JP2021536473A - 5−モルホリン−4−イル−ピラゾロ[4,3−b]ピリジン誘導体 - Google Patents
5−モルホリン−4−イル−ピラゾロ[4,3−b]ピリジン誘導体 Download PDFInfo
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- JP2021536473A JP2021536473A JP2021512689A JP2021512689A JP2021536473A JP 2021536473 A JP2021536473 A JP 2021536473A JP 2021512689 A JP2021512689 A JP 2021512689A JP 2021512689 A JP2021512689 A JP 2021512689A JP 2021536473 A JP2021536473 A JP 2021536473A
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- Japan
- Prior art keywords
- methyl
- pyrazolo
- pyridine
- pyrazole
- morpholine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- BBDPAZNVBQSVTO-UHFFFAOYSA-N 4-(1H-pyrazolo[4,3-b]pyridin-5-yl)morpholine Chemical class N1(CCOCC1)C1=CC=C2C(=N1)C=NN2 BBDPAZNVBQSVTO-UHFFFAOYSA-N 0.000 title description 2
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- 238000011282 treatment Methods 0.000 claims abstract description 27
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- 201000010099 disease Diseases 0.000 claims abstract description 20
- -1 COOA Chemical group 0.000 claims description 369
- 239000000203 mixture Substances 0.000 claims description 83
- 150000003839 salts Chemical class 0.000 claims description 71
- 239000004480 active ingredient Substances 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 15
- 239000012453 solvate Substances 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 10
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- 229910052731 fluorine Inorganic materials 0.000 claims description 9
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- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 5
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- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
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- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000005493 quinolyl group Chemical group 0.000 claims description 5
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 28
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical class C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- 239000012043 crude product Substances 0.000 description 23
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 22
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 18
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
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- SRJMSYRRWDHNEX-GFCCVEGCSA-N (3R)-3-methyl-4-[1-methyl-7-(1-methylsulfonylcyclopropyl)-3-(1H-pyrazol-5-yl)pyrazolo[4,3-b]pyridin-5-yl]morpholine Chemical compound CS(=O)(=O)C1(CC1)C1=C2C(=NC(=C1)N1[C@@H](COCC1)C)C(=NN2C)C1=NNC=C1 SRJMSYRRWDHNEX-GFCCVEGCSA-N 0.000 description 16
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
Description
本発明は、貴重な特性、とりわけ医薬の調製のために使用され得るものを有する新規化合物を見出す目的を有した。
本発明は、ATR(Ataxia telangiectasia mutated and Rad3-related kinase;毛細血管拡張性運動失調症変異およびRad3に関するキナーゼ)を阻害する5−モルホリン−4−イル−ピラゾロ[4,3−b]ピリジン誘導体に関する。したがって、本発明の化合物は、がんなどの疾患を処置することにおいて有用である。
本発明の化学物質は、ATRのインヒビターであり、および数多の、具体的にがんの処置における、治療的用途を有する。
宿主または患者は、任意の哺乳類の動物種、例えば霊長目の動物種、具体的にヒト;マウス、ラットおよびハムスターを包含する齧歯類の動物;ウサギ;ウマ、ウシ、イヌ、ネコ、等々に属し得る。動物モデルは、ヒトの疾患の処置についてのモデルを提供する実験的調査に関心がある。
がんの処置のための他の二環式複素環式化合物が、WO 2013/130660 A1に、およびWO 2017/121684 A1に記載されている。
本発明は、式IaおよびIb
R1は、H、Het、Ar、(CH2)nOH、1−メチルスルホニル−シクロプロパ−1−イル、CONH2、CONHA、CONA2、Cyc、OAまたはCH(A)SO2Aを示し、
R2は、H、A、(CH2)nAr、(CH2)nCycまたは(CH2)nHetを示し、
R3は、HまたはAを示し、
Arは、フェニル、ナフチルまたはビフェニルを示し、その各々は、非置換であるか、またはNH2、NHA、NA2、COOH、COOA、CONH2、CONHA、CONA2、NHCOA、CHO、COA、SO3H、SO2NH2、O(CH2)pNH2、(CH2)nHet1、O(CH2)nHet1、(CH2)nAr1、O(CH2)nAr1、O(CH2)pCONH2、O(CH2)pNHCOA、Hal、SOA、S(=O、=NH)A、SO2A、A、CNおよび/もしくは(CH2)nOHによって単置換、二置換、もしくは三置換されており、
Het1は、1〜4個のN、Oおよび/またはS原子を有する単環式または二環式の芳香族、不飽和または飽和ヘテロ環を示し、それは、非置換であるか、またはHal、A、COOA、NH2、NHAおよび/もしくはNA2によって単置換、二置換、もしくは三置換されていてもよく、
Aは、1〜6個のC原子を有する非分枝または分枝のアルキルを示し、ここで、1〜7個のH原子は、OH、F、Clおよび/もしくはBrによって置き換えられていてもよく、ならびに/または、ここで、1もしくは2の非隣接CH2基は、Oおよび/もしくはNH基によって置き換えられていてもよく、
Halは、F、Cl、BrまたはIを示し、
nは、0、1、2、3または4を示し、
pは、1、2、3または4を示す、
で表される化合物、およびその薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率におけるそれらの混合物に関する。
その上、本発明は、式IaおよびIbで表される化合物の薬学的に許容し得る 誘導体に関する。
本発明はまた、塩の溶媒和物にも関すると理解される。
本明細書に使用されるとき、および他に指示されない限り、用語「プロドラッグ」は、活性化合物、具体的には式Iで表される化合物を提供するために、加水分解、酸化、またはそうでなければ生物学的条件下(in vitroまたはin vivo)で反応することができる、式Iで表される化合物の誘導体を意味する。プロドラッグの例は、これらに限定されないが、生物加水分解性部分、例えば生物加水分解性アミド、生物加水分解性エステル、生物加水分解性カルバマート、生物加水分解性カルボナート、生物加水分解性ウレイド、および生物加水分解性ホスファート類似体などを包含する式Iで表される化合物の誘導体および代謝体を包含する。
加えて、「治療的に有効な量」という表現は、この量を投与されていない対応する対象と比較して、以下の結果:
疾患、症候群、状態、愁訴、障害もしくは副作用の、改善された処置、治癒、予防もしくは解消、またはまた、疾患、愁訴もしくは障害の進行の低減
を有する量を示す。
「治療的に有効な量」という表現はまた、正常な生理学的機能を増加させるために有効である量も網羅する。
これらは、具体的に好ましくは、立体異性の化合物の混合物である。
「互変異性体」は、互いに平衡にある化合物の異性体の形態を指す。異性体の形態の濃度は、化合物が見出される環境に依存するだろうし、および例えば、化合物が固体であるか、または有機溶液中もしくは水性溶液中にあるかに依存して異なってもよい。
Aはアルキルを示し、これは、非分枝(線状)または分枝であり、および1、2、3、4、5、6、7または8個のC原子を有する。Aは、好ましくは、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチルまたはtert−ブチル、また、さらにまた、ペンチル、1−、2−または3−メチルブチル、1,1−、1,2−または2,2−ジメチルプロピル、1−エチルプロピル、ヘキシル、1−、2−、3−または4−メチルペンチル、1,1−、1,2−、1,3−、2,2−、2,3−または3,3−ジメチルブチル、1−または2−エチルブチル、1−エチル−1−メチルプロピル、1−エチル−2−メチルプロピル、1,1,2−または1,2,2−トリメチルプロピル、さらにより好ましくは、例えば、トリフルオロメチルを示す。
その上、Aは、好ましくは、CH2OCH3、CH2CH2OHまたはCH2CH2OCH3を示す。
Cycは、シクロプロリル(cycloprolyl)、シクロブチル、シクロペンチル、シクロヘキシルまたはシクロへプチルを示す。
複素環式置換基ピリジル=ピリジニル。
複素環式ラジカルはまた、部分的または完全に水素化されていてもよい。
複素環式ラジカルはまた、部分的または完全に水素化されていてもよい。
式IaおよびIbで表される化合物は、1以上のキラル中心を有してもよく、およびしたがって、様々な立体異性体の形態で出現し得る。式IaおよびIbは、すべてのこれらの形態を網羅する。
IacおよびIbcにおいて、R3は、Hまたはメチルを示し;
IadおよびIbdにおいて、R1は、H、Het、Ar、(CH2)nOH、1−メチルスルホニル−シクロプロパ−1−イル、CONH2、CONHA、CONA2、Cyc、OAまたはCH(A)SO2Aを示し;
R3は、HまたはAを示し、
Hetは、1H−ピロロ[2,3−b]ピリジニル、1H−ピロロ[2,3−c]ピリジニル、インドリル、ベンズイミダゾリル、イミダゾリル、1,2,3,4−テトラヒドロイソキノリル、ピリジル、ピリミジニル、トリアゾリル、ピラゾリル、キノリル、イソキノリル、キナゾリニル、フラニル、テトラヒドロフラニル、ピラニル、3,6−ジヒドロ−2H−ピラニル、テトラヒドロピラニル、3,6−ジヒドロ−2H−チオピラニルまたはヘキサヒドロ−チオピラニルを示し、その各々は、非置換であるか、またはA、SOA、SO2A、Halおよび/もしくは=Oによって単置換、二置換、もしくは三置換されており、
Arは、フェニルを示し、それは、非置換であるか、またはSOA、S(=O、=NH)A、SO2A、A、CNおよび/もしくは(CH2)nOHによって単置換、二置換、もしくは三置換されており、
Cycは、3、4、5、6または7個のC原子を有する環状アルキルを示し、
Halは、F、Cl、BrまたはIを示し、
nは、0、1、2、3または4を示す、
およびその薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率におけるそれらの混合物。
式IaおよびIbで表される化合物およびまたそれらの調製のための出発材料は、加えて、文献(例えば、Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgartなどの、標準的な著作物)に記載されるとおり、それ自体公知の方法によって、正確には公知でありおよび該反応に好適な反応条件下で、調製される。本明細書でより詳細には言及されない、それ自体公知の変化形の使用もまた本明細書でなされ得る。
本発明に従う該化合物は、それらの最終的な非塩形態において使用され得る。他方、本発明はまた、これらの化合物の、当該技術分野における公知の手順によって様々な有機酸および無機酸ならびに塩基から導き出され得る、それらの薬学的に許容し得る塩の形態における使用を網羅する。式IaおよびIbで表される化合物の薬学的に許容し得る塩形態は、大部分は、従来の方法によって調製される。式IaおよびIbで表される化合物がカルボキシル基を含有する場合、その好適な塩の1種は、化合物と好適な塩基とを反応させて、対応する塩基付加塩を与えることによって形成され得る。かかる塩基は、例えば、水酸化カリウム、水酸化ナトリウムおよび水酸化リチウムを包含するアルカリ金属水酸化物;アルカリ土類金属水酸化物、例えば水酸化バリウムおよび水酸化カルシウムなど;アルカリ金属アルコキシド、例えばカリウムエトキシドおよびナトリウムプロポキシドなど;ならびに、様々な有機塩基、例えばピペリジン、ジエタノールアミンおよびN−メチルグルタミンなどである。式IaおよびIbで表される化合物のアルミニウム塩も同じく包含される。
具体的に好ましいのは、塩酸塩、二塩酸塩、臭化水素酸塩、マレイン酸塩、メシル酸塩、リン酸塩、硫酸塩およびコハク酸塩である。
式IaおよびIbで表される化合物がその同位体標識された形態を包含することが、さらにまた意図される。式IaおよびIbで表される化合物の同位体標識された形態は、化合物の1以上の原子が通常天然に存在する原子質量または原子の質量数とは異なる原子質量または質量数を有する原子(単数)または原子(複数)によって置き換えられているという事実は別として、この化合物と同一である。容易に商業的に入手可能であり、および周知の方法によって式IaおよびIbで表される化合物中へ組み込まれ得る同位体の例は、水素、炭素、窒素、酸素、リン、フッ素および塩素の同位体、例えば、夫々、2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18Fおよび36CIを包含する。上述の同位体および/または他の原子の他の同位体の1以上を含有する式IaおよびIbで表される化合物またはその薬学的に許容し得る塩は、本発明の一部であることが意図される。
式IaおよびIbで表される化合物、およびその薬学的塩、互変異性体および立体異性体はまた、リポソーム送達系、例えば、小さな単層ベシクル、大きな単層ベシクル、および多重膜ベシクルなどの形態で投与され得る。リポソームは、様々なリン脂質、例えばコレステロール、ステアリルアミンまたはホスファチジルコリンなどから形成され得る。
局所投与に適合した医薬化合物は、軟膏、クリーム、懸濁液、ローション、粉末、溶液、ペースト、ゲル、スプレー、エアロゾルまたは油として処方され得る。
目への局所適用に適合した医薬製剤は、点眼剤を包含し、ここで活性成分は、好適な担体、とりわけ水性溶媒中に溶解されるか、または懸濁される。
口における局所適用に適合した医薬製剤は、薬用キャンディー、トローチおよび洗口剤を網羅する。
直腸投与に適合した医薬製剤は、坐薬または浣腸剤の形態で投与され得る。
膣内投与に適合した医薬製剤は、膣坐薬、タンポン、クリーム、ゲル、ペースト、泡体またはスプレー製剤として投与され得る。
(a)有効量の、式IaおよびIbで表される化合物、および/またはその薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率におけるそれらの混合物、ならびに
(b)有効量のさらなる医薬活性成分
の個別のパックからなるセット(キット)にも関する。
ならびに、有効量の溶解形態または凍結乾燥形態でのさらなる医薬活性成分
を含有する個別のアンプルを含んでもよい。
本化合物は、がんの処置における、哺乳動物のための、とくにヒトのための医薬活性成分として好適である。
本発明は、式IaおよびIbで表される化合物、および/またはその薬学的に許容し得る塩、互変異性体および立体異性体の、がんの処置または予防のための医薬の調製のための使用を網羅する。
その上、本発明は、がんの処置または予防のための使用のための、式IaおよびIbで表される化合物、および/またはその薬学的に許容し得る塩、互変異性体および立体異性体を網羅する。
本発明は、具体的に言うと、ATRの阻害のための使用のための、式IaおよびIbで表される化合物、およびその薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率におけるそれらの混合物に関する。
好ましくは、本発明は、疾患ががんである方法に関する。
開示された式IaおよびIbで表される化合物は、抗がん剤を包含する他の公知の治療剤と組み合わせて投与され得る。本明細書で使用されるとき、用語「抗がん剤」は、がんを処置する目的でがんを患う患者に投与される任意の剤に関する。
上記に定義された抗がん処置は、単剤治療として適用されてもよく、または本明細書に開示された式Iで表される化合物に加えて、従来の外科手術もしくは放射線治療もしくは薬物治療を含んでもよい。かかる薬物治療、例として化学治療または標的治療は、1以上の、好ましくは1の以下の抗腫瘍剤を包含してもよい。
アルトレタミン、ベンダムスチン、ブスルファン、カルムスチン、クロラムブシル、クロルメチン、シクロホスファミド、ダカルバジン、イホスファミド、インプロスルファン、トシラート、ロムスチン、メルファラン、ミトブロニトール、ミトラクトール、ニムスチン、ラニムスチン、テモゾロミド、チオテパ、トレオスルファン、メクロレタミン、カルボコン;
アパジコン、ホテムスチン、グルホスファミド、パリホスファミド、ピポブロマン、トロホスファミド、ウラムスチン、TH−3024、VAL−0834など;
カルボプラチン、シスプラチン、エプタプラチン、ミリプラチン水和物、オキサリプラチン、ロバプラチン、ネダプラチン、ピコプラチン、サトラプラチン;
ロバプラチン、ネダプラチン、ピコプラチン、サトラプラチンなど;
アムルビシン、ビサントレン、デシタビン、ミトキサントロン、プロカルバジン、トラベクテジン、クロファラビン;
アムサクリン、ブロスタリシン、ピクサントロン、ラロムスチン1、3など;
エトポシド、イリノテカン、ラゾキサン、ソブゾキサン、テニポシド、トポテカン;
アモナフィド、ベロテカン、エリプチニウムアセタート、ボレロキシンなど;
カバジタキセル、ドセタキセル、エリブリン、イクサベピロン、パクリタキセル、ビンブラスチン、ビンクリスチン、ビノレルビン、ビンデシン、ビンフルニン;
フォスブレタブリン、テセタキセルなど;
アスパラギナーゼ3、アザシチジン、レボホリナートカルシウム、カペシタビン、クラドリビン、シタラビン、エノシタビン、フロクスウリジン、フルダラビン、フルオロウラシル、ゲムシタビン、メルカプトプリン、メトトレキサート、ネララビン、ペメトレキセド、プララトレキサート、アザチオプリン、チオグアニン、カルモフール;
ドキシフルリジン、エラシタラビン、ラルチトレキセド、サパシタビン、テガフール2、3、トリメトレキサートなど;
ブレオマイシン、ダクチノマイシン、ドキソルビシン、エピルビシン、イダルビシン、レバミソール、ミルテホシン、マイトマイシンC、ロミデプシン、ストレプトゾシン、バルルビシン、ジノスタチン、ゾルビシン、ダウノルビシン、プリカマイシン;
アクラルビシン、ペプロマイシン、ピラルビシンなど;
アバレリックス、アビラテロン、ビカルタミド、ブセレリン、カルステロン、クロロトリアニセン、デガレリクス、デキサメタゾン、エストラジオール、フルオコルトロン、フルオキシメステロン、フルタミド、フルベストラント、ゴセレリン、ヒストレリン、リュープロレリン、メゲストロール、ミトタン、ナファレリン、ナンドロロン、ニルタミド、オクトレオチド、プレドニゾロン、ラロキシフェン、タモキシフェン、サイロトロピンアルファ、トレミフェン、トリロスタン、トリプトレリン、ジエチルスチルベストロール;
アコルビフェン、ダナゾール、デスロレリン、エピチオスタノール、オルテロネル、エンザルタミド1,3など;
アミノグルテチミド、アナストロゾール、エキセメスタン、ファドロゾール、レトロゾール、テストラクトン;
ホルメスタンなど;
クリゾチニブ、ダサチニブ、エルロチニブ、イマチニブ、ラパチニブ、ニロチニブ、パゾパニブ、レゴラフェニブ、ルキソリチニブ、ソラフェニブ、スニチニブ、バンデタニブ、ベムラフェニブ、ボスチニブ、ゲフィチニブ、アキシチニブ;
アファチニブ、アリサーチブ、ダブラフェニブ、ダコミチニブ、ジナシクリブ、ドビチニブ、エンザスタウリン、ニンテダニブ、レンバチニブ、リニファニブ、リンシチニブ、マシチニブ、ミドスタウリン、モテサニブ、ネラチニブ、オランチニブ、ペリフォシン、ポナチニブ、ラドチニブ、リゴセルチブ、テポチニブ、ティピファニブ、チバンチニブ、チボザニブ、トラメチニブ、ピマセルチブ、ブリバニブアラニナート、セジラニブ、アパチニブ4、カボザンチニブS−マラート1,3、イブルチニブ1,3、イコチニブ4、ブパルリシブ2、シパチニブ4、コビメチニブ1,3、イデラリシブ1,3、フェドラチニブ1、XL−6474など;
メトキサレン3;
ポルフィマーナトリウム、タラポルフィン、テモポルフィンなど;
アレムツズマブ、ベシレソマブ、ブレンツキシマブベドチン、セツキシマブ、デノスマブ、イピリムマブ、オファツムマブ、パニツムマブ、リツキシマブ、トシツモマブ、トラスツズマブ、ベバシズマブ、ペルツズマブ2,3;
カツマキソマブ、エロツズマブ、エプラツズマブ、ファーレツズマブ、モガムリズマブ、ネシツムマブ、ニモツズマブ、オビヌツズマブ、オカラツズマブ、オレゴボマブ、ラムシルマブ、リロツムマブ、シルツキシマブ、トシリズマブ、ザルツムマブ、ザノリムマブ、マツズマブ、ダロツズマブ1,2,3、オナルツズマブ1,3、ラコツモマブ1、タバルマブ1,3、EMD−5257974、アベルマブ、ニボルマブ1,3など;
アルデスロイキン、インターフェロンアルファ2、インターフェロンアルファ2a3、インターフェロンアルファ2b2、3;
セルモロイキン、タソネルミン、テセロイキン、オプレルベキン1,3、組換えインターフェロンベータ−1a4など;
デニロイキンジフチトクス、イブリツモマブチウキセタン、イオベングアンI123、プレドニムスチン、トラスツズマブエムタンシン、エストラムスチン、ゲムツズマブ、オゾガマイシン、アフリベルセプト;
シントレデキンベスドトックス、エドトレオチド、イノツズマブオゾガマイシン、ナプツモマブエスタフェナトクス、オポルツズマブモナトックス、テクネチウム(99mTc)アルシツモマブ1,3、ビンタフォリド1,3など;
シプロイセル3;ビテスペン3、エメペピムト−S3、oncoVAX4、リンドペピムト3、troVax4、MGN−16014、MGN−17034など;
アリトレチノイン、ベキサロテン、ボルテゾミブ、エベロリムス、イバンドロン酸、イミキモド、レナリドミド、レンチナン、メチロシン、ミファムルチド、パミドロン酸、ペグアスパルガーゼ、ペントスタチン、シプロイセル3、シゾフィラン、タミバロテン、テムシロリムス、サリドマイド、トレチノイン、ビスモデギブ、ゾレドロン酸、ボリノスタット;セレコキシブ、シレンジチド、エンチノスタット、エタニダゾール、ガネテスピブ、イドロノキシル、イニパリブ、イキサゾミブ、ロニダミン、ニモラゾール、パノビノスタット、ペレチノイン、プリチデプシン、ポマリドミド、プロコダゾール、リダフォロリムス、タスキニモド、テロトリスタット、チマルファシン、チラパザミン、トセドスタット、トラベデルセン、ウベニメクス、バルスポダル、ゲンジシン4、ピシバニール4、レオリシン4、レタスピマイシン塩酸塩1、3、トレバナニブ2,3、ビルリジン4、カルフィルゾミブ1,3、エンドスタチン4、イムコテル4、ベリノスタット3、MGN−17034;
オラパリブ、ベリパリブ。
1Prop. INN(提唱された国際一般名(Proposed International Nonproprietary Name))
2Rec. INN(推奨された国際一般名(Recommended International Nonproprietary names))
3USAN(米国一般名(United States Adopted Name))
4 no INN.
aq(水性)、h(時間)、g(グラム)、L(リットル)、mg(ミリグラム)、MHz(メガヘルツ)、min(分)、mm(ミリメートル)、mmol(ミリモル)、mM(ミリモル)、m.p.(融点)、eq(当量)、mL(ミリリットル)、L(マイクロリットル)、ACN(アセトニトリル)、AcOH(酢酸)、CDCl3(重水素化クロロホルム)、CD3OD(重水素化メタノール)、CH3CN(アセトニトリル)、c−hex(シクロヘキサン)、DCC(ジシクロヘキシルカルボジイミド)、DCM(ジクロロメタン)、DIC(ジイソプロピルカルボジイミド)、DIEA(ジイソプロピルエチル−アミン)、DMF(ジメチルホルムアミド)、DMSO(ジメチルスルホキシド)、DMSO−d6(重水素化ジメチルスルホキシド)、EDC(1−(3−ジメチル−アミノ−プロピル)−3−エチルカルボジイミド)、ESI(エレクトロスプレーイオン化)、EtOAc(酢酸エチル)、Et2O(ジエチルエーテル)、EtOH(エタノール)、HATU(ジメチルアミノ−([1,2,3]トリアゾロ[4,5−b]ピリジン−3−イルオキシ)−メチレン]−ジメチル−アンモニウムヘキサフルオロホスファート)、
例において提供されるLCMSデータは、保持時間、純度および/またはm/zにおける質量と共に与えられる。結果は、次のとおり得られた:マススペクトル: LC/MS Waters ZMD (ESI)またはHP 1100シリーズのHewlett Packard System (イオン源: Electrospray (ポジティブモード)またはWaters Acquity H Class SQD;スキャン:100−1000m/z;フラグメンテーション電圧:60V;ガス温度:300℃、DAD:220nm。流速:2.4ml/Min。使用されたスプリッターはMSのDAD後の流速を0.75ml/Minまで低減させた;カラム: Chromolith Speed ROD RP-18e 50-4.6;溶媒: Merck KgaA社からのLiChrosolv-qualityまたは方法において言及されるとおりのもの。
方法A:ジクロロメタン/メタノール 10:1
方法B:酢酸エチル/石油エーテル 2:3)
方法C:(酢酸エチル/石油エーテル 3:7)
方法D:(n−ヘプタン/EtOAc)。
方法E:酢酸エチル/石油エーテル 1:1
方法F:酢酸エチル/PE 1:10
方法G:酢酸エチル/石油エーテル 1:5
方法H:ジクロロメタン/メタノール 2:3
方法J:EA/PE 10:1
方法K:CH3CN/H2O 3:7
方法L:DCM−MeOH−勾配
方法M:n−ヘプタン/EtOAc勾配
方法N:n−ヘプタン/EtOAc/MeOH勾配
方法O:DCM/MeOH勾配
方法P:酢酸エチル/石油エーテル勾配
IC50値を、ATR/ATRIP酵素アッセイによって決定した。アッセイは、2つのステップを含む:酵素反応および検出ステップ。第一に、ATR/ATRIPタンパク質(毛細血管拡張性運動失調症変異およびRad3に関するキナーゼ/ATR相互タンパク質)の混合物、異なる濃度での本件の化合物、基質タンパク質としてのp53およびアデノシン三リン酸(ATP)を、アッセイ緩衝液中でインキュベートする。ATRによって、Ser15でのp53および他の残基はリン酸化される。次いで、リン酸化されたp53の量を、特定の抗体およびTR−FRETアッセイ技術を使用して検出する。
ATP=アデノシン三リン酸
TR−FRET=時間分解蛍光共鳴エネルギー移動
HTRF(登録商標)=均一時間分解蛍光
HEPES=2−(4−(2−ヒドロキシエチル)−1−ピペラジニル)−エタンスルホン酸
Mg(CH3COO)2=酢酸マグネシウム
MnCl2=塩化マンガン(II)
BSA=ウシ血清アルブミン
EDTA=エチレンジアミンテトラアセタート
TRF=時間分解蛍光
Chk1キナーゼは、ATRの下流として作用し、DNA損傷チェックポイント制御において中心的役割を有する。Chk1の活性化は、Ser317およびSer345(ATRによるリン酸化/活性化のための優先的な標的とみなされる)に関与し、阻止されたDNA複製および遺伝毒性ストレスのある形態に応じて生じる。Ser345でのリン酸化は、チェックポイント活性化に伴い、Chk1を核に局在化させる役割を果たす。
このアッセイは、化合物およびヒドロキシ尿素(dNTP欠乏のためフォーク複製進行阻害を促進する)を用いる処置に伴い、ならびに免疫化学細胞的な手順およびハイコンテントイメージングを使用して、HT29結腸腺癌細胞中のChk1(Ser345)のリン酸化における減少を測定する。
核に局在化したpChk1シグナルを、ImageXpress Ultra confocalハイコンテントリーダー上で検出し、%陽性細胞(核)として報告する。
このアッセイにおいて、急速活性型遅延整流性カリウム電流(IKr)を媒介するKv11.1(hERG)イオンチャネル電流に対する試験化合物の潜在的なin vitro効果を調査する。このアッセイを、安定したKv11.1(hERG)をトランスフェクトしたヒト胚性腎臓細胞株(HEK293)を用いて、室温で行われる全細胞パッチクランプ法によって実行する。
以下の式において、「abs」は、指し示されるとおりの絶対立体化学を意味する。アザインダゾール誘導体は、合成スキーム1に従って合成され得る。
スキーム1:アザインダゾール10への合成ルート
3(R2=H)から開始し、保護基は、アザインダゾールコアに導入され得、11へ至る。以下のステップは、スキーム1のとおり記載されるとおりである。保護基は最後のステップにおいて12から除去され得、非置換アザインダゾール13を生産する。
2,6−ジクロロ−3−ニトロピリジン−4−アミン14は、Sandmeyer条件下で15へ臭素化され得る。Suzukiタイプ反応は、16へつながる。メチルモルホリンは、Buchwald条件下で、または、塩基性条件下で求核芳香族置換を介して、17へ導入され得る。ニトロ基は、H2/PdCまたはFeまたはSnCl2を用いてアミン18へ還元され得る。19への環化は、酢酸中亜硝酸ナトリウムを用いて実行可能である。化合物は、NBS、NIS、Br2またはI2を用いて20へハロゲン化され得、および7へアルキル化され得る。代替的に、7は19から21へのアルキル化、およびNBSまたはNISを用いたハロゲン化によって調製され得る。ステップ7〜10は、スキーム1に記載されるとおりである。
アザインダゾール5は、ボロン酸22へ変換され得る。Suzukiタイプ反応は、スキーム1に記載されるとおり、6を生産し、10へ反応され得る。
アザインダゾール5からPdCl2およびdppfなどのホスフィンリガンドを用いて開始し、アザインダゾール23が調製され得る。代替的に、アザインダゾール25は、Buchwald条件下でアザインダゾール23へ反応され得る。24への反応ステップは、アザインダゾール10の合成について記載されるスキーム1のとおりである。
アザインダゾール5は、26へカルボニル化され得、NBSまたはNISを用いて27へハロゲン化され得る。Suzukiタイプ反応は、アザインダゾール28を生産する。エステルの、例としてLiBH4を用いた還元は、アルコール29をもたらし、脱離基、TfまたはClなどへ、30(R4=脱離基)へ転換され得る。R4は、スルフィナートを用いてスルホン31へ交換され得る。(ジメチルアミノ)メチルジメチルアミンを用いて、アルケン32は合成され得る。ヨウ化メタンスルホニルとの反応は、シクロプロピルスルホン33を生産する。ピラゾール脱保護に続き、アザインダゾール34が単離され得る。
アザインダゾール27は、例としてLiBH4を用いて、アルコール34へ還元され、脱離基、TfまたはClなどへ、35(R4=脱離基)へ転換され得る。R4は、スルフィナートを用いてスルホン36へ交換され得る。ジブロメタン(dibromethane)またはジクロロエタンとの反応は、シクロプロピル37をもたらし、上の反応スキームに記載されるとおりのアザインダゾール34へ合成され得る。
LC/MS(方法A) Rt 1.338min、[MH]+ 390.0。
LC/MS(方法B): Rt 1.544min、[MH]+ 376.0。
LC/MS(方法C):Rt 0.821min;[MH]+ 390.2。
LC/MS(方法D):Rt 0.782min、[MH]+ 390.2。
LC/MS(方法B):Rt 1.993min、[MH]+ 437.1。
LC/MS(方法F):Rt 1.298min、[MH]+ 453.1。
LC/MS(方法E):Rt 1.199min、[MH]+ 452.0。
LC/MS(方法F):Rt2.024 min;[MH]+452。
LC/MS(方法E):Rt 1.191;[MH]+ 454.0。
LC/MS(方法H):Rt 1.258min [MH]+ 415.3。
LC/MS(方法G):Rt 1.212min、[MH]+ 468.3。
LC/MS(方法E):Rt 1.285min、[MH]+394.0。
LC/MS(方法G):Rt 1.265min、[MH]+ 468.0。
LC/MS(方法E):RT 1.021min、[MH]+ 390.1。
LC/MS(方法D):Rt 0.867min、[MH]+ 357.2。
例26に代替する合成ルートのためのビルディングブロック:3−ブロモ−7−クロロメチル−1−メチル−5−((R)−3−メチル−モルホリン−4−イル)−1H−ピラゾロ[4,3−b]ピリジン
LC/MS(方法F):Rt 1.981min;[MH]+ 453.1。
LC/MS(方法C):Rt 0.947min;[MH]+ 376.2。
LC/MS(方法K):Rt 1.177min [MH]+379.3。
LC/MS(方法A):RT 1.475min、[MH]+ 339.3。
LC/MS(方法J):RT 1.030min、[MH]+ 389.1。
LC/MS(方法C):Rt 1.058min;[MH]+ 444.2。
LC/MS(方法W):Rt 0.870min、[MH]+ 369.0。
LC/MS(方法C):Rt 0.991min;[MH]+ 467。
LC/MS(方法D)Rt 1.129min、[MH]+ 397.1。
LC/MS(方法X):Rt 0.953min、[MH]+ 413.1。
LC/MS(方法R):Rt 0.483min;[MH]+ 376.2。
LC/MS(方法E):Rt 1.034min、[MH]+ 357.2。
例A:注射バイアル
3lの再蒸留水中の100gの式Iの活性成分および5gのリン酸水素二ナトリウムの溶液を2N塩酸を使用してpH6.5まで調整し、滅菌濾過し、注射バイアル中へ移し、滅菌条件下で凍結乾燥させ、滅菌条件下で密封する。各注射バイアルは、5mgの活性成分を含有する。
20gの式Iの活性成分と100gの大豆レシチンおよび1400gのカカオバターの混合物を溶融し、型中に注ぎ、冷却するようにする。各坐薬は、20mgの活性成分を含有する。
溶液を、940mlの再蒸留水中1gの式Iの活性成分、9.38gのNaH2PO4・2H2O、28.48gのNa2HPO4・12H2Oおよび0.1gのベンザルコニウムクロリドから調製する。pHを6.8まで調整し、溶液を最大1lにし、照射によって滅菌する。この溶液は、点眼薬の形態で使用され得る。
500mgの式Iの活性成分を、無菌条件下で99.5gのワセリンと混合する。
1kgの式Iの活性成分、4kgのラクトース、1.2kgのジャガイモデンプン、0.2kgのタルクおよび0.1kgのステアリン酸マグネシウムの混合物を従来のやり方で圧縮することで、各錠剤が10mgの活性成分を含有するように錠剤が与えられる。
錠剤を、例Eに類似して圧縮し、続いて従来のやり方において、スクロース、ジャガイモデンプン、タルク、トラガラントおよび色素のコーティングで被覆する。
2kgの式Iの活性成分を、従来のやり方において、各カプセルが20mgの活性成分を含有するように、硬質ゼラチンカプセル中に導入する。
60lの再蒸留水中1kgの式Iの活性成分の溶液を滅菌濾過し、アンプル中に移し、滅菌条件下で凍結乾燥させ、滅菌条件下で密封する。各アンプルは、10mgの活性成分を含有する。
Claims (10)
- 式IaまたはIb
R1は、H、Het、Ar、(CH2)nOH、1−メチルスルホニル−シクロプロパ−1−イル、CONH2、CONHA、CONA2、Cyc、OAまたはCH(A)SO2Aを示し、
R2は、H、A、(CH2)nAr、(CH2)nCycまたは(CH2)nHetを示し、
R3は、HまたはAを示し、
Hetは、1〜4個のN、Oおよび/またはS原子を有する単環式または二環式の芳香族、不飽和または飽和ヘテロ環を示し、それは、非置換であるか、またはNH2、NHA、NA2、COOH、COOA、CONH2、CONHA、CONA2、CONHAr、CN、OH、(CH2)nAr1、O(CH2)nAr1、A、SOA、SO2A、Hal、=NHおよび/もしくは=Oによって単置換、二置換、もしくは三置換されていてもよく、
Arは、フェニル、ナフチルまたはビフェニルを示し、その各々は、非置換であるか、またはNH2、NHA、NA2、COOH、COOA、CONH2、CONHA、CONA2、NHCOA、CHO、COA、SO3H、SO2NH2、O(CH2)pNH2、(CH2)nHet1、O(CH2)nHet1、(CH2)nAr1、O(CH2)nAr1、O(CH2)pCONH2、O(CH2)pNHCOA、Hal、SOA、S(=O、=NH)A、SO2A、A、CNおよび/もしくは(CH2)nOHによって単置換、二置換、もしくは三置換されており、
Ar1は、非置換であるか、またはHal、A、OHおよび/もしくはOAによって単置換、二置換、もしくは三置換されているフェニルを示し、
Het1は、1〜4個のN、Oおよび/またはS原子を有する単環式または二環式の芳香族、不飽和または飽和ヘテロ環を示し、それは、非置換であるか、Hal、A、COOA、NH2、NHAおよび/もしくはNA2によって単置換、二置換、もしくは三置換されていてもよく、
Aは、1〜6個のC原子を有する非分枝または分枝のアルキルを示し、ここで、1〜7個のH原子は、OH、F、Clおよび/もしくはBrによって置き換えられていてもよく、ならびに/または、ここで、1もしくは2の非隣接CH2は、Oおよび/もしくはNH基によって置き換えられていてもよく、
Cycは、3、4、5、6または7個のC原子を有する環状アルキルを示し、
Halは、F、Cl、BrまたはIを示し、
nは、0、1、2、3または4を示し、
pは、1、2、3または4を示す、
で表される化合物、およびその薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率におけるそれらの混合物。 - Hetが、1H−ピロロ[2,3−b]ピリジニル、1H−ピロロ[2,3−c]ピリジニル、インドリル、ベンズイミダゾリル、イミダゾリル、1,2,3,4−テトラヒドロイソキノリル、ピリジル、ピリミジニル、トリアゾリル、ピラゾリル、キノリル、イソキノリル、キナゾリニル、フラニル、テトラヒドロフラニル、ピラニル、3,6−ジヒドロ−2H−ピラニル、テトラヒドロピラニル、3,6−ジヒドロ−2H−チオピラニルまたはヘキサヒドロ−チオピラニルを示し、その各々が、非置換であるか、またはA、SOA、SO2A、Halおよび/もしくは=Oによって単置換、二置換、もしくは三置換されている、
請求項1に記載の化合物、およびその薬学的に許容し得る溶媒和物、塩、互変異性体および立体異性体、ならびにあらゆる比率におけるそれらの混合物。 - Arが、フェニルを示し、それが、非置換であるか、またはSOA、S(=O、=NH)A、SO2A、A、CNおよび/もしくは(CH2)nOHによって単置換、二置換、もしくは三置換されている、
請求項1または2に記載の化合物、およびその薬学的に許容し得る溶媒和物、塩、互変異性体および立体異性体、ならびにあらゆる比率におけるそれらの混合物。 - R1が、H、Het、Ar、(CH2)nOH、1−メチルスルホニル−シクロプロパ−1−イル、CONH2、CONHA、CONA2、Cyc、OAまたはCH(A)SO2Aを示し、
R2が、H、A、(CH2)nAr、(CH2)nCycまたは(CH2)nHetを示し、
R3が、HまたはAを示し、
Hetが、1H−ピロロ[2,3−b]ピリジニル、1H−ピロロ[2,3−c]ピリジニル、インドリル、ベンズイミダゾリル、イミダゾリル、1,2,3,4−テトラヒドロイソキノリル、ピリジル、ピリミジニル、トリアゾリル、ピラゾリル、キノリル、イソキノリル、キナゾリニル、フラニル、テトラヒドロフラニル、ピラニル、3,6−ジヒドロ−2H−ピラニル、テトラヒドロピラニル、3,6−ジヒドロ−2H−チオピラニルまたはヘキサヒドロ−チオピラニルを示し、その各々が、非置換であるか、またはA、SOA、SO2A、Halおよび/もしくは=Oによって単置換、二置換、もしくは三置換されており、
Arが、フェニルを示し、それが、非置換であるか、またはSOA、S(=O、=NH)A、SO2A、A、CNおよび/もしくは(CH2)nOHによって単置換、二置換、もしくは三置換されており、
Aが、1〜6個のC原子を有する非分枝または分枝のアルキルを示し、ここで、1〜7個のH原子が、OH、F、Clおよび/もしくはBrによって置き換えられていてもよく、ならびに/または、ここで、1もしくは2の非隣接CH2基が、Oおよび/もしくはNH基によって置き換えられていてもよく、
Cycが、3、4、5、6または7個のC原子を有する環状アルキルを示し、
Halが、F、Cl、BrまたはIを示し、
nが、0、1、2、3または4を示す、
請求項1〜3のいずれか一項に記載の化合物、およびその薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率におけるそれらの混合物。 - 請求項1に記載の記載の式IaまたはIbで表される化合物、および/またはその薬学的に許容し得る塩、溶媒和物、互変異性体および立体異性体、ならびにあらゆる比率におけるそれらの混合物の少なくとも1種と、任意に薬学的に許容し得る担体、賦形剤またはビヒクルとを含む、医薬。
- がん、加齢性黄斑変性症(AMD)、脈絡膜新生血管(CNV)、糖尿病網膜症、糖尿病黄斑浮腫(DME)、進行性骨化性線維異形成症、炎症、血管新生関連障害および細菌感染症の処置および/または予防のための使用のための、請求項1に記載の式Iaまたは式Ibで表される化合物、およびその薬学的に許容し得る塩、溶媒和物、互変異性体および立体異性体、ならびにあらゆる比率におけるそれらの混合物。
- 頭部、頸部、目、口、喉、食道、気管支、喉頭、咽頭、胸部、骨、肺、結腸、直腸、胃、前立腺、膀胱、子宮、子宮頸、乳房、卵巣、精巣または他の生殖器、皮膚、甲状腺、血液、リンパ節、腎臓、肝臓、膵臓、脳、中枢神経系のがん、固形腫瘍および血液由来の腫瘍の処置および/または予防のための使用のための、請求項7に記載の化合物。
- 請求項1に記載の記載の式IaまたはIbで表される化合物、および/またはその薬学的に許容し得る塩、溶媒和物、および立体異性体、ならびにあらゆる比率におけるそれらの混合物の少なくとも1種と、さらなる医薬活性成分の少なくとも1種とを含む、医薬。
- (a)有効量の、請求項1に記載の式IaまたはIbで表される化合物および/またはその薬学的に許容し得る塩、溶媒和物、塩および立体異性体、ならびにあらゆる比率におけるそれらの混合物、ならびに
(b)有効量のさらなる医薬活性成分
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PT3176170T (pt) | 2012-06-13 | 2019-02-05 | Incyte Holdings Corp | Compostos tricíclicos substituídos como inibidores de fgfr |
PE20152033A1 (es) | 2013-04-19 | 2016-01-21 | Incyte Holdings Corp | Heterociclos bicicliclos como inhibidores de fgfr |
EP3617205B1 (en) | 2015-02-20 | 2021-08-04 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
CN112867716A (zh) | 2018-05-04 | 2021-05-28 | 因赛特公司 | Fgfr抑制剂的固体形式和其制备方法 |
WO2020185532A1 (en) | 2019-03-08 | 2020-09-17 | Incyte Corporation | Methods of treating cancer with an fgfr inhibitor |
CN112142744A (zh) * | 2019-06-28 | 2020-12-29 | 上海瑛派药业有限公司 | 取代的稠合杂芳双环化合物作为激酶抑制剂及其应用 |
WO2021007269A1 (en) * | 2019-07-09 | 2021-01-14 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
JOP20220083A1 (ar) | 2019-10-14 | 2023-01-30 | Incyte Corp | حلقات غير متجانسة ثنائية الحلقة كمثبطات لـ fgfr |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US20230018728A1 (en) * | 2019-11-21 | 2023-01-19 | Jiangsu Hengrui Medicine Co., Ltd. | Pyrazolo-heteroaryl derivative, preparation method therefor, and medical use thereof |
CA3162010A1 (en) | 2019-12-04 | 2021-06-10 | Incyte Corporation | Derivatives of an fgfr inhibitor |
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AU2021302146A1 (en) * | 2020-07-03 | 2023-01-19 | Antengene Discovery Limited | ATR inhibitors and uses thereof |
KR20230039675A (ko) * | 2020-07-13 | 2023-03-21 | 베이징 타이드 파마슈티컬 코퍼레이션 리미티드 | Atr 키나제 억제제로 사용되는 피라졸로피리미딘 화합물 |
TW202220993A (zh) * | 2020-08-07 | 2022-06-01 | 香港商德琪研發有限公司 | Atr抑制劑及其用途 |
US20240043419A1 (en) * | 2020-09-27 | 2024-02-08 | Medshine Discovery Inc. | Class of 1,7-naphthyridine compounds and application thereof |
EP4267581A1 (en) * | 2020-12-25 | 2023-11-01 | Impact Therapeutics (Shanghai), Inc | Substituted imidazo[1,5-b]pyridazine compounds as kinase inhibitors and use thereof |
CN117355524A (zh) * | 2021-05-21 | 2024-01-05 | 江苏恒瑞医药股份有限公司 | 一种吡唑并杂芳基类衍生物的可药用盐及其结晶形式 |
US11939331B2 (en) | 2021-06-09 | 2024-03-26 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
TW202321256A (zh) | 2021-07-27 | 2023-06-01 | 大陸商上海輝啟生物醫藥科技有限公司 | 8-氧-3-氮雜雙環[3.2.1]辛烷類化合物或其鹽及其製備方法和用途 |
WO2023109883A1 (zh) * | 2021-12-15 | 2023-06-22 | 上海翊石医药科技有限公司 | 一类芳杂环取代的化合物及其制备方法和用途 |
WO2023116865A1 (zh) * | 2021-12-23 | 2023-06-29 | 优领医药科技(上海)有限公司 | 含吡唑类衍生物、其药学上可接受的盐及其制备方法和应用 |
WO2023131234A1 (en) * | 2022-01-06 | 2023-07-13 | Shanghai Antengene Corporation Limited | Crystalline forms of an atr inhibitor |
CN115745995A (zh) * | 2022-01-10 | 2023-03-07 | 苏州浦合医药科技有限公司 | Atr抑制剂及其用途 |
WO2023138621A1 (en) * | 2022-01-19 | 2023-07-27 | Shanghai Antengene Corporation Limited | Atr inhibitors and uses thereof |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2010111624A (ja) * | 2008-11-06 | 2010-05-20 | Shionogi & Co Ltd | Ttk阻害作用を有するインダゾール誘導体 |
US20110053923A1 (en) | 2008-12-22 | 2011-03-03 | Astrazeneca | Chemical compounds 610 |
WO2013130660A1 (en) | 2012-02-28 | 2013-09-06 | Amgen Inc. | Amides as pim inhibitors |
KR20160101188A (ko) * | 2013-12-23 | 2016-08-24 | 메르크 파텐트 게엠베하 | 이미다조피라지논 유도체 |
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EP3402795B1 (en) | 2016-01-14 | 2019-10-30 | Bayer Pharma Aktiengesellschaft | 5-substituted 2-(morpholin-4-yl)-1,7-naphthyridines |
US10934304B2 (en) | 2016-10-05 | 2021-03-02 | Recurium Ip Holdings, Llc | Spirocyclic compounds |
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