JP6646044B2 - キナーゼ阻害剤としての化合物および組成物 - Google Patents
キナーゼ阻害剤としての化合物および組成物 Download PDFInfo
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- JP6646044B2 JP6646044B2 JP2017513761A JP2017513761A JP6646044B2 JP 6646044 B2 JP6646044 B2 JP 6646044B2 JP 2017513761 A JP2017513761 A JP 2017513761A JP 2017513761 A JP2017513761 A JP 2017513761A JP 6646044 B2 JP6646044 B2 JP 6646044B2
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
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- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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Description
Lは、−NHC(O)−および−C(O)NH−から選択され、
Y1は、NおよびCHから選択され、
R1は、H、ハロ、イソプロピル、メチル−スルホニル、OR6、NR5R6、メトキシ−エトキシ、2−オキサ−5−アザビシクロ[2.2.1]ヘプタン−5−イル、3−オキサ−8−アザビシクロ[3.2.1]オクタン−8−イル、8−オキサ−3−アザビシクロ[3.2.1]オクタン−3−イル、2−オキソ−1,2−ジヒドロピリジン−4−イル、テトラヒドロ−2H−ピラニル、4−オキソピリジン−1(4H)−イル、ピラゾリル、ピリダジニルおよびアゼチジニルから選択され、ここで、前記アゼチジニル、ピラゾリルまたは2−オキソ−1,2−ジヒドロピリジン−4−イルは、置換されていないか、またはメチルおよびヒドロキシから独立して選択される1〜3つの基により置換されており、
R2は、Hおよびメチルから選択され、
R3は、H、メチルおよびアミノから選択され、
R4は、
ここで、
R5は、Hおよびメチルから選択され、
R6は、Hおよびメチル、エチル、プロピル、イソプロピル、シクロプロピル、メトキシ、ヒドロキシ−エチル、メトキシ−エチル、テトラヒドロ−2H−ピラニル、ピリジニル、テトラヒドロフラニルおよびオキセタニルから選択されるか、またはR5とR6は、R5とR6が結合している窒素と一緒になって、モルホリノ、2−オキソピリジン−1(2H)−イル、1,1−ジオキシドチオモルホリノ、ピペラジニル、ピロリジニル、イミダゾリルおよびピラゾリルから選択される基を形成し、ここで、前記モルホリノ、ピラゾリルまたはイミダゾリルは、置換されていないか、または1〜2つのメチル基により置換されていてよく、
R7は、H、メチル、−CF3、−C(CH3)2CN、−C(CH3)2OH、−C(CH3)2F、−CF2CH3、−CF2H、イソプロピル、シクロプロピルおよびメチル−スルホニルから選択され、ここで、前記シクロプロピルは、置換されていないかまたはシアノにより置換されており、
R8は、H、メチル、エチル、イソプロピル、−C(CH3)2OHおよび−C(CH3)2NH2から選択され、R9は、Hおよびエチルから選択される)の化合物を提供する。
a)賦形剤、例えば、ラクトース、デキストロース、スクロース、マンニトール、ソルビトール、セルロースおよび/またはグリシン、
b)やはり錠剤のための、滑沢剤、例えば、シリカ、タルカム、ステアリン酸、そのマグネシウム塩もしくはカルシウム塩、および/またはポリエチレングリコール、
c)必要に応じて、結合剤、例えば、ケイ酸アルミニウムマグネシウム、デンプンペースト、ゼラチン、トラガカント、メチルセルロース、カルボキシメチルセルロースナトリウム、および/またはポリビニルピロリドン、
d)崩壊剤、例えば、デンプン、寒天、アルギン酸もしくはそのナトリウム塩、または発泡混合物、ならびに/あるいは
e)吸収剤、着色剤、着香剤および甘味剤。
本発明は、本発明の化合物を調製するための方法も含む。記載されている反応において、反応性官能基、例えば、ヒドロキシ、アミノ、イミノ、チオまたはカルボキシ基を保護する必要となり得、この場合、これらの官能基は、最終生成物において、反応においてそれらが望ましくない関与をするのを回避することが望ましいものである。従来の保護基は、慣例に従って使用することができ、例えば、T.W. Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry”, John Wiley and Sons, 1991を参照されたい。
本発明の化合物は、遊離塩基の形態の本化合物を薬学的に許容される無機酸または有機酸と反応させることにより、薬学的に許容される酸付加塩として調製することができる。あるいは、本発明の化合物の薬学的に許容される塩基付加塩は、遊離酸形態の本化合物を薬学的に許容される無機塩基または有機塩基と反応させることにより調製することができる。
(a)反応スキームIの方法、および
(b)場合により、本発明の化合物を薬学的に許容される塩に変換すること、
(c)場合により、本発明の化合物の塩形態を非塩形態に変換すること、
(d)場合により、本発明の化合物の非酸化形態を薬学的に許容されるN−オキシドに変換すること、
(e)場合により、本発明の化合物のN−オキシドをその非酸化形態に変換すること、
(f)場合により、異性体の混合物から、本発明の化合物の個々の異性体、例えば、立体異性体を分割すること、
(g)場合により、誘導体化されていない本発明の化合物を薬学的に許容されるプロドラッグ誘導体に変換すること、および
(h)場合により、本発明の化合物のプロドラッグ誘導体をその誘導体化されていない形態に変換すること
を含む方法によって作製することができる。
N−(3−(6−アミノ−5−シアノピリジン−3−イル)−4−メチルフェニル)−3−(トリフルオロメチル)ベンズアミド
N−(3−(2−クロロ−5−シアノピリジン−3−イル)−4−メチルフェニル)−2−(2−シアノプロパン−2−イル)イソニコチンアミド
N−(3−(6−クロロ−5−シアノピリジン−3−イル)−4−メチルフェニル)−2−(2−シアノプロパン−2−イル)イソニコチンアミド
N−(3−(6−クロロ−5−シアノピリジン−3−イル)−4−メチルフェニル)−3−(トリフルオロメチル)ベンズアミド
N−(3−(6−クロロ−5−シアノピリジン−3−イル)−4−メチルフェニル)−2−(トリフルオロメチル)イソニコチンアミド
N−(6’−クロロ−5’−シアノ−2−メチル−[3,3’−ビピリジン]−5−イル)−2−(2−シアノプロパン−2−イル)イソニコチンアミド
N−(6’−クロロ−5’−シアノ−2−メチル−[3,3’−ビピリジン]−5−イル)−2−(トリフルオロメチル)イソニコチンアミド
N−(3−(5−シアノ−6−((テトラヒドロ−2H−ピラン−4−イル)アミノ)ピリジン−3−イル)−4−メチルフェニル)−3−(トリフルオロメチル)ベンズアミド
N−(3−(5−シアノ−6−モルホリノピリジン−3−イル)−4−メチルフェニル)−2−(2−シアノプロパン−2−イル)イソニコチンアミド
N−(3−(5−シアノ−6−(3−ヒドロキシアゼチジン−1−イル)ピリジン−3−イル)−4−メチルフェニル)−2−(2−シアノプロパン−2−イル)イソニコチンアミド
N−(3−(5−シアノ−6−(3−ヒドロキシアゼチジン−1−イル)ピリジン−3−イル)−4−メチルフェニル)−3−(トリフルオロメチル)ベンズアミド
N−(3−(5−シアノ−6−モルホリノピリジン−3−イル)−4−メチルフェニル)−3−(トリフルオロメチル)ベンズアミド
N−(5’−シアノ−6’−(2−メトキシエトキシ)−2−メチル−[3,3’−ビピリジン]−5−イル)−2−(2−シアノプロパン−2−イル)イソニコチンアミド
N−(5’−シアノ−6’−エトキシ−2−メチル−[3,3’−ビピリジン]−5−イル)−2−(2−シアノプロパン−2−イル)イソニコチンアミド
N−(5’−シアノ−2−メチル−[3,3’:6’,4’’−ターピリジン]−5−イル)−2−(トリフルオロメチル)イソニコチンアミド
N−(5’−シアノ−2−メチル−6’−(1−メチル−1H−ピラゾール−4−イル)−[3,3’−ビピリジン]−5−イル)−2−(2−シアノプロパン−2−イル)イソニコチンアミド
N−(3−(5−シアノ−6−(1−メチル−1H−ピラゾール−4−イル)ピリジン−3−イル)−4−メチルフェニル)−2−(1,1−ジフルオロエチル)イソニコチンアミド
N−(5’−シアノ−6’−イソプロピル−2−メチル−[3,3’−ビピリジン]−5−イル)−2−(トリフルオロメチル)イソニコチンアミド
N−(5’−シアノ−6’−イソプロピル−2−メチル−[3,3’−ビピリジン]−5−イル)−2−(2−シアノプロパン−2−イル)イソニコチンアミド
N−(5’−シアノ−2−メチル−6’−(テトラヒドロ−2H−ピラン−4−イル)−[3,3’−ビピリジン]−5−イル)−2−(2−シアノプロパン−2−イル)イソニコチンアミド
4−(アミノメチル)−N−(3−(5−シアノ−6−(ジメチルアミノ)ピリジン−3−イル)−4−メチルフェニル)−3−(トリフルオロメチル)ベンズアミド
3−(5−シアノ−6−(ピペラジン−1−イル)ピリジン−3−イル)−4−メチル−N−(2−(トリフルオロメチル)ピリジン−4−イル)ベンズアミド
3−(5−シアノ−6−(ピペラジン−1−イル)ピリジン−3−イル)−4−メチル−N−(2−(メチルスルホニル)ピリジン−4−イル)ベンズアミド
本発明による化合物の活性は、周知のインビトロ法およびインビボ法によって評価することができる。本明細書において提示されているRaf阻害データは、以下の手順を使用して得た。
Claims (12)
- 式IまたはII:
Lは、−NHC(O)−および−C(O)NH−から選択され、
Y1は、NおよびCHから選択され、
R1は、H、ハロ、イソプロピル、メチル−スルホニル、OR6、NR5R6、メトキシ
−エトキシ、2−オキサ−5−アザビシクロ[2.2.1]ヘプタン−5−イル、3−オ
キサ−8−アザビシクロ[3.2.1]オクタン−8−イル、8−オキサ−3−アザビシ
クロ[3.2.1]オクタン−3−イル、2−オキソ−1,2−ジヒドロピリジン−4−
イル、テトラヒドロ−2H−ピラニル、4−オキソピリジン−1(4H)−イル、ピラゾ
リル、ピリダジニルおよびアゼチジニルから選択され、ここで、前記アゼチジニル、ピラ
ゾリルまたは2−オキソ−1,2−ジヒドロピリジン−4−イルは、置換されていないか
、またはメチルおよびヒドロキシから独立して選択される1〜3つの基により置換されて
おり、
R2は、Hおよびメチルから選択され、
R3は、H、メチルおよびアミノから選択され、
R4は、
ここで、
R5は、Hおよびメチルから選択され、
R6は、Hおよびメチル、エチル、プロピル、イソプロピル、シクロプロピル、メトキシ
、ヒドロキシ−エチル、メトキシ−エチル、テトラヒドロ−2H−ピラニル、ピリジニル
、テトラヒドロフラニルおよびオキセタニルから選択されるか、またはR5とR6は、R
5とR6が結合している窒素と一緒になって、モルホリノ、2−オキソピリジン−1(2
H)−イル、1,1−ジオキシドチオモルホリノ、ピペラジニル、ピロリジニル、イミダ
ゾリルおよびピラゾリルから選択される基を形成し、ここで、前記モルホリノ、ピラゾリ
ルまたはイミダゾリルは、置換されていないか、または1〜2つのメチル基により置換さ
れていてよく、
R7は、H、メチル、−CF3、−C(CH3)2CN、−C(CH3)2OH、−C(
CH3)2F、−CF2CH3、−CF2H、イソプロピル、シクロプロピルおよびメチ
ル−スルホニルから選択され、ここで、前記シクロプロピルは、置換されていないかまた
はシアノにより置換されており、
R8は、H、メチル、エチル、イソプロピル、−C(CH3)2OHおよび−C(CH3
)2NH2から選択され、
R9は、Hおよびエチルから選択される)の化合物、または薬学的に許容されるその塩。 - 式Ia:
Y1は、NおよびCHから選択され、
R1は、H、ハロ、イソプロピル、メチル−スルホニル、OR6、NR5R6、メトキシ
−エトキシ、2−オキサ−5−アザビシクロ[2.2.1]ヘプタン−5−イル、3−オ
キサ−8−アザビシクロ[3.2.1]オクタン−8−イル、8−オキサ−3−アザビシ
クロ[3.2.1]オクタン−3−イル、2−オキソ−1,2−ジヒドロピリジン−4−
イル、テトラヒドロ−2H−ピラニル、4−オキソピリジン−1(4H)−イル、ピラゾ
リル、ピリダジニルおよびアゼチジニルから選択され、ここで、前記アゼチジニル、ピラ
ゾリルまたは2−オキソ−1,2−ジヒドロピリジン−4−イルは、置換されていないか
、またはメチルおよびヒドロキシから独立して選択される1〜3つの基により置換されて
おり、
R2は、Hおよびメチルから選択され、
R3は、H、メチルおよびアミノから選択され、
R7は、H、メチル、−CF3、−C(CH3)2CN、−C(CH3)2OH、−C(
CH3)2F、−CF2CH3、−CF2H、イソプロピル、シクロプロピルおよびメチ
ル−スルホニルから選択され、ここで、前記シクロプロピルは、置換されていないかまた
はシアノにより置換されており、
R8は、H、メチル、エチル、イソプロピル、−C(CH3)2OHおよび−C(CH3
)2NH2から選択される)で表される請求項1に記載の化合物、または薬学的に許容さ
れるその塩。 -
- 式Ib:
Y1は、NおよびCHから選択され、
R1は、H、ハロ、イソプロピル、メチル−スルホニル、OR6、NR5R6、メトキシ
−エトキシ、2−オキサ−5−アザビシクロ[2.2.1]ヘプタン−5−イル、3−オ
キサ−8−アザビシクロ[3.2.1]オクタン−8−イル、8−オキサ−3−アザビシ
クロ[3.2.1]オクタン−3−イル、2−オキソ−1,2−ジヒドロピリジン−4−
イル、テトラヒドロ−2H−ピラニル、4−オキソピリジン−1(4H)−イル、ピラゾ
リル、ピリダジニルおよびアゼチジニルから選択され、ここで、前記アゼチジニル、ピラ
ゾリルまたは2−オキソ−1,2−ジヒドロピリジン−4−イルは、置換されていないか
、またはメチルおよびヒドロキシから独立して選択される1〜3つの基により置換されて
おり、
R2は、Hおよびメチルから選択され、
R3は、H、メチルおよびアミノから選択され、
R7は、H、メチル、−CF3、−C(CH3)2CN、−C(CH3)2OH、−C(
CH3)2F、−CF2CH3、−CF2H、イソプロピル、シクロプロピルおよびメチ
ル−スルホニルから選択され、ここで、前記シクロプロピルは、置換されていないかまた
はシアノにより置換されている)で表される請求項1に記載の化合物、または薬学的に許
容されるその塩。 -
-
-
- 請求項1〜7のいずれか1項に記載の化合物または薬学的に許容されるその塩、および
1種または複数の薬学的に許容される担体を含む、医薬組成物。 - 治療有効量の請求項1〜7のいずれか1項に記載の化合物または薬学的に許容されるそ
の塩、および1種または複数の治療上活性な共剤を含む、組合せ剤。 - 増殖性障害を処置する薬剤を製造するための、請求項1〜7のいずれか1項に記載の化
合物または薬学的に許容されるその塩の使用。 - 前記増殖性障害ががんから選択される、請求項10に記載の使用。
- 前記がんが黒色腫から選択される、請求項11に記載の使用。
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TW202112767A (zh) | 2019-06-17 | 2021-04-01 | 美商佩特拉製藥公司 | 作為磷脂酸肌醇磷酸激酶抑制劑之胺基吡啶衍生物 |
EP4298094A1 (en) * | 2021-02-24 | 2024-01-03 | Insilico Medicine IP Limited | Analogs for the treatment of disease |
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