R2が、C1~6ヒドロキシアルコキシ、C1~6アルコキシC1~6アルコキシ、ヘテロシクロアルキルオキシ、及びヘテロシクロアルキルC1~6アルコキシからなる群から選択され、R4が、C1~6ハロアルキル及びC1~6シアノアルキルからなる群から選択され、R1、R3及びR5がそれぞれHである、請求項6に記載のキナーゼ阻害剤。
- 式(Ib):
Xは、
Y及びZの一方は炭素であり、他方は窒素であり、
A環は、
R4及びR5は、それぞれ独立してH、C1~6アルキル、C1~6ハロアルキル、C1~6シアノアルキル、R6で任意に置換されたピペラジニルC1~6アルキル、R6で任意に置換されたフェニル、R6で任意に置換されたイミダゾリル、R6で任意に置換されたチエニル、R6で任意に置換されたピリジル、及びアミノスルホニルからなる群から選択されるか、又はR4はR5と共に、
R6は、独立してC1~6アルキル及びC1~6ハロアルキルからなる群から選択される)の化合物、又はその薬学的に許容可能な塩、溶媒和物、エステル、酸、代謝物若しくはプロドラッグを含む、請求項1~5のいずれか一項に記載のキナーゼ阻害剤。 - 請求項1~12のいずれか一項に記載のキナーゼ阻害剤と、薬学的に許容可能な担体又は賦形剤と、任意に別の治療薬とを含む、医薬組成物。
- チロシンキナーゼRAF及び/又はRASの活性の阻害に使用される、請求項1~12のいずれか一項に記載のキナーゼ阻害剤。
- チロシンキナーゼRAF及び/又はRASの活性によって調節若しくは影響を受ける、又はその活性に関与する疾患、障害又は病態の治療、予防又は改善に使用される、請求項1~12のいずれか一項に記載のキナーゼ阻害剤。
- 前記疾患、障害又は病態が、固形腫瘍、肉腫、消化管間質腫瘍、結腸直腸癌、急性骨髄芽球性白血病、慢性骨髄性白血病、甲状腺癌、全身性肥満細胞症、好酸球増多症候群、線維症、エリテマトーデス、移植片対宿主病、神経線維腫症、肺高血圧症、アルツハイマー病、精上皮腫、未分化胚細胞腫、肥満細胞腫、肺癌、気管支癌、精巣上皮内腫瘍、黒色腫、乳癌、神経芽細胞腫、甲状腺乳頭癌/甲状腺濾胞癌、悪性リンパ腫、非ホジキンリンパ腫、多発性内分泌腫瘍症2型、褐色細胞腫、甲状腺癌、副甲状腺過形成/副甲状腺腫、結腸癌、結腸直腸腺腫、卵巣癌、前立腺癌、神経膠芽細胞腫、脳腫瘍、悪性神経膠腫、膵臓癌、悪性胸膜内皮腫、血管芽細胞腫、血管腫、腎臓癌、肝臓癌、副腎癌、膀胱癌、胃癌、直腸癌、膣癌、子宮頸癌、子宮内膜癌、多発性骨髄腫、頭頸部腫瘍、新生物、又はそれらの組合せからなる群から選択される増殖性疾患である、請求項15に記載の使用のためのキナーゼ阻害剤。
- 前記疾患、障害、又は病態が、頭頸部癌、甲状腺癌、黒色腫、結腸直腸癌、肺癌、乳癌、膵臓癌、食道癌、肝臓癌、白血病、新生物、又はそれらの組合せからなる群から選択される増殖性疾患である、請求項15に記載の使用のためのキナーゼ阻害剤。
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