JP2018536705A - ブルトン型チロシンキナーゼのイミダゾピラジン阻害剤 - Google Patents
ブルトン型チロシンキナーゼのイミダゾピラジン阻害剤 Download PDFInfo
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- JP2018536705A JP2018536705A JP2018541596A JP2018541596A JP2018536705A JP 2018536705 A JP2018536705 A JP 2018536705A JP 2018541596 A JP2018541596 A JP 2018541596A JP 2018541596 A JP2018541596 A JP 2018541596A JP 2018536705 A JP2018536705 A JP 2018536705A
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
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- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
ある実施形態において、本発明は、複素環化合物、これらの化合物を含む医薬組成物、および治療におけるそれらの使用に関する。ある実施形態において、本発明は、過剰増殖性疾患、炎症性疾患、免疫疾患、または自己免疫疾患の治療におけるイミダゾピラジン化合物の使用に関する。
Bリンパ球活性化は、適応免疫応答の発生において重要である。逸脱したBリンパ球活性化は、多くの自己免疫疾患の特徴であり、したがって、この免疫応答の調節は、治療上興味深い。最近、自己免疫疾患におけるB細胞治療の成功が確立された。リツキシマブ(抗CD20治療)による関節リウマチ(RA)患者の治療は、認められた臨床治療である。より最近の臨床試験研究は、リツキシマブによる治療が、再発寛解型多発性硬化症(RRMS)および全身性エリテマトーデス(SLE)患者における病徴も改善することを示す。この成功は、B細胞免疫を標的にする自己免疫疾患における将来の治療の可能性を裏付ける。
一態様において、BTK阻害剤は、以下の構造を有する式(I)の化合物:
(式中:
R1が、水素またはメトキシであり、ここで、メトキシが、1つまたは2つのフルオロで任意選択により置換され;
Xが、
であり;
R2が、水素、ハロゲン、メチル、メトキシ、またはエトキシであり、ここで、メチル、メトキシ、およびエトキシがそれぞれ、1つ、2つ、または3つのフルオロで任意選択により置換され;
Yが、
であり;
R3が、Hまたはメチルである)
またはその薬学的に許容できる塩、共結晶、エステル、プロドラッグ、溶媒和物、水和物もしくは誘導体である。
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(2−ピリジル)ベンズアミド(式E−1);
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(2−ピリジル)ベンズアミド(式E−2);
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド(式E−3);
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミド(式E−4);
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミド(式E−5);
4−[8−アミノ−3−[(1S)−1−[[(E)−4−メトキシブタ−2−エノイル]−メチル−アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド(式E−6);
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミド(式E−7);
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミド(式E−8);
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(2−ピリジル)ベンズアミド(式E−9);
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミド(式E−10);
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド(式E−11);
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミド(式E−12);
4−[8−アミノ−3−[(1S)−1−[[(E)−4−メトキシブタ−2−エノイル]アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド(式E−13);
4−[8−アミノ−3−[(1S)−1−[[(E)−4−メトキシブタ−2−エノイル]アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミド(式E−14);
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−チアゾール−2−イル−ベンズアミド(式E−15);
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド(式E−16);
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミド(式E−17);
(R)−4−(8−アミノ−3−(1−(ブタ−2−イノイル)ピロリジン−2−イル)イミダゾ[1,5−a]ピラジン−1−イル)−N−(チアゾール−4−イル)ベンズアミド(式E−24)からなる群から選択される式(I)の化合物;およびその薬学的に許容できる塩、共結晶、エステル、プロドラッグ、溶媒和物、水和物もしくは誘導体を含む。
本発明の好ましい実施形態が、本明細書に示され、記載されているが、このような実施形態は、例として示されるに過ぎず、本発明の範囲を特に限定することは意図されていない。本発明の記載される実施形態の様々な代替例が、本発明を実施するのに用いられ得る。
本発明のBTK阻害剤は、(不可逆的に)標的に共有結合するBTK阻害剤および(可逆的に)標的に非共有結合的に結合するBTK阻害剤を含む。一実施形態において、BTK阻害剤は、BTKの481位においてシステイン残基に共有結合する。
(式中:
R1が、水素またはメトキシであり、ここで、メトキシが、1つまたは2つのフルオロで任意選択により置換され;
Xが、
であり;
R2が、水素、ハロゲン、メチル、メトキシ、またはエトキシであり、ここで、メチル、メトキシ、およびエトキシがそれぞれ、1つ、2つ、または3つのフルオロで任意選択により置換され;
Yが、
であり;
R3が、Hまたはメチルである)
またはその薬学的に許容できる塩、共結晶、エステル、プロドラッグ、溶媒和物、水和物もしくは誘導体である。
R1が水素であり;
Xが、
であり;
R2が、水素、ハロゲン、メチル、メトキシ、またはエトキシであり、ここで、メチル、メトキシ、およびエトキシがそれぞれ、1つ、2つ、または3つのフルオロで任意選択により置換され;
Yが、
である。
R1がメトキシであり;
Xが、
であり;
Yが、
であり;
R3が、Hまたはメチルである。
R1が水素であり;
Xが、
であり;
Yが、
であり;
R3が、Hまたはメチルである。
Xが、
であり;
R2が、水素、ハロゲン、メチル、メトキシ、またはエトキシであり、ここで、メチル、メトキシ、およびエトキシがそれぞれ、1つ、2つ、または3つのフルオロで任意選択により置換され;
Yが、
であり;
R3が、Hまたはメチルである。
Xが、
であり;
R2が、水素、ハロゲン、メチル、メトキシ、またはエトキシであり、ここで、メチル、メトキシ、およびエトキシがそれぞれ、1つ、2つ、または3つのフルオロで任意選択により置換され;
Yが、
であり;
R3が、Hまたはメチルである。
Xが、
であり;
R2が、水素、ハロゲン、メチル、メトキシ、またはエトキシであり、ここで、メチル、メトキシ、およびエトキシがそれぞれ、1つ、2つ、または3つのフルオロで任意選択により置換され;
Yが、
であり;
R3が、Hまたはメチルである。
Xが、
であり;
R2が、水素、ハロゲン、メチル、メトキシ、またはエトキシであり、ここで、メチル、メトキシ、およびエトキシがそれぞれ、1つ、2つ、または3つのフルオロで任意選択により置換され;
Yが、
であり;
R3が、Hまたはメチルである。
Xが、
であり;
R2が、水素、ハロゲン、メチル、メトキシ、またはエトキシであり、ここで、メチル、メトキシ、およびエトキシがそれぞれ、1つ、2つ、または3つのフルオロで任意選択により置換され;
Yが、
である。
Xが、
であり;
R2が、水素、ハロゲン、メチル、メトキシ、またはエトキシであり、ここで、メチル、メトキシ、およびエトキシがそれぞれ、1つ、2つ、または3つのフルオロで任意選択により置換され;
Yが、
である。
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(2−ピリジル)ベンズアミド(式E−1);
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(2−ピリジル)ベンズアミド(式E−2);
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド(式E−3);
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミド(式E−4);
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミド(式E−5);
4−[8−アミノ−3−[(1S)−1−[[(E)−4−メトキシブタ−2−エノイル]−メチル−アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド(式E−6);
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミド(式E−7);
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミド(式E−8);
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(2−ピリジル)ベンズアミド(式E−9);
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミド(式E−10);
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド(式E−11);
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミド(式E−12);
4−[8−アミノ−3−[(1S)−1−[[(E)−4−メトキシブタ−2−エノイル]アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド(式E−13);
4−[8−アミノ−3−[(1S)−1−[[(E)−4−メトキシブタ−2−エノイル]アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミド(式E−14);
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−チアゾール−2−イル−ベンズアミド(式E−15);
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド(式E−16);
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミド(式E−17);
(R)−4−(8−アミノ−3−(1−(ブタ−2−イノイル)ピロリジン−2−イル)イミダゾ[1,5−a]ピラジン−1−イル)−N−(チアゾール−4−イル)ベンズアミド(式E−24)
からなる群から選択される式(I)の化合物;およびその薬学的に許容できる塩、共結晶、エステル、プロドラッグ、溶媒和物、水和物もしくは誘導体である。
からなる群から選択される化合物、その鏡像異性体、およびその薬学的に許容できる塩、共結晶、エステル、プロドラッグ、溶媒和物、水和物もしくは誘導体である。
選択された実施形態において、本発明は、固形腫瘍癌、リンパ腫および白血病を治療するための医薬組成物を提供する。
選択された実施形態において、本発明は、本明細書に開示されるBTK阻害剤および経口投与に好適な薬剤賦形剤を含有する、経口投与用の医薬組成物を提供する。
選択された実施形態において、本発明は、BTK阻害剤および注射に好適な薬剤賦形剤を含有する注射用の医薬組成物を提供する。組成物中の薬剤の成分および量は、本明細書に記載されるとおりである。
投与されるBTK阻害剤の量は、治療される哺乳動物、疾患または病態の重症度、投与速度、化合物の性質(disposition)および処方医師の裁量に依存する。しかしながら、有効な投与量は、単回または分割投与で、1日当たりkg体重当たり約0.001〜約100mg、例えば、約1〜約35mg/kg/日の範囲である。70kgのヒトの場合、これは、約0.05〜7g/日、例えば、約0.05〜約2.5g/日になるであろう。ある場合には、上記の範囲の下限未満の投与量レベルが、十分以上であり得る一方、他の場合には、さらに多い用量が、例えば、このようなより多い用量を、1日を通した投与のためにいくつかの少ない用量に分割することによって、有害な副作用を引き起こさずに用いられ得る。
ある実施形態において、本発明は、哺乳動物における過剰増殖性疾患、炎症性疾患、免疫疾患、または自己免疫疾患を治療する方法であって、治療的有効量のBTK阻害剤、またはBTK阻害剤の薬学的に許容できる塩、共結晶、エステル、プロドラッグ、溶媒和物、水和物もしくは誘導体を前記哺乳動物に投与することを含む方法に関する。
HATU:O−(7−アザベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスフェート
POCl3:オキシ塩化リン(V)
DMF:N,N−ジメチルホルムアミド
NBS:N−ブロモスクシンイミド
DCM:ジクロロメタン
EtOAc:酢酸エチル
KOAc:酢酸カリウム
IPA:2−プロパノール
ACN:アセトニトリル
MW:マイクロ波
AcOH:酢酸
DIPEA:N,N−ジイソプロピルエチルアミン
THF:テトラヒドロフラン
EtOH:エタノール
EDCI:1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド
DMAP:ジメチルアミノピリジン
HPLC:高速液体クロマトグラフィー
LiHMDS:リチウムヘキサメチルジシラジド
MeOH:メタノール
n−BuLi:n−ブチルリチウム
NMR:核磁気共鳴
LC−MS:液体クロマトグラフィー−質量分析法
SCX−2:強酸性カチオン交換−2
KOtBu:カリウムtert.ブトキシド
T3P:プロピルホスホン酸無水物
RT:室温
Rt:保持時間
NMP:1−メチル−2−ピロリジノン
TFA:トリフルオロ酢酸
DMSO:ジメチルスルホキシド
DIAD:アゾジカルボン酸ジイソプロピル
THP:テトラヒドロピラン
TBDMS:tert−ブチルジメチルシリル
TEA:トリエチルアミン
Pd2(dba)3:トリス(ジベンジリデンアセトン)ジパラジウム(0)
PdCl2(dppf).DCM:ジクロロメタンとの錯体である、[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)
TLC:薄層クロマトグラフィー
PE:相交換
CDCl3:クロロホルム−d
HBr:臭化水素
K2CO3:炭酸カリウム
m/z:質量電荷比
本発明に含まれるBTK阻害剤は、有機化学の技術分野において周知の方法によって調製され得る。例えば、March,Advanced Organic Chemistry,4th Edition,John Wiley & Sons,2001を参照されたい。合成プロセス中、該当する分子のいずれかにおける感受性または反応性基を保護することが必要であるか、および/または望ましいことがある。これは、Greene and Wutts,Protective Groups in Organic Synthesis,3rd Edition,John Wiley & Sons,1999に記載されるものなどの従来の保護基によって達成される。保護基は、当該技術分野において周知の方法を用いて、好都合なその後の段階で任意選択により除去される。
以下の液体クロマトグラフィー(LC)および質量分析法(MS)方法が、本発明に含まれる化合物を特性評価するのに使用され得る。
LC−MS分光計(Agilent)
検出器:DAD(210、254および280nm)
質量検出器:API−ES(10〜2000amu、正/負イオンモード)
溶離剤(移動相):A:MilliQ水中0.1%のギ酸、B:アセトニトリル
カラム:Waters XTerra C18 MS、50×4.6mmの内径、2.5μm
流量:0.5mL/分
LC−MS分光計(Waters);検出器:DAD(214nm)
質量検出器:API−ES(100〜1000amu、正/負イオンモード)
溶離剤(移動相):A:水中0.1%のトリフルオロ酢酸(TFA);B:アセトニトリル
LC−MSフロー方法:勾配
カラム:Acquity HSS-T3(2.1×100mm×1.8μm)
流量:0.3mL/分
HPLC:Gilson分析HPLCシステム
カラム:Phenomenex Luna C18(2)(100×2.00mm、5μm)
検出器:UV/Vis(210/240nm)
流量:1mL/分
溶離剤(移動相):A:アセトニトリル、B:アセトニトリル/MilliQ水=1/9(v/v)、C:MilliQ水中0.1%のTFA
HPLC:Waters分析HPLCシステム;カラム:SunFire-C18(4.6×50mm、5μm)
検出器:UV/Vis(210/240nm)
流量:1mL/分
溶離剤(移動相):A:水中5mMの酢酸アンモニウム、B:アセトニトリル
HPLC:Waters分析HPLCシステム;カラム:X-Bridge Shield-RP-18(4.6×250mm、5μm)
検出器:プログラム可能なダイオードアレイ
流量:1mL/分
溶離剤:A:水中2mMの酢酸アンモニウム、B:アセトニトリル
4−ブロモ−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミドの調製。DMF(150mL)中の4−(トリフルオロメチル)ピリジン−2−アミン(13.0g、80.1mmol)および4−ブロモ−2−メトキシ−安息香酸(18.5g、80.1mmol)の溶液を0℃に冷却し、N,N−ジイソプロピルエチルアミン(44.2mL、240.3mmol)を加え、次に、プロピルホスホン酸無水物溶液(ジクロロメタン中50%、76.4g、120.1mmol)を滴下して加え、反応混合物を80℃で16時間加熱した。反応混合物を冷却し、水(300mL)で希釈した。得られた固体をろ過して取り出し、水(300mL)で洗浄した。この固体を、ジクロロメタン(200mL)中10%のメタノールに溶解させ、水で洗浄した。有機部分を硫酸ナトリウム上で乾燥させ、ろ過し、濃縮して、4−ブロモ−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミド(17.0g、56.8%)を淡褐色の固体として得た。
ベンジルN−[(1S)−2−[(3−クロロピラジン−2−イル)メチルアミノ]−1−メチル−2−オキソ−エチル]−N−メチル−カルバメートの調製。N,N−ジイソプロピルエチルアミン(19.35mL、111.09mmol)を、ジクロロメタン(250mL)中の、(2S)−2−[ベンジルオキシカルボニル(メチル)アミノ]プロパン酸(6.59g、27.77mmol)と、(3−クロロピラジン−2−イル)メタンアミン塩酸塩(5.00g、27.77mmol)と、HATU(15.84g、41.66mmol)との混合物に、10分間で滴下して加え、得られた混合物を20℃で3時間撹拌した。混合物を、飽和炭酸水素ナトリウム水溶液(200mL)で1回、および飽和塩化アンモニウム水溶液(200mL)で1回洗浄した。有機層を硫酸ナトリウム上で乾燥させ、ろ過し、蒸発乾固させた。残渣を、シリカゲルにおけるフラッシュカラムクロマトグラフィー(ヘプタン中0〜100%の酢酸エチル)によって精製して、ベンジルN−[(1S)−2−[(3−クロロピラジン−2−イル)メチルアミノ]−1−メチル−2−オキソ−エチル]−N−メチル−カルバメート(9.2g、91.3%)を無色油として得た。データ:LC−MS(方法A)Rt:5.32分;m/z 363.2(M+H)+。
ベンジルN−[(1S)−1−[8−アミノ−1−[4−(2−ピリジルカルバモイル)フェニル]イミダゾ[1,5−a]ピラジン−3−イル]エチル]−N−メチル−カルバメートの調製。中間体I−2(300mg、0.74mmol)を、1,4−ジオキサン(15mL)中のN−(2−ピリジル)−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンズアミド(313mg、0.96mmol)に加え、2Mの炭酸カリウム水溶液(3mL)を加え、混合物を、5分間にわたってN2ガスでパージした。ビス(dppf)Pd(II)Cl2(30.3mg、0.04mmol)を加え、混合物を再度パージし、反応混合物を、マイクロ波中で、140℃で30分間撹拌した。反応混合物を水(50mL)に注ぎ、酢酸エチル(100mL)で2回抽出した。組み合わされた有機抽出物を飽和塩水(100mL)で1回洗浄し、硫酸ナトリウム上で乾燥させ、減圧下で濃縮した。残渣を、フラッシュカラムクロマトグラフィー(ジクロロメタン中0〜8%のメタノール)によって精製して、ベンジルN−[(1S)−1−[8−アミノ−1−[4−(2−ピリジルカルバモイル)フェニル]イミダゾ[1,5−a]ピラジン−3−イル]エチル]−N−メチル−カルバメート(205mg、53.0%)を黄色の油として得た。データ:LC−MS(方法A)Rt:4.69分;m/z 522.2(M+H)+。
4−ブロモ−2−メトキシ−N−(2−ピリジル)ベンズアミドの調製。ジクロロメタン(250mL)中の4−ブロモ−2−メトキシ−安息香酸(15.3g、66.2mmol)の溶液に、ピリジン−2−アミン(6.9g、72.8mmol)およびDIPEA(34.6mL、198.7mmol)を加えた。HATU(32.7g、86.1mmol)を加え、混合物を室温で一晩撹拌した。水(200mL)を加え、反応混合物を1時間撹拌した。有機層を減圧下で濃縮した。DCM(50mL)を加え、溶液を週末にかけて結晶化させた。固体をろ過して取り出し、ジエチルエーテル(10mL)で2回洗浄し、減圧下で乾燥させて、4−ブロモ−2−メトキシ−N−(2−ピリジル)ベンズアミド(14.4g、66.8%)を淡褐色の結晶として得た。データ:LC−MS(方法A)Rt:6.05分;m/z 307.0+309.0(1:1)(M+H)+。
4−[8−アミノ−3−[(1S)−1−(メチルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(2−ピリジル)ベンズアミドの調製。中間体I−2およびI−4を用いて、中間体I−3について記載されるのと類似の方法でこの化合物を調製して、表題化合物(2工程で、320mg、100%)を淡黄色の固体として得た。データ:LC−MS(方法A)Rt:2.38分;m/z 418.2(M+H)+。
N−(5−メチル−2−ピリジル)−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンズアミドの調製。4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)安息香酸(3.0g、12.09mmol)、5−メチルピリジン−2−アミン(1.43g、13.3mmol)、EDCI(2.55g、13.3mmol)およびDMAP(177.3mg、1.45mmol)を、DCM(50mL)に溶解させた。反応混合物を21℃で一晩撹拌した。50mLの3%のクエン酸水溶液を反応混合物に加え、反応混合物を15分間撹拌した。有機層を、50mLの1%のクエン酸水溶液および塩水(50mL)で連続して洗浄し、PEフィルタ上に注ぎ、減圧下で濃縮して、表題化合物をオフホワイトの固体(3.52g、86.0%)として得た。データ:LC−MS Rt:6.397分;m/z 339.3(M+H)+;1H NMR(400MHz、CDCl3、300K):δ=8.86(1H,s)、8.32(1H,d,J=8.5Hz)、8.12(1H,m)、7.93(4H,s)、7.60(1H,dd,J1=2.3Hz、J2=8.5Hz)、2.33(3H,s)、1.37(12H,s)。
4−[8−アミノ−3−[(1S)−1−(メチルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミドの調製。中間体I−2およびI−6を用いて、中間体I−3について記載されるのと類似の方法でこの化合物を調製して、表題化合物(2工程で、275mg、92%)を淡黄色の固体として得た。データ:LC−MS(方法A)Rt:1.60分;m/z 402.1(M+H)+。
2−メトキシ−N−(5−メチル−2−ピリジル)−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンズアミドの調製。2−メトキシ−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)安息香酸を用いて、中間体I−6について記載されるのと類似の方法でこの化合物を調製して、表題化合物(4.21g、75.2%)をオフホワイトの固体として得た。データ:LC−MS Rt:7.178分;m/z 369.3(M+H)+;1H NMR(400MHz、CDCl3、300K):δ=10.34(1H,s)、8.33(1H,d,J=8.6Hz)、8.25(1H,d,J=7.7Hz)、8.14(1H,m)、7.55(2H,d,J=7.8Hz)、7.44(1H,s)、4.12(3H,s)、2.31(3H,s)、1.37(12H,s)。
4−[8−アミノ−3−[(1S)−1−(メチルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミドの調製。中間体I−2およびI−8を用いて、中間体I−3について記載されるのと類似の方法でこの化合物を調製して、表題化合物(2工程で、209mg、66%)を淡黄色の固体として得た。データ:LC−MS(方法A)Rt:2.86分;m/z 432.2(M+H)+。
ベンジル(2S)−2−(8−アミノ−1−ブロモ−イミダゾ[1,5−a]ピラジン−3−イル)ピロリジン−1−カルボキシレート硫酸塩の調製。国際特許出願公開番号国際公開第2013/010868A1号パンフレット(その開示内容が、参照により本明細書に援用される)に記載されるのと類似の方法でこの化合物を調製して、表題化合物をベージュ色の固体として得た。データ:LC−MS(方法A)Rt:3.736分;m/z 414.1+416.1(1:1)(M+H)+。
4−[8−アミノ−3−[(2S)−ピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミドの調製。中間体I−1およびI−10を用いて、中間体I−3について記載されるのと類似の方法でこの化合物を調製して、表題化合物(2工程で、165mg、47%)を淡黄色の固体として得た。データ:LC−MS(方法A)Rt:3.86分;m/z 498.3(M+H)+。
ベンジルN−[(1S)−1−(8−アミノ−1−ブロモ−イミダゾ[1,5−a]ピラジン−3−イル)エチル]カルバメートの調製。(2S)−2−(ベンジルオキシカルボニルアミノ)プロパン酸を用いて、中間体I−2について記載されるのと類似の方法でこの化合物を調製して、表題化合物(4工程で、1.8g、42%)を白色の固体として得た。データ:LC−MS(方法A)Rt:3.59分;m/z 390.0+392.0(1:1)(M+H)+。
4−[8−アミノ−3−[(1S)−1−アミノエチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミドの調製。中間体I−1およびI−12を用いて、中間体I−3について記載されるのと類似の方法でこの化合物を調製して、表題化合物(2工程で、79mg、65%)を得た。データ:LC−MS(方法A)Rt:3.771分;m/z 472.2(M+H)+。
4−[8−アミノ−3−[(1S)−1−アミノエチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(2−ピリジル)ベンズアミドの調製。中間体I−4およびI−12を用いて、中間体I−3について記載されるのと類似の方法でこの化合物を調製して、表題化合物(2工程で、164mg、66%)を黄色の固体として得た。データ:LC−MS(方法A)Rt:2.04分;m/z 404.1(M+H)+。
4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミドの調製。4−(トリフルオロメチル)ピリジン−2−アミンを用いて、中間体I−6について記載されるのと類似の方法でこの化合物を調製して、表題化合物(694mg、43.9%)を白色の固体として得た。データ:LC−MS(方法A)Rt:7.74分;m/z 393.3(M+H)+。
4−[8−アミノ−3−[(1S)−1−アミノエチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミドの調製。中間体I−12およびI−15を用いて、中間体I−3について記載されるのと類似の方法でこの化合物を調製して、表題化合物(2工程で、135mg、59.6%)を黄色の固体として得た。データ:LC−MS(方法A)Rt:3.40分;m/z 442.2(M+H)+。
4−[8−アミノ−3−[(1S)−1−アミノエチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミドの調製。中間体I−12およびI−6を用いて、中間体I−3について記載されるのと類似の方法でこの化合物を調製して、表題化合物(2工程で、217mg、70%)を淡黄色の固体として得た。データ:LC−MS(方法A)Rt:1.28分;m/z 388.2(M+H)+。
4−[8−アミノ−3−[(1S)−1−アミノエチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミドの調製。中間体I−12およびI−8を用いて、中間体I−3について記載されるのと類似の方法でこの化合物を調製して、表題化合物(2工程で、219mg、77%)を黄色の固体として得た。データ:LC−MS(方法A)Rt:2.68分;m/z 418.2(M+H)+。
4−ブロモ−2−メトキシ−ベンゾイルクロリドの調製。4−ブロモ−2−メトキシ−安息香酸(8.38g、36.27mmol)を、DCM(75mL)に溶解させた。塩化チオニル(5.29mL、72.54mmol)および触媒量のDMFを加えた。反応混合物を還流状態で3時間撹拌した。反応混合物を減圧下で濃縮し、油ポンプ上で乾燥させて、定量的収率(9.5g)で黄色の固体を得た。
4−[8−アミノ−3−[(2S)−ピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−チアゾール−2−イル−ベンズアミドの調製。中間体I−10およびI−19を用いて、中間体I−3について記載されるのと類似の方法でこの化合物を調製して、表題化合物(2工程で、89mg、42%)を黄色の固体として得た。データ:LC−MS(方法A)Rt:2.851分;m/z 436.3(M+H)+。
4−[8−アミノ−3−[(2S)−ピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミドの調製。中間体I−10およびI−6を用いて、中間体I−3について記載されるのと類似の方法でこの化合物を調製して、表題化合物(2工程で、176mg、87%)を黄色の固体として得た。データ:LC−MS(方法A)Rt:1.728分;m/z 414.2(M+H)+。
4−[8−アミノ−3−[(2S)−ピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミドの調製。中間体I−10およびI−8を用いて、中間体I−3について記載されるのと類似の方法でこの化合物を調製して、表題化合物(2工程で、187mg、87%)を黄色の固体として得た。データ:LC−MS(方法A)Rt:2.975分;m/z 444.2(M+H)+。
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(2−ピリジル)ベンズアミドの調製。プロピルホスホン酸無水物溶液(DMF中50%)(0.08mL、0.15mmol)を、ジクロロメタン(10mL)中のトリエチルアミン(0.05mL、0.39mmol)、ブタ−2−イン酸(13.67mg、0.16mmol)および中間体I−3(60mg、0.15mmol)の溶液に加え、混合物を室温で2時間撹拌した。反応混合物をSiO2カラム上に直接充填し、フラッシュカラムクロマトグラフィー(ジクロロメタン中0〜8%のメタノール)によって精製し、最も純粋な画分を組み合わせて、濃縮した。残渣を、アセトニトリル/水(1:1)からの懸濁液として凍結乾燥して、表題化合物(56.9mg、81.0%)を淡黄色の固体として得た。データ:LC−MS Rt:3.77分;m/z 454.2(M+H)+;HPLC(方法C)Rt:4.95分、100%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.88(1H,s)、8.43(1H,ddd,J1=4.8Hz、J2=1.9Hz、J3=0.9Hz)、8.25(1H,dt,J1=8.3Hz、J2=0.9Hz)、8.19(2H,dd,J1=8.5Hz、J2=1.5Hz)、7.88(1H,m)、7.79(2H,dd,J1=8.5Hz、J2=2.2Hz)、7.40(0.3H,d J=5.1Hz)、7.32(0.7H,d J=5.1Hz)、7.25(0.3H,d,J=4.9)、7.20(1.7H,m)、6.28(2H,br.s)、6.16(1H,m)、2.88(2.1H,s)、2.60(0.9H,s)、2.16(0.9H,s)、2.05(2.1H,s)、1.74(0.9H,d,J=6.9Hz)、1.65(2.1H,d,J=6.9Hz)。
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(2−ピリジル)ベンズアミドの調製。中間体I−5およびブタ−2−イン酸を用いて、実施例E−1について記載されるのと類似の方法でこの化合物を調製して、表題化合物(67mg、57%)を淡黄色の固体として得た。データ:LC−MS(方法A)Rt:4.19分;m/z 484.1(M+H)+;HPLC(方法C)Rt:5.93分、99.0%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.50(1H,s)、8.38(1H,m)、8.30(1H,d,J=8.2Hz)、8.05(1H,d,J=8.0Hz)、7.87(1H,m)、7.43(2H,m)、7.39(0.3H,d,J=5.0Hz)、7.30(0.7H,d,J=5.1Hz),7.24(0.3H,d,J=4.9Hz)、7.18(1.7H,m)、6.35(2H,m)、6.14(1H,m)、4,08(3H,s)、2.87(2H,s)、2,60(1H,s)、2.14(1H,s)、2.03(2H,s)、1.73(1H,d,6.8Hz)、1.64(2H,d,J=6.8Hz)。
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミドの調製。中間体I−7およびブタ−2−イン酸を用いて、実施例E−1について記載されるのと類似の方法でこの化合物を調製して、表題化合物(67mg、57%)を淡黄色の固体として得た。データ:LC−MS(方法A)Rt:3.89分;m/z 468.3(M+H)+;HPLC(方法C)Rt:5.25分、99.9%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.79(1H,s)、8.26(1H,m)、8.19(2H,dd,J1=8.6Hz、J2=1.6Hz)、8.14(1H,d,J=8.5Hz)、7.78(2H,dd,J1=8.6Hz、J2=2.3Hz)、7.70(1H,dd,J1=8.6Hz、J2=2.0Hz)、7.40(0.3H,d,J=5.0Hz)、7.31(0.7H,d,J=5.0Hz)、7.25(0.3H,d,J=4.9Hz)、7.19(0.7H,d,J=4.9Hz)、6.28(2H,m)、6.16(1H,m)、2.88(2H,s)、2.61(1H,s)、2.31(3H,s)、2.16(1H,s)、2.05(2H,s)、1.74(1H,d,J=6.8Hz)、1.65(2H,d,J=6.8Hz)。
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミドの調製。中間体I−9およびブタ−2−イン酸を用いて、実施例E−1について記載されるのと類似の方法でこの化合物を調製して、表題化合物(68mg、59%)を白色の固体として得た。データ:LC−MS(方法A)Rt:4.39分;m/z 498.2(M+H)+;HPLC(方法C)Rt:5.90分、100%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.42(1H,s)、8.20(2H,m)、8.05(1H,d,J=8.0Hz)、7.69(1H,dd,J1=8.6Hz、J2=2.3Hz)、7.17−7.45(4H,m)、6.35(2H,m)。6.14(1H,m)、4.07(3H,s)、2.86(2H,s)、2.60(1H,s)、2.29(3H,s)、2.04(2H,s)、1.97(1H,s)、1.73(1H,d,J=6.8Hz)、1.64(2H,d,J=6.8Hz)。
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミドの調製。中間体I−11およびブタ−2−イン酸を用いて、実施例E−1について記載されるのと類似の方法でこの化合物を調製して、表題化合物(54mg、89%)を淡黄色の固体として得た。データ:LC−MS(方法A)Rt:5.05分;m/z 564.4(M+H)+;HPLC(方法C)Rt:6.82分、99.1%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.86(1H,s)、8.66(1H,d,J=5.1Hz)、8.62(1H,s)、8.01(1H,dd,J1=8.1Hz、J2=1.9Hz)、7.82(0.4H,d,J=5.1Hz)、7.80(0.6H,d,J=5.1Hz)、7.56(1H,d,J=5.1Hz)、7.40(2H,m)、7.18(0.4H,d,J=4.9Hz)、7.14(0.6H,d,J=4.9Hz)、6.26(2H,m)、5.74(0.4H,dd,J1=7.6Hz、J2=4.1Hz)、5.48(0.6H,dd,J1=7.6Hz、J2=4.1Hz)、4.06(3H,s)、3.83(1.3H,m)、3.61(0.7H,m)、2.48−1.65(7H,m)。
4−[8−アミノ−3−[(1S)−1−[[(E)−4−メトキシブタ−2−エノイル]−メチル−アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミドの調製。中間体I−7および(E)−4−メトキシブタ−2−エン酸を用いて、実施例E−1について記載されるのと類似の方法でこの化合物を調製した。収量26.8mg(42%)。データ:LC−MS(方法A)Rt:3.85分;m/z 500.2(M+H)+;HPLC(方法C)Rt:5.35分、97.3%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.79(1H,s)、8.26(1H,d,J=2.4Hz)、8.19(2H,d,J=8.5Hz)、8.14(1H,d,J=8.7Hz)、7.79(2H,d,J=8.6Hz)、7.70(1H,dd,J1=8.7Hz、J2=2.3Hz)、7.38(1H,d,J=5.0Hz)、7.16(1H,d,J=4.9Hz)、6.85(1H,dt,J1=15.0Hz、J2=4.2Hz)、6.55(1H,d,J=15.2Hz)、6.33(1H,q,J1、J2=7.1Hz)、6.24(2H,s)、4.10(1H,dd,J1=2.1Hz、J2=2.7Hz)、3.31(3H,s)、2.79(3H,s)、2.31(3H,s)1.64(3H,d,J=6.8Hz)。
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミドの調製。中間体I−1およびブタ−2−イン酸を用いて、実施例E−1について記載されるのと類似の方法でこの化合物を調製した。収量35.5mg(62%)。データ:LC−MS(方法A)Rt:5.20分;m/z 552.1(M+H)+;HPLC(方法C)Rt:7.11分、99.4%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.87(1H,s)、8.66(1H,d,J=5.2Hz)、8.61(1H,s)、8.02(1H,d,J=8.0Hz)、7.57(1H,d,J=5.1Hz)、7.42(2H,m)、7.40(0.3H,s)、7.28(0.7H,s)、7.24(0.3H,s)、7.19(0.7H,s)、6.35(2H,br.s)、6.15(1H,m)、4.06(3H,s)、2.87(2H,s)、2.61(1H,s)、2.15(1H,s)、2.04(2H,s)、1.73(1H,d,J=6.8Hz)、1.64(2H,d,J=6.8Hz)。
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミドの調製。中間体I−13およびブタ−2−イン酸を用いて、実施例E−1について記載されるのと類似の方法で、31.1mg(54%)の収量でこの化合物を調製した。データ:LC−MS(方法A)Rt:4.78分;m/z 538.2(M+H)+;HPLC(方法C)Rt:6.40分、99.8%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.87(1H,s)、9.22(1H,d,J=8.0Hz)、8.67(1H,d,J=5.2Hz)、8.61(1H,s)、8.02(1H,d,J=8.0Hz)、7.56(2H,m)、7.42(2H,m)、7.16(1H,d,J=4.9Hz)、6.28(2H,br.s)、5.48(1H,m)、4.06(3H,s)、1.98(3H,s)、1.59(3H,d,J=6.9Hz)。
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(2−ピリジル)ベンズアミドの調製。中間体I−14を用いて、実施例E−1について記載されるのと類似の方法でこの化合物を調製して、表題化合物(55.5mg、47.4%)を黄色の固体として得た。データ:LC−MS(方法A)Rt:3.68分;m/z 470.1(M+H)+;HPLC(方法C)Rt:4.76分、97.3%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.51(1H,s)、9.22(1H,d,J=8.0Hz)、8.39(1H,m)、8.32(1H,d,J=8.3Hz)、8.07(1H,d,J=8.0Hz)、7.89(1H,m)、7.56(1H,d,J=5.1Hz)、7.43(1H,m)、7.40(1H,m)、7.20(1H,m)、7.17(1H,d,J=4.9Hz)、6.29(2H,s)、5.50(1H,m)、4.08(3H,s)、1.96(3H,s)、1.60(3H,d,J=6.9Hz)。
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミドの調製。中間体I−16を用いて、実施例E−1について記載されるのと類似の方法でこの化合物を調製して、表題化合物(45.3mg、83.9%)を淡黄色の固体として得た。データ:LC−MS(方法A)Rt:4.52分;m/z 508.1(M+H)+;HPLC(方法C)Rt:5.80分、100%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=11.36(1H,s)、9.18(1H,d,J=8.2Hz)、8.70(1H,d,J=5.1Hz)、8.58(1H,m)、8.19(2H,d,J=8.5Hz)、7.77(2H,d,J=8.5Hz)、7.56(1H,m)、7.53(1H,d,J=5.1Hz)、7.15(1H,d,J=5.0)、6.21(2H,s)、5,48(1H,m)、1.95(3H,s)、1.59(3H,d,J=6.9Hz)。
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミドの調製。中間体I−17を用いて、実施例E−11について記載されるのと類似の方法でこの化合物を調製して、表題化合物(25.7mg、21.8%)を淡黄色の固体として得た。データ:LC−MS(方法A)Rt:3.41分;m/z 454.1(M+H)+;HPLC(方法C)Rt:4.43分、99.5%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.78(1H,s)、9.20(1H,d,J=8.2Hz)、8.26(1H,m)、8.18(2H,d,J=8.6Hz)、8.14(1H,d,J=8.5Hz)、7.76(2H,d,J=8.5Hz)、7.70(1H,dd,J1=8.3Hz、J2=2.4Hz))、7.54(1H,d,J=5.1Hz)、7.16(1H,d,J=5.0Hz)、6.21(2H,s)、5.50(1H,m)、2.31(3H,s)、1.95(3H,s)、1.60(3H,d,J=7.0Hz)。
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミドの調製。中間体I−18を用いて、実施例E−1について記載されるのと類似の方法でこの化合物を調製して、表題化合物(55.4mg、44.9%)を黄色の固体として得た。データ:LC−MS(方法A)Rt:3.89分;m/z 484.1(M+H)+;HPLC(方法C)Rt:5.12分、96.2%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.43(1H,s)、9.21(1H,d,J=8.0Hz)、8.22(2H,m)、8.07(1H,d,J=8.0Hz)、7.71(1H,dd,J1=8.5Hz、J2=2.2Hz)、7.56(1H,d,J=5.0Hz)、7.41(2H,m)、7.16(1H,d,J=4.9Hz)、6.29(2H,s)、5.49(1H,m)、4.08(3H,s)、2.30(3H,s)、1.96(3H,s)、1.60(3H,d,J=7.0Hz)。
4−[8−アミノ−3−[(1S)−1−[[(E)−4−メトキシブタ−2−エノイル]アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミドの調製。中間体I−17および(E)−4−メトキシブタ−2−エン酸を用いて、実施例E−1について記載されるのと類似の方法でこの化合物を調製して、表題化合物(24.0mg、57.6%)を淡黄色の固体として得た。データ:LC−MS(方法A)Rt:3.41分;m/z 486.2(M+H)+;HPLC(方法C)Rt:4.47分、98.2%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.76(1H,s)、8.69(1H,d,J=8.2Hz)、8.24(1H,m)、8.16(2H,d,J=8.6Hz)、8.12(1H,d,J=8.5Hz)、7.75(2H,d,J=8.6Hz)、7.68(1H,dd,J1=8.5Hz、J2=1.8Hz)、7.56(1H,d,J=5.1Hz)、7.13(1H,d,J=4.9)、6.69(1H,m)、6.18(2H,s)、6.10(1H,m)、5.56(1H,m)、4.02(2H,m)、3.27(3H,s)、2.30(3H,s)、1.62(3H,d,J=6.8Hz)。
4−[8−アミノ−3−[(1S)−1−[[(E)−4−メトキシブタ−2−エノイル]アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミドの調製。中間体I−18および(E)−4−メトキシブタ−2−エン酸を用いて、実施例E−1について記載されるのと類似の方法でこの化合物を調製して、表題化合物(30.5mg、36.4%)を淡黄色の固体として得た。データ:LC−MS(方法A)Rt:3.89分;m/z 516.2(M+H)+;HPLC(方法C)Rt:4.55分、98.8%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.41(1H,s)、8.71(1H,d,J=8.7Hz)、8.20(2H,m)、8.05(1H,d,J=8.0Hz)、7.69(1H,m)、7.58(2H,d,J=5.0Hz)、7.39(2H,m)、7.13(1H,d,J=5.0Hz)、6.69(1H,m)、6.26(2H,s)、6.10(1H,m)、5.56(1H,m)、4.06(3H,s)、4.02(2H,m)、3.27(3H,s)、2.29(3H,s)、1.62(3H,d,J=6.9Hz)。
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−チアゾール−2−イル−ベンズアミドの調製。実施例E−1について記載されるのと類似の方法でこの化合物を調製して、表題化合物(12.6mg、21.8%)を黄色の固体として得た。データ:LC−MS Rt:4.095分;m/z 502.3(M+H)+;HPLC(方法C)Rt:5.42分、99.5%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=11.82(1H,s)、7.88(2H,m)、7.82(1H,d,J=5.1Hz)、7.56(1H,d,J=3.6Hz)、7.40(1H,dt,J1=1.3Hz、J2=3.7Hz)、7.36(1H,dd,J1=1.3Hz、J2=7.9Hz)、7.32(1H,d,J=3.6Hz)、7.17(1H,dd,J1=5.0Hz、J2=16.1Hz)、6.26(2H,br d,J=27.0Hz)、5.47−5.77(1H,m)、4.03(3H,d,J=2.3Hz)、3.84(1H,t、J=6.7Hz)、3.62(1H,m)、2.69(1H,m)、2.34(2H,m)、2.15(1H,m)、2.03(2H,s)、1.66(1H,s)。
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミドの調製。実施例E−1について記載されるのと類似の方法でこの化合物を調製して、表題化合物(30.3mg、33.9%)を黄色の固体として得た。データ:LC−MS Rt:3.84分;m/z 480.2(M+H)+;HPLC(方法C)Rt:4.92分、99.9%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.79(1H,s)、8.26(8.26、1H)、8.17(2H,dd,J1=1.6Hz、J2=6.8Hz)、8.14(1H,d,J=8.4Hz)、7.82−7.91(1H,dd,J1=5.1Hz、J2=22.8Hz)、7.68−7.78(3H,m)、7.16(1H,dd,J1=5.0Hz、J2=14.9Hz)、6.35(2H,br s)、5.47−5.77(1H,m)、3.84(2H,t、J=6.8Hz)、3.61(1H,m)、2.41(1H,m)、2.31(3H,s)、2.16(1H,m)、2.03(2H,s)、2.00(1H,m)、1.65(1H,s)。
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミドの調製。実施例E−1について記載されるのと類似の方法でこの化合物を調製して、表題化合物(48.3mg、56.0%)を淡黄色の固体として得た。データ:LC−MS Rt:4.26分;m/z 510.2(M+H)+;HPLC(方法C)Rt:5.57分、100%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=10.42(1H,s)、8.22(2H,q,J=2.3Hz)、8.05(1H,dd,J1=2.0Hz、J2=8.1Hz)、7.84(1H,dd,J1=5.2Hz、J2=25.2Hz)、7.70(1H,dd,J1=2.3Hz、J2=8.3Hz)、7.40(2H,m)、7.17(1H,dd,J1=4.9Hz、J2=16.1Hz)。6.26(2H,br d,J=27.7Hz)、5.46−5.78(1H,m)、4.08(3H,d,J=2.4Hz)、3.84(2H,t、J=6.4Hz)、3.62(1H,m)、2.38(2H,m)、2.30(3H,s)、2.15(1H,m)、2.03(2H,s)、1.66(1H,s)。
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−N−チアゾール−4−イル−ベンズアミドの調製。1,4−ジオキサン(5mL)中の中間体I−23(200mg、0.50mmol、1.0当量)、中間体I−25(277mg、0.70mmol、1.2当量)、2Mの炭酸カリウム水溶液(0.16mL、1.10mmol、2.0当量)の溶液を、5分間にわたって脱気した。PdCl2(dppf)2(18mg、0.03mmol、0.05当量)を加え、次に、反応混合物を、5分間にわたって再度脱気し、100℃で16時間撹拌した。完了後、反応混合物を水で希釈し、酢酸エチルで抽出した。有機層を無水硫酸ナトリウム上で乾燥させ、濃縮した。残渣を、HPLC分取精製によって精製して、表題化合物(15mg、6%)を白色の固体として得た。データ:LC−MS(方法G)Rt:3.96分;m/z 475.5(M+H)+。HPLC(方法H)Rt:8.43分、95%の純度;1H NMR(400MHz、DMSO−d6、300K):δ=11.49(1H,s)、9.05(1H,d,J=2.24Hz)、8.16(2H,dd J=2.60Hz J=8.38Hz)、7.89−7.84(1H,m)、7.81(1H,d,J=7.28Hz)、7.74−7.71(2H,m)、7.13(1H,dd,J=4.92Hz J=15.76Hz)、6.14(2H,bs)、5.72−5.46(1H,m)、3.83−3.80(1H,t)、3.60−3.58(1H,m)、2.49−2.36(1H,m)、2.28−2.10(2H,m)、2.05−1.92(3H,m)、1.62(1H,s)。
BTK酵素活性は、以下に概説されるように、IMAP(固定化金属イオンアフィニティーに基づく蛍光偏光)アッセイを用いて測定される。
全血を、ヘパリン被覆されたVacutainer管(BD Biosciences,San Jose,CA)中に収集し、Ficoll-Hypaque(Pharmacia,Uppsala,Sweden)を用いたPBMCの単離に使用した。単離されたPBMCを、後の使用のために、90%のFCS/10%のDMSO中で凍結保存した。
Claims (17)
- 以下の構造を有する式(I)の化合物:
(式中:
R1が、水素またはメトキシであり、ここで、メトキシが、1つまたは2つのフルオロで任意選択により置換され;
Xが、
であり;
R2が、水素、ハロゲン、メチル、メトキシ、またはエトキシであり、ここで、メチル、メトキシ、およびエトキシがそれぞれ、1つ、2つ、または3つのフルオロで任意選択により置換され;
Yが、
であり;
R3が、Hまたはメチルである)
またはその薬学的に許容できる塩。 - R1が水素であり;
Xが、
であり;
R2が、水素、ハロゲン、メチル、メトキシ、またはエトキシであり、ここで、メチル、メトキシ、およびエトキシがそれぞれ、1つ、2つ、または3つのフルオロで任意選択により置換され;
Yが、
である、請求項1に記載の化合物。 - R1がメトキシであり;
Xが、
であり;
Yが、
であり;
R3が、Hまたはメチルである、請求項1に記載の化合物。 - R1が水素であり;
Xが、
であり;
Yが、
であり;
R3が、Hまたはメチルである、請求項1に記載の化合物。 - 4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(2−ピリジル)ベンズアミド;
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミド;
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(2−ピリジル)ベンズアミド;
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−チアゾール−2−イル−ベンズアミド;
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド;
4−[8−アミノ−3−[(2S)−1−ブタ−2−イノイルピロリジン−2−イル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミド;
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド;
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミド;
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド;
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(2−ピリジル)ベンズアミド;
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミド;
4−[8−アミノ−3−[(1S)−1−[[(E)−4−メトキシブタ−2−エノイル]−メチル−アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド;
4−[8−アミノ−3−[(1S)−1−[[(E)−4−メトキシブタ−2−エノイル]アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−(5−メチル−2−ピリジル)ベンズアミド;
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミド;
4−[8−アミノ−3−[(1S)−1−(ブタ−2−イノイルアミノ)エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミド;
4−[8−アミノ−3−[(1S)−1−[[(E)−4−メトキシブタ−2−エノイル]アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−(5−メチル−2−ピリジル)ベンズアミド;
4−[8−アミノ−3−[(1S)−1−[ブタ−2−イノイル(メチル)アミノ]エチル]イミダゾ[1,5−a]ピラジン−1−イル]−2−メトキシ−N−[4−(トリフルオロメチル)−2−ピリジル]ベンズアミド;
(R)−4−(8−アミノ−3−(1−(ブタ−2−イノイル)ピロリジン−2−イル)イミダゾ[1,5−a]ピラジン−1−イル)−N−(チアゾール−4−イル)ベンズアミド
からなる群から選択される化合物。 - 過剰増殖性疾患、炎症性疾患、免疫疾患、または自己免疫疾患の治療に使用するための、請求項1〜5のいずれか一項に記載の化合物。
- 必要とする患者における過剰増殖性疾患、炎症性疾患、免疫疾患、または自己免疫疾患の治療のための薬剤の製造のための、請求項1〜5のいずれか一項に記載の化合物の使用。
- 前記過剰増殖性疾患、炎症性疾患、免疫疾患、または自己免疫疾患が、膀胱癌、頭頸部癌、膵管腺癌(PDA)、膵臓癌、結腸癌、乳癌(mammary carcinoma)、乳癌(breast cancer)、線維肉腫、中皮腫、腎細胞癌、肺癌、胸腺腫、前立腺癌、大腸癌、卵巣癌、急性骨髄性白血病、胸腺癌、脳腫瘍、扁平上皮細胞癌、皮膚癌、眼癌、網膜芽細胞腫、黒色腫、眼内黒色腫、口腔癌および口腔咽頭癌、胃癌(gastric cancer)、胃癌(stomach cancer)、子宮頸癌、頭部癌、頸部癌、腎臓癌(renal cancer)、腎臓癌(kidney cancer)、肝臓癌、卵巣癌、前立腺癌、大腸癌、食道癌、精巣癌、婦人科癌、甲状腺癌、後天性免疫不全症候群(AIDS)関連リンパ腫、カポジ肉腫、ウイルス誘導性癌、膠芽細胞腫、食道腫瘍、血液学的腫瘍、非小細胞肺癌、慢性骨髄性白血病、びまん性大細胞型B細胞リンパ腫、食道腫瘍、濾胞中心リンパ腫、頭頸部腫瘍、C型肝炎ウイルス感染、肝細胞癌、ホジキンリンパ腫、転移性結腸癌、多発性骨髄腫、非ホジキンリンパ腫、原発性中枢神経系リンパ腫、卵巣腫瘍、膵臓腫瘍、腎細胞癌、小細胞肺癌、IV期黒色腫、腫瘍血管新生、慢性炎症性疾患、関節リウマチ、アテローム性動脈硬化症、炎症性腸疾患、乾癬、湿疹、強皮症、糖尿病、糖尿病性網膜症、未熟網膜症、加齢性黄斑変性症、血管腫、神経膠腫、黒色腫、潰瘍性大腸炎、アトピー性皮膚炎、回腸嚢炎、脊椎関節炎、ブドウ膜炎、ベーチェット病、リウマチ性多発筋痛、巨細胞性動脈炎、サルコイドーシス、川崎病、若年性特発性関節炎、汗腺膿瘍、シェーグレン症候群、乾癬性関節炎、若年性関節リウマチ、強直性脊椎炎、クローン病、紅斑性狼瘡、およびループス腎炎からなる群から選択される、請求項7に記載の使用。
- 必要とする患者における過剰増殖性疾患、炎症性疾患、免疫疾患、または自己免疫疾患を治療する方法であって、治療的有効量の請求項1〜5のいずれか一項に記載の化合物を、前記患者に投与する工程を含む方法。
- 前記過剰増殖性疾患が、膀胱癌、頭頸部癌、膵管腺癌(PDA)、膵臓癌、結腸癌、乳癌(mammary carcinoma)、乳癌(breast cancer)、線維肉腫、中皮腫、腎細胞癌、肺癌、胸腺腫、前立腺癌、大腸癌、卵巣癌、急性骨髄性白血病、胸腺癌、脳腫瘍、扁平上皮細胞癌、皮膚癌、眼癌、網膜芽細胞腫、黒色腫、眼内黒色腫、口腔癌および口腔咽頭癌、胃癌(gastric cancer)、胃癌(stomach cancer)、子宮頸癌、頭部癌、頸部癌、腎臓癌(renal cancer)、腎臓癌(kidney cancer)、肝臓癌、卵巣癌、前立腺癌、大腸癌、食道癌、精巣癌、婦人科癌、甲状腺癌、後天性免疫不全症候群(AIDS)関連リンパ腫、カポジ肉腫、ウイルス誘導性癌、膠芽細胞腫、食道腫瘍、血液学的腫瘍、非小細胞肺癌、慢性骨髄性白血病、びまん性大細胞型B細胞リンパ腫、食道腫瘍、濾胞中心リンパ腫、頭頸部腫瘍、C型肝炎ウイルス感染、肝細胞癌、ホジキン病、転移性結腸癌、多発性骨髄腫、非ホジキンリンパ腫、原発性中枢神経系リンパ腫、卵巣腫瘍、膵臓腫瘍、腎細胞癌、小細胞肺癌、およびIV期黒色腫からなる群から選択される、請求項9に記載の方法。
- 前記炎症性疾患、免疫疾患、または自己免疫疾患が、腫瘍血管新生、慢性炎症性疾患、関節リウマチ、アテローム性動脈硬化症、炎症性腸疾患、乾癬、湿疹、および強皮症などの皮膚疾患、1型糖尿病、2型糖尿病、糖尿病性網膜症、未熟網膜症、加齢性黄斑変性症、血管腫、神経膠腫および黒色腫、潰瘍性大腸炎、アトピー性皮膚炎、回腸嚢炎、脊椎関節炎、ブドウ膜炎、ベーチェット病、リウマチ性多発筋痛、巨細胞性動脈炎、サルコイドーシス、川崎病、若年性特発性関節炎、汗腺膿瘍、シェーグレン症候群、乾癬性関節炎、若年性関節リウマチ、強直性脊椎炎、クローン病、紅斑性狼瘡、ループス腎炎、ヒト白血球抗原(HLA)関連疾患、自己抗体、免疫療法、アジソン病、自己免疫性多内分泌腺症候群1型(APS−1)、自己免疫性多内分泌腺症候群2型(APS−2)、グレーブス病、橋本甲状腺炎、多内分泌自己免疫、医原性自己免疫、特発性上皮小体機能低下症、白斑、およびループス腎炎からなる群から選択される、請求項9に記載の方法。
- 必要とする患者における固形腫瘍癌を治療する方法であって、治療的有効量の請求項1〜5のいずれか一項に記載の化合物を、前記患者に投与する工程を含み、前記治療的有効量が、前記固形腫瘍癌細胞と、マクロファージ、単球、肥満細胞、ヘルパーT細胞、細胞傷害性T細胞、制御性T細胞、ナチュラルキラー細胞、骨髄由来免疫抑制細胞、制御性B細胞、好中球、樹枝状細胞、および線維芽細胞からなる群から選択される少なくとも1つの微小環境との間のシグナル伝達を阻害するのに有効である方法。
- 前記固形腫瘍癌が、膵臓癌、乳癌、卵巣癌、黒色腫、肺癌、頭頸部癌、および大腸癌からなる群から選択される、請求項12に記載の方法。
- 請求項1〜5のいずれか一項に記載の化合物と、少なくとも1つの薬学的に許容できる賦形剤とを含む医薬組成物。
- 必要とする患者における過剰増殖性疾患、炎症性疾患、免疫疾患、または自己免疫疾患を治療するのに使用するための、請求項14に記載の医薬組成物。
- 前記過剰増殖性疾患が、膀胱癌、頭頸部癌、膵管腺癌(PDA)、膵臓癌、結腸癌、乳癌(mammary carcinoma)、乳癌(breast cancer)、線維肉腫、中皮腫、腎細胞癌、肺癌、胸腺腫、前立腺癌、大腸癌、卵巣癌、急性骨髄性白血病、胸腺癌、脳腫瘍、扁平上皮細胞癌、皮膚癌、眼癌、網膜芽細胞腫、黒色腫、眼内黒色腫、口腔癌および口腔咽頭癌、胃癌(gastric cancer)、胃癌(stomach cancer)、子宮頸癌、頭部癌、頸部癌、腎臓癌(renal cancer)、腎臓癌(kidney cancer)、肝臓癌、卵巣癌、前立腺癌、大腸癌、食道癌、精巣癌、婦人科癌、甲状腺癌、後天性免疫不全症候群(AIDS)関連リンパ腫、カポジ肉腫、ウイルス誘導性癌、膠芽細胞腫、食道腫瘍、血液学的腫瘍、非小細胞肺癌、慢性骨髄性白血病、びまん性大細胞型B細胞リンパ腫、食道腫瘍、濾胞中心リンパ腫、頭頸部腫瘍、C型肝炎ウイルス感染、肝細胞癌、ホジキン病、転移性結腸癌、多発性骨髄腫、非ホジキンリンパ腫、原発性中枢神経系リンパ腫、卵巣腫瘍、膵臓腫瘍、腎細胞癌、小細胞肺癌、およびIV期黒色腫からなる群から選択される、請求項15に記載の医薬組成物。
- 前記炎症性疾患、免疫疾患、または自己免疫疾患が、腫瘍血管新生、慢性炎症性疾患、関節リウマチ、アテローム性動脈硬化症、炎症性腸疾患、乾癬、湿疹、および強皮症などの皮膚疾患、1型糖尿病、2型糖尿病、糖尿病性網膜症、未熟網膜症、加齢性黄斑変性症、血管腫、神経膠腫および黒色腫、潰瘍性大腸炎、アトピー性皮膚炎、回腸嚢炎、脊椎関節炎、ブドウ膜炎、ベーチェット病、リウマチ性多発筋痛、巨細胞性動脈炎、サルコイドーシス、川崎病、若年性特発性関節炎、汗腺膿瘍、シェーグレン症候群、乾癬性関節炎、若年性関節リウマチ、強直性脊椎炎、クローン病、紅斑性狼瘡、ループス腎炎、ヒト白血球抗原(HLA)関連疾患、自己抗体、免疫療法、アジソン病、自己免疫性多内分泌腺症候群1型(APS−1)、自己免疫性多内分泌腺症候群2型(APS−2)、グレーブス病、橋本甲状腺炎、多内分泌自己免疫、医原性自己免疫、特発性上皮小体機能低下症、白斑、およびループス腎炎からなる群から選択される、請求項15に記載の医薬組成物。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017077507A1 (en) * | 2015-11-06 | 2017-05-11 | Acerta Pharma B.V. | Imidazopyrazine inhibitors of bruton's tyrosine kinase |
US10640512B2 (en) | 2016-06-30 | 2020-05-05 | Hangzhou Sanyintai Pharmaceutical Technology Co., Ltd. | Imidazopyrazinamine phenyl derivative and use thereof |
CN108101905A (zh) * | 2016-11-24 | 2018-06-01 | 中国科学院上海药物研究所 | 嘧啶并[5,4-b]吲嗪或嘧啶并[5,4-b]吡呤化合物、其制备方法及用途 |
CN110494433B (zh) | 2017-03-22 | 2023-03-17 | 廖细斌 | 布鲁顿酪氨酸激酶抑制剂 |
WO2018191815A1 (en) * | 2017-04-20 | 2018-10-25 | Apotex Inc. | Processes for the preparation of acalabrutinib and intermediates thereof |
WO2019013562A1 (ko) * | 2017-07-12 | 2019-01-17 | 주식회사 대웅제약 | 신규한 1h-피라졸로피리딘 유도체 및 이를 포함하는 약학 조성물 |
KR102384924B1 (ko) * | 2017-07-12 | 2022-04-08 | 주식회사 대웅제약 | 신규한 1h-피라졸로피리딘 유도체 및 이를 포함하는 약학 조성물 |
CN109836416B (zh) * | 2017-11-27 | 2023-02-03 | 苏州鹏旭医药科技有限公司 | 一种化合物的制备方法 |
WO2019090269A1 (en) * | 2017-11-06 | 2019-05-09 | Peng Wang | Processes to produce acalabrutinib |
CN108129483B (zh) * | 2018-01-26 | 2019-06-04 | 成都施贝康生物医药科技有限公司 | 一种btk抑制剂及其应用 |
CN108250186B (zh) * | 2018-02-07 | 2020-01-14 | 杭州科巢生物科技有限公司 | Acalabrutinib及其中间体的合成方法 |
KR102106821B1 (ko) | 2018-04-27 | 2020-05-06 | 재단법인대구경북과학기술원 | 이브루티닙을 유효성분으로 포함하는 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물 |
CN109053780B (zh) * | 2018-07-05 | 2020-09-29 | 浙江合聚生物医药有限公司 | 一种抗肿瘤药物Acalabrutinib关键中间体的制备方法 |
JP7439095B2 (ja) * | 2018-08-29 | 2024-02-27 | アセルタ・ファーマ・ベスローテン・フェンノートシャップ | 4-{8-アミノ-3-[(2S)-1-(ブタ-2-イノイル)-ピロリジン-2-イル]イミダゾ[1,5-a]-ピラジン-1-イル}N-(ピリジン-2-イル)-ベンズアミドの調製のためのプロセス |
US11891405B2 (en) | 2018-09-14 | 2024-02-06 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Furo[3,4-b]pyrrole-containing BTK inhibitor |
BR112021018168B1 (pt) | 2019-03-21 | 2023-11-28 | Onxeo | Composição farmacêutica, combinação e kit compreendendo uma molécula dbait e um inibidor de quinase para o tratamento de câncer |
WO2020225831A1 (en) * | 2019-05-09 | 2020-11-12 | Msn Laboratories Private Limited, R&D Center | Improved process for the preparation of 4-{8-amino-3-[(2s)-1-(but-2-ynoyl)pyrrolidin-2-yl] imidazo[1,5-a]pyrazin-1-yl)}-n-(pyridine-2-yl)benzamide |
WO2021008441A1 (zh) * | 2019-07-12 | 2021-01-21 | 正大天晴药业集团股份有限公司 | 含有5-氮杂螺庚烷的btk抑制剂 |
KR20220098759A (ko) | 2019-11-08 | 2022-07-12 | 인쎄름 (엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔) | 키나제 억제제에 대해 내성을 획득한 암의 치료 방법 |
WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
WO2022140246A1 (en) | 2020-12-21 | 2022-06-30 | Hangzhou Jijing Pharmaceutical Technology Limited | Methods and compounds for targeted autophagy |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014520866A (ja) * | 2011-07-19 | 2014-08-25 | メルク・シャープ・アンド・ドーム・コーポレーション | Btk阻害薬 |
JP2014520870A (ja) * | 2011-07-19 | 2014-08-25 | メルク・シャープ・アンド・ドーム・ベー・フェー | Btk阻害剤としての4−イミダゾピリダジン−1−イル−ベンズアミドおよび4−イミダゾトリアジン−1−イル−ベンズアミド |
WO2015057992A1 (en) * | 2013-10-16 | 2015-04-23 | Izumi Raquel | Btk inhibitors for hematopoietic mobilization |
WO2015110923A2 (en) * | 2014-01-21 | 2015-07-30 | Acerta Pharma B.V. | Methods of treating chronic lymphocytic leukemia and small lymphocytic leukemia usng a btk inhibitor |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0565233A (ja) | 1991-03-08 | 1993-03-19 | Mitsui Toatsu Chem Inc | モノクローナル抗体含有凍結乾燥製剤 |
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
MXPA04000747A (es) | 2001-07-25 | 2004-07-08 | Protein Desing Labs Inc | Formulacion farmaceutica liofilizada estable de anticuerpos igg. |
WO2007147001A2 (en) | 2006-06-14 | 2007-12-21 | Imclone Systems Incorporated | Lyophilized formulations of anti-egfr antibodies |
US7894450B2 (en) | 2007-12-31 | 2011-02-22 | Nortel Network, Ltd. | Implementation of VPNs over a link state protocol controlled ethernet network |
AU2009204483B2 (en) | 2008-01-04 | 2014-03-13 | Intellikine, Llc | Certain chemical entities, compositions and methods |
US8193182B2 (en) | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
WO2016024227A1 (en) * | 2014-08-11 | 2016-02-18 | Acerta Pharma B.V. | Btk inhibitors to treat solid tumors through modulation of the tumor microenvironment |
WO2017077507A1 (en) * | 2015-11-06 | 2017-05-11 | Acerta Pharma B.V. | Imidazopyrazine inhibitors of bruton's tyrosine kinase |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014520866A (ja) * | 2011-07-19 | 2014-08-25 | メルク・シャープ・アンド・ドーム・コーポレーション | Btk阻害薬 |
JP2014520870A (ja) * | 2011-07-19 | 2014-08-25 | メルク・シャープ・アンド・ドーム・ベー・フェー | Btk阻害剤としての4−イミダゾピリダジン−1−イル−ベンズアミドおよび4−イミダゾトリアジン−1−イル−ベンズアミド |
WO2015057992A1 (en) * | 2013-10-16 | 2015-04-23 | Izumi Raquel | Btk inhibitors for hematopoietic mobilization |
WO2015110923A2 (en) * | 2014-01-21 | 2015-07-30 | Acerta Pharma B.V. | Methods of treating chronic lymphocytic leukemia and small lymphocytic leukemia usng a btk inhibitor |
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