JP2013515074A - ホスファチジルイノシトール3−キナーゼのイソインドリノンインヒビター - Google Patents
ホスファチジルイノシトール3−キナーゼのイソインドリノンインヒビター Download PDFInfo
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- JP2013515074A JP2013515074A JP2012546137A JP2012546137A JP2013515074A JP 2013515074 A JP2013515074 A JP 2013515074A JP 2012546137 A JP2012546137 A JP 2012546137A JP 2012546137 A JP2012546137 A JP 2012546137A JP 2013515074 A JP2013515074 A JP 2013515074A
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- aliphatic
- alkyl
- compound
- hydrogen
- pharmaceutically acceptable
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- 108091007960 PI3Ks Proteins 0.000 title claims abstract description 27
- 239000003112 inhibitor Substances 0.000 title abstract description 9
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 title description 24
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 title description 2
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 title 1
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- 238000000034 method Methods 0.000 claims abstract description 45
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- 125000001931 aliphatic group Chemical group 0.000 claims description 197
- -1 — (CH 2 ) 0-2 OH Chemical group 0.000 claims description 171
- 125000000217 alkyl group Chemical group 0.000 claims description 103
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- 239000001257 hydrogen Substances 0.000 claims description 89
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 81
- 125000000623 heterocyclic group Chemical group 0.000 claims description 61
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- 125000001153 fluoro group Chemical group F* 0.000 claims description 38
- 125000004429 atom Chemical group 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
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- 125000004122 cyclic group Chemical group 0.000 claims description 18
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
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- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
- 229940042385 glatiramer Drugs 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
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- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 2
- 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 claims description 2
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 2
- 206010015037 epilepsy Diseases 0.000 claims description 2
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 2
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 2
- 229940126062 Compound A Drugs 0.000 claims 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 1
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 abstract 1
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- 239000000243 solution Substances 0.000 description 60
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Abstract
Description
本発明は、ホスファチジルイノシトール3−キナーゼ(PI3K)のインヒビターとして有用な化合物に関する。本発明はまた、本発明の化合物を含む薬学的に許容され得る組成物、および様々な障害の処置においてその組成物を使用する方法も提供する。
PI3Kは、イノシトール環の3’−OHにおける膜脂質ホスファチジルイノシトール(PI)のリン酸化を触媒して、PI3−リン酸[PI(3)P、PIP]、PI3,4−二リン酸[PI(3,4)P2、PIP2]およびPI3,4,5−三リン酸[PI(3,4,5)P3、PIP3]を生成する脂質キナーゼのファミリーである。PI(3,4)P2およびPI(3,4,5)P3は、様々な細胞内のシグナル伝達タンパク質に対するリクルートメント部位として作用し、そしてそれらは、原形質膜の細胞質面に向かって細胞外のシグナルに応答するシグナル伝達複合体を形成する。
本発明の化合物およびその薬学的に許容され得る組成物が、PI3K、特にPI3Kγのインヒビターとして有効であると見出された。したがって、本発明は、一般式:
定義および一般的な用語
本明細書中で使用されるとき、別段示されない限り、以下の定義が適用されるものとする。本発明の目的上、化学元素は、Periodic Table of the Elements,CAS versionおよびHandbook of Chemistry and Physics,75th Ed.1994に従って特定される。さらに、有機化学の通則は、“Organic Chemistry,”Thomas Sorrell,University Science Books,Sausalito:1999および“March’s Advanced Organic Chemistry,”5th Ed.,Smith,M.B.and March,J.,eds.John Wiley & Sons,New York:2001(これらの内容全体が本明細書で参考として援用される)に記載されている。
1つの態様において、本発明は、式I:
X1は、NまたはCHであり;
X2は、N、CHまたはC−CH3であり;
R1は、フェニル環、5〜6員ヘテロアリール環、ピリドン環、または9〜10員縮合二環式のヘテロアリールもしくは複素環式環系から選択され、ここで、前記環または環系の各々は、独立して存在する1個または2個のR1aで必要に応じて置換され、前記ヘテロアリールまたは複素環式環の各々は、窒素、酸素または硫黄から選択される1個、2個または3個のヘテロ原子を有し;
R1aは、クロロ、フルオロ、C1−8脂肪族、−(CH2)0−2C3−6脂環式、窒素、酸素または硫黄から選択される最大2個のヘテロ原子を有する−(CH2)0−2−5〜6員複素環式、−CN、−C(O)C1−4脂肪族、−C(O)NH(C1−4脂肪族)、−C(O)N(C1−4脂肪族)2、−C(O)OC1−4脂肪族、−S(O)2NH(C1−4脂肪族)、−S(O)2N(C1−4脂肪族)2または−S(O)2C1−4脂肪族であり、ここで、R1aの前記脂肪族または脂環式の最大3個の隣接していない炭素原子は、−O−、−S−または−N(R1b)−で置換され得、R1aの前記脂肪族、脂環式または複素環式の各々は、必要に応じてかつ独立して、最大4個のJRで置換され;
各JRは、独立して、フルオロ、オキソ、−(CH2)0−2CN、−(CH2)0−2CF3、−C(O)R1b、−C(O)N(R1b)2、−C(O)O(R1b)、−N(R1b)2、−N(R1b)C(O)R1b、−(CH2)0−2OR1b、フェニルもしくは5〜6員ヘテロアリール、4−6ヘテロシクリルまたは9−11縮合二環式のヘテロアリールもしくはヘテロシクリルであり、前記ヘテロアリールまたはヘテロシクリル環の各々は、窒素、酸素または硫黄から選択される最大3個の原子を有し、前記脂環式、フェニル、ヘテロアリールまたはヘテロシクリルの各々は、最大2個のR1cで必要に応じて置換され;
各R1bは、独立して、水素、C1−8脂肪族、−(CH2)0−1C3−6脂環式、またはNもしくはOから選択される最大2個のヘテロ原子を有する−(CH2)0−1C4−6複素環式から選択されるか、または2つのR1bが、それらが結合している原子と一体となって、5〜6員複素環式環を形成し、ここで、脂肪族、脂環式または複素環式の各々は、最大3個のF原子または最大2個の−OH、−C1−2アルキルもしくは−OC1−2アルキル基で必要に応じて置換され;
各R1cは、独立して、フルオロ、クロロ、C1−4脂肪族、−(CH2)0−2OH、−CN、−C(O)C1−4脂肪族または−C(O)OC1−4脂肪族であり;
R2は、水素、F、Cl、CF3、C1−2脂肪族、C3−4脂環式、−N(CH3)2、−N(CH2)3、−OCF3、−OCHF2または−OC1−2脂肪族であり;
R3は、水素、C1−6脂肪族、C3−6脂環式、NもしくはOから選択される1個もしくは2個の原子を有するC4−7ヘテロシクリル、−(CH2)0−1CF3、−OH、−OC1−6脂肪族、−OC3−6脂環式、1つの酸素原子を有する−OC3−6ヘテロシクリル、−O(CH2)2OC1−2脂肪族もしくは−OC1−2アルキルC(O)OC1−3脂肪族、またはベンジルであり;そして
R4は、水素またはC1−6アルキルであるか;またはR3およびR4は、それらが結合している炭素と一体となって、3〜6員脂環式環、NもしくはOから選択される最大2個の原子を有する3〜6員複素環式環、またはC2アルケニルを形成し、ここで、R3、R4、またはR3とR4とが一体となったときの前記脂肪族、脂環式もしくはヘテロシクリルの各々は、最大3個のF原子、または最大2個のC1−2アルキル、−C(O)C1−4アルキル、−C(O)OC1−4アルキル、−OHもしくは−OC1−2アルキル基で必要に応じて置換され;
Aは、NまたはCRAであり;
Bは、NもしくはCRBであるか、またはA=Bは、硫黄原子であり;
Cは、NまたはCRCであり;
Dは、NまたはCRDであり;
Eは、NまたはCREであり、ここで、A、B、C、DまたはEのうちの2個以下が、Nであり;
RAは、水素、CH3またはOCH3であり;
RBは、水素、F、Cl、C1−3脂肪族、−(CH2)0−1CF3、−(CH2)0−1CHF2または−O(CH2)0−1CF3であり;
RCは、水素、F、Cl、C1−3脂肪族、−(CH2)0−1CF3、−(CH2)0−1CHF2、N(R1b)2、−OH、−O(CH2)0−1CF3または−OC1−8脂肪族であり、ここで、前記脂肪族の最大2個の隣接していない炭素原子は、−O−で置換され得;
RDは、水素、フルオロ、クロロ、C1−4脂肪族、−C(O)OH、−C(O)OC1−4脂肪族、−C(O)N(R1b)2、−CN、−C(RD1)=N−OR1b、−N(R1b)2、−N(RD1)C(O)C1−4脂肪族、−N(RD1)C(O)フェニル、−N(RD1)S(O)2C1−4脂肪族、−N(RD1)S(O)2N(R1b)2、−N(RD1)S(O)2フェニル−OH、−OC1−8脂肪族、−O(CH2)0−1C3−6脂環式、−SC1−4脂肪族、−S(O)C1−4脂肪族、−S(O)2C1−4脂肪族または−S(O)2N(R1b)2であり;ここで、RDの前記脂肪族、脂環式または複素環式の最大2個の隣接していない炭素原子は、−O−で置換され得、RDの前記脂肪族、脂環式またはフェニルの各々は、最大5個のフッ素原子で置換され得るか;またはRDおよびRCは、それらが結合している原子と一体となって、フェニル環またはピリジル環を形成し;
各RD1は、独立して、水素またはC1−2アルキルであり;そして
REは、水素、F、Cl、−NHC(O)C1−8脂肪族、−OH、−OC1−2脂肪族、−(CH2)0−1CF3、−(CH2)0−1CHF2、C1−3脂肪族、C3−4脂環式、N(R1b)2、アゼチジン−1−イルである。
X1は、CHまたはNであり;
R1は、フェニル環、5員ヘテロアリール環、6員ヘテロアリール環、または9もしくは10員縮合二環式のヘテロアリールもしくは複素環式環系から選択され、ここで、前記環または環系の各々は、独立して存在する1個または2個のR1aで必要に応じて置換され、前記ヘテロアリールまたは複素環式環の各々は、窒素、酸素または硫黄から選択される1個、2個または3個のヘテロ原子を有し;
R1aは、クロロ、フルオロ、C1−6脂肪族、C3−6脂環式、−CN、−C(O)R1b、−C(O)N(R1b)2、−C(O)O(R1b)または−OR1bであり、ここで、前記脂肪族または脂環式の各々は、最大3個のJRで必要に応じて置換され;
各JRは、独立して、フルオロ、オキソ、−CN、−C(O)R1b、−C(O)N(R1b)2、−C(O)O(R1b)、−N(R1b)2、−N(R1b)C(O)R1b、−OR1b、または窒素、酸素もしくは硫黄から選択される最大3個の原子を有する5員のヘテロアリールもしくはヘテロシクリルであり;
各R1bは、独立して、水素、C1−4脂肪族またはC3−6脂環式から選択され;
R2は、水素、F、Cl、CF3またはCH3であり;
Bは、Nであり;
Cは、CRCであり、ここで、RCは、水素、フルオロ、クロロ、C1−3脂肪族、CF3、−OCF3または−OC1−2脂肪族であり;そして
Dは、CRDであり、ここで、RDは、フルオロ、クロロ、C1−3脂肪族、CF3、−OCF3または−OC1−2脂肪族である。
R1は、
R1aは、必要に応じてかつ独立して、−CN、最大3個のF原子、または最大2個のCH3、−OC1−2アルキルもしくは−OH基で置換される−C1−4アルキルであり;
R2は、C1−2アルキルであり;
R3は、水素、−OH、−OC1−4アルキル、または最大2個の−OH基で必要に応じて置換されるC1−4アルキルであり;
R4は、水素もしくはCH3であるか、またはR3およびR4は一体となって、最大2個のOH基で必要に応じて置換されるC3−6シクロアルキル環、またはC1−4アルキル、−C(O)C1−4アルキルもしくはC(O)OC1−4アルキルで必要に応じて置換される、1つの酸素原子もしくは窒素原子を有する4〜6員複素環式環を形成し;
RCは、水素、F、C1−2アルキルまたは−OC1−2アルキルであり;そして
RDは、−ORD1、−C(O)N(RD1)RD2、−S(O)2N(RD1)RD2、−S(O)1−2RD2、−N(RD1)S(O)2RD2または−N(RD1)S(O)2N(RD1)RD2であり、ここで、
RD1は、水素またはC1−2アルキルであり、RD2は、C1−4アルキル、−(CH2)0−1C3−6シクロアルキル、または最大2個の酸素原子もしくは窒素原子を有する−(CH2)0−1C4−6ヘテロシクリルであり、アルキル、シクロアルキルまたはヘテロシクリルの各々は、最大3個のF原子または最大2個の−OH基で必要に応じて置換される。
R1は、
R2は、CH3であり;
R3は、水素、C1−2アルキル、OHまたはOCH3であり;
R4は、水素またはCH3であり;
RCは、水素であり;そして
RDは、−OC1−2アルキルまたは−OC3−5シクロアルキル(各々、最大3個のフッ素原子で必要に応じて置換される)である。
R1は、
R2は、CH3であり;
R3は、水素、C1−2アルキル、OHまたはOCH3であり;
R4は、水素またはCH3であり;
RCは、水素、F、Cl、C1−3脂肪族、(CH2)0−1CF3、−OCF3または−OC1−8脂肪族であり;そして
RDは、−C(O)NHC1−8脂肪族である。
別の実施形態において、本発明は、本明細書中に記載される任意の式またはクラスの化合物を含む薬学的組成物を提供する。さらなる実施形態において、本発明は、表1の化合物を含む薬学的組成物を提供する。さらなる実施形態において、その組成物は、追加の治療薬をさらに含む。
本発明の1つの態様において、本発明は、患者の脳または脊髄における、PI3Kが介在する状態または疾患を処置するかまたはその重症度を下げる方法を特徴とする。用語「PI3Kが介在する疾患」は、本明細書中で使用されるとき、PI3Kアイソフォームが関与することが知られている任意の疾患または他の有害な状態のことを意味する。1つの実施形態において、PI3Kアイソフォームは、PI3Kγである。
本明細書中で使用されるとき、すべての省略形、シンボルおよび慣例は、現代の科学文献において使用されているものと一致する。例えば、Janet S.Dodd,ed.,The ACS Style Guide:A Manual for Authors and Editors,2nd Ed.,Washington,D.C.:American Chemical Society,1997を参照のこと。以下の定義は、本明細書中で使用される用語および省略形を説明している:
ATP アデノシン三リン酸
ブライン 飽和NaCl水溶液
Cp*RuCl(cod) クロロ(ペンタメチルシクロペンタジエニル)(シクロオクタジエン)ルテニウム(II)
DCM ジクロロメタン
DIEA ジイソプロピルエチルアミン
DMA ジメチルアセトアミド
DMAP 4−ジメチルアミノピリジン
DMF ジメチルホルムアミド
DMSO メチルスルホキシド
dppfPdCl2 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・ジクロロメタン
DTT ジチオトレイトール
EDCI 1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド
ESMS エレクトロスプレー質量分析
Et2O エチルエーテル
EtOAc 酢酸エチル
EtOH エチルアルコール
HATU 2−(7−アザ−1H−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
HEPES 4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸
HPLC 高速液体クロマトグラフィー
LC−MS 液体クロマトグラフィー−質量分析
m−CPBA メタ−クロロ過安息香酸
Me メチル
MeOH メタノール
MTBE メチルt−ブチルエーテル
MC メチルセルロース
NMP N−メチルピロリジン
PBS リン酸緩衝食塩水
Pd(Cy)3Cl2 ジクロロ−ビス(トリシクロヘキシルホスホラニル)パラジウム(II)
Ph フェニル
RTまたはrt 室温(20℃〜25℃)
tBu 第三級ブチル
TCA トリクロロ酢酸
THF テトラヒドロフラン
TEA トリエチルアミン
一般的な合成手順
通常、本発明の化合物は、本明細書中に記載される方法または当業者に公知の他の方法によって調製され得る。
式Iの化合物は、スキーム1の経路A〜Kに示されるように調製され得、ここで、A、B、C、D、E、X1、X2、R1およびR2の各々は、説明の他の箇所に記載されているとおりであり、R3およびR4の各々は、Hである。このスキームの経路Aに示されるように、XがCHである式Iの化合物の場合、式A1のハロゲン化アリールを、N−ブロモスクシンイミド(NBS)で処理することによって、式A2のブロモアルキル化合物が生成される。続いて、そのブロモアルキル化合物と式A3のアミンとの反応により、式A4の5−ハロイソインドリノンが生成される。適切なパラジウム触媒の存在下での式A4の化合物と式A5のボロン酸またはボロネートとの反応により、X1およびX2の各々がCHである式Iの化合物が生成される。ハロゲン化アリールまたはハロゲン化ヘテロアリールからボロネートまたはボロン酸を調製するための手順は、Boronic Acids,ISBN:3−527−30991−8,Wiley−VCH,2005(Dennis G.Hall,editor)に記載されている。一例を挙げれば、そのハロゲンは、臭素であり、そのボロネートは、臭化アリールまたは臭化ヘテロアリールを、4,4,5,5−テトラメチル−2−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−1,3,2−ジオキサボロランと反応させることによって調製される。その後のカップリング反応において、そのように形成されたボロネートまたはボロン酸は、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・ジクロロメタン(dppfPdCl2)の存在下で、ハロゲン化アリールまたはハロゲン化ヘテロアリールと反応され得る。
スキーム2の工程2−iに示されるように、100mLのDMF中のNaH(4.0g,鉱油中60%,0.1mol)の懸濁液に、10mLの無水エチルアルコール(4.6g,0.1mol)/DMF溶液を室温にて加えた。水素ガスが発生した後、その反応混合物を室温にて30分間撹拌し、得られたエトキシド溶液を、60℃の100mLのDMF中の3,5−ジブロモピリジン(11.84g,0.05mol,Aldrich Chemical Co.から入手)の溶液に移した。その反応物を60℃で4時間撹拌し、次いで、室温に戻した。ブラインおよび酢酸エチルを加え、有機相を分離し、MgSO4で乾燥し、濾過し、揮発性物質を減圧下で除去した。得られた粗材料を、所望の生成物を20%酢酸エチル/ヘキサン類で溶出するシリカゲルクロマトグラフィーで精製することにより、3−ブロモ−5−エトキシピリジンを得た(化合物2001,4.25g,42%収率):
スキーム3(a)の工程3(a)−iに示されるように、2−クロロ−3−ヒドロキシピリジン(化合物2005,2.0g,15.4mmol,Aldrich Chemical Co.から入手)を、クロロジフルオロ酢酸ナトリウム(4.71g,30.9mmol,Lancaster Synthesis,Inc.から入手)および無水炭酸カリウム(2.56g;18.5mmol)とともに40mLのDMFおよび5.0mLの水に溶解させた。その反応混合物を油浴内で、100℃で2時間加熱した。別の当量のクロロジフルオロ酢酸ナトリウムおよび1.2当量の炭酸カリウムを加え、加熱をさらに2.0時間続けた。この時点の後に、反応物を冷却し、揮発性物質を減圧下で除去した。残渣をブラインと酢酸エチルとに分配し、有機相をブラインで1回以上洗浄し、Na2SO4で乾燥し、濾過し、揮発性物質を減圧下で除去した。その生成物を、ヘキサン類/DCMからDCMのグラジエントで溶出するシリカゲルクロマトグラフィーで精製することにより、2−クロロ−3−(ジフルオロメトキシ)ピリジンを白色固体として得た(化合物2006,2.0g,72%収率):ESMS(M+H)180;
スキーム3(b)の工程3(b)−iに示されるように、5−ブロモ−2−クロロ−3−メトキシピリジン(1.0g,4.5mmol,実施例2における化合物2003と同じ様式で、3−ブロモ−5−メトキシピリジンから出発して調製した)をナトリウムエトキシド/エタノール溶液(5.05mL,21%w/v,13.5mmol)で処理し、その反応混合物に100℃で20分間マイクロ波を照射した。水を加え、エタノールを減圧下で蒸発させた。得られた水溶液をDCMおよびエーテルで抽出した後、合わせた抽出物をMgSO4で乾燥した。濾過した後、揮発性物質を減圧下で除去することにより、5−ブロモ−2−エトキシ−3−メトキシピリジンを得た(化合物2011),0.72g,69%収率):ESMS(M+H)232.32/234.23。スキーム3(b)の工程3(b)−iiに示されるように、化合物2012(ESMS(M+H)218.32/220.23)を、エタノール中のナトリウムエトキシドの代わりにメタノール中のナトリウムメトキシドを用いて化合物2011と同じ様式で調製した。
スキーム4(a)の工程4(a)−iに示されるように、ヨードエタン(13.69g,7.021mL,87.75mmol)を、200mLのDMF中の、5−ブロモ−2−メチルピリジン−3−オール(5.5g,29.25mmol)およびK2CO3(12.13g,87.75mmol)に加えた。その混合物を70℃で一晩撹拌し、その混合物に飽和NaHCO3を加えた。その混合物をEtOAc(3×)で抽出し、合わせた有機相を水(3×)およびブラインで洗浄した。硫酸ナトリウムで乾燥した後、その混合物を濾過し、減圧下で濃縮した。残渣を中圧シリカゲルクロマトグラフィー(ヘキサン中30%EtOAc)で精製することにより、5−ブロモ−3−エトキシ−2−メチルピリジンを得た(化合物2013,4.6g,65%収率):ESMS(M+H)216.18;
スキーム4(b)の工程4(b)−iに示されるように、HATU(8.194g,2.55mmol)およびDIPEA(5.570g,7.507mL,43.10mmol)を、DMF(50mL)中の5−ブロモ−2−メトキシピリジン−3−カルボン酸(5g,21.55mmol)の溶液に加えた。得られた溶液を10分間撹拌した後、エタンアミン塩酸(1.757g,2.196mL,21.55mmol)を加えた。得られた溶液を室温で5時間撹拌した。その反応混合物に水(100mL)および酢酸エチル(100mL)を加えた。有機層を分離し、無水硫酸ナトリウムで乾燥し、濾過し、減圧下で濃縮した。粗残渣をシリカゲルクロマトグラフィー(ジクロロメタン中の0〜2%メタノールのグラジエント)で精製することにより、5−ブロモ−N−エチル−2−メトキシニコチンアミドをオフホワイトの固体として得た(化合物2015,3.4g):
スキーム5の工程5−iに示されるように、メチル4−ブロモ−2−(ブロモメチル)ベンゾエート(化合物2018,2.08g,6.75mmol,1−(4−ブロモ−2−メチルフェニル)エタノンとNBSとを反応させることによって調製される)、1H−ピラゾール−4−アミン(561mg,6.75mmol)およびDIEA(873mg,1.18mL,6.75mmol)をDMF(7.78mL)中で混合し、110℃で90分間加熱した。その反応混合物をMeOH(60mL)で希釈し、得られた白色の結晶性固体を濾集し、真空乾燥することにより、5−ブロモ−2−(1H−ピラゾール−4−イル)イソインドリン−1−オンを得た(化合物2019,1.21g,4.35mmol,64%収率):ESMS(Μ+Η)279.99。
スキーム6の工程6−iに示されるように、2,3−ジメトキシ−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ピリジン(化合物2021,920mg,3.47mmol)、メチル4−ブロモ−2,6−ジメチル−ベンゾエート(844mg,3.47mmol)およびCs2CO3(2.26g,6.94mmol)を、密閉されたチューブ内でDMSO(12mL)に溶かした。その溶液に窒素ガスを5分間通して泡立て、dppfPdCl2(141mg,0.174mmol)を加え、その容器を密閉した。その反応混合物を窒素雰囲気下、90℃で60分間加熱した。冷却した後、その混合物をEtOAc/水に注ぎ込んだ。有機相を水、ブラインで洗浄し、Florisil(登録商標)のプラグに通し、減圧下で濃縮することにより、固体を得た。その固体をMeOHに懸濁させ、濾集することにより、メチル4−(5,6−ジメトキシ−3−ピリジル)−2,6−ジメチル−ベンゾエートを得た(化合物2022,310mg)。濾液を濃縮し、シリカゲルクロマトグラフィー(0〜50%EtOAc/hex)で精製することにより、さらなる400mgの化合物2022を得た(総収量710mg,2.4mmol,68%収率)。この化合物をそのままその後の反応において使用した。
スキーム7の工程7−iに示されるように、密閉されたチューブ内にて、2,3−ジメトキシ−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ピリジン(503mg,1.9mmol)、メチル4−ブロモ−2−クロロ−6−メチル−ベンゾエート(500mg,1.9mmol)およびCs2CO3(1.24g,3.8mmol)をDMSO(7mL)中で混合した。その溶液に窒素ガスを5分間通して泡立て、dppfPdCl2(78mg,0.1mmol)を加え、その容器を密閉した。その反応混合物を窒素雰囲気下、60分間90℃で加熱した。冷却した後、その混合物をEtOAc/水に注ぎ込んだ。有機層を水、ブラインで洗浄し、Florisil(登録商標)のプラグに通し、減圧下で濃縮した。得られた油状物をシリカゲルクロマトグラフィー(0〜50%EtOAc/ヘキサン類)で精製することにより、メチル2−クロロ−4−(5,6−ジメトキシ−3−ピリジル)−6−メチル−ベンゾエートを得た(化合物2025,367mg,1.14mmol,60%収率):ESMS(M+H)322.12。
スキーム8の工程8−iに示されるように、国際特許出願公開番号WO2006/095159の手順に従って、オキシ塩化リン(45mL)中のエチル2−メチル−6−オキソ−1,6−ジヒドロピリジン−3−カルボキシレート(5.92g,32.6mmol)の混合物を、90℃で1時間加熱した。冷却した後、その反応混合物を減圧下で濃縮し、残渣に氷水を加えた後、28%水酸化アンモニウムを加えることにより、pHを7に調整した。得られた白色固体を濾集し、氷水で洗浄し、高減圧下で乾燥することにより、エチル6−クロロ−2−メチルニコチネートを得た(化合物2027,6.18g,94.7%収率):ESMS(M+1)200.19;
スキーム9の工程9−iに示されるように、エチル4,6−ジヒドロキシ−2−メチルピリジン−3−カルボキシレート(Accla Biochem Inc.)を50mLのPOCl3に懸濁させ、窒素雰囲気下、5時間90℃に加熱した。その反応混合物を冷却し、減圧下で濃縮した。薄黒い油状物に撹拌しながら氷を加えた後、酢酸エチルおよび水を加えた。有機相を水、ブラインで洗浄し、硫酸ナトリウムで乾燥した。濾過した後、揮発性物質を減圧下で除去し、粗生成物をシリカゲルクロマトグラフィーで精製することにより、エチル4,6−ジクロロ−2−メチルニコチネートを淡黄色油状物として得た(化合物2030,62%収率):ESMS(Μ+Η)234/236/238;
スキーム10の工程10−iおよび10−iiに示されるように、化合物2032から化合物88への変換と同様の様式で、化合物2031を化合物82に変換した。
スキーム11の工程11−iに示されるように、2,5−ジメチルニコチン酸(化合物2034,519mg,3.43mmol)を、マイクロ波用バイアル内で1,1,1−トリエトキシエタン(5.57g,6.29mL,34.3mmol)に溶解させた。その反応混合物を5分間、150℃に加熱した。30mLのDCMで希釈した後、有機相を10mLの飽和NaHCO3で洗浄した。有機層を相分離器に通し、次いで、減圧下で濃縮することにより、エチル2,5−ジメチルニコチネート(化合物2035,390mg,63%収率)を黄色油状物として得た:ESMS(M+1)179.89;
スキーム12の工程12−iに示されるように、DMF/アセトニトリル/水(1:1:0.5)中の、化合物2021(111mg,0.42mmol)と、炭酸ナトリウム(97mg,0.91mmol)と、2−クロロ−4−メチル−6−(1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−b]ピリジン−5−オン(化合物2040,104mg,0.42mmol;実施例11の工程11−vにおける化合物2039の調製と同様の様式でエチル6−クロロ−2−(クロロメチル)−4−メチルニコチネートから調製される)との脱気された混合物に、Pd(PPh3)4(50mg,0.04mmol)を加えた。その反応混合物を密閉チューブ内で、90℃で48時間加熱した。水(5mL)を加え、その混合物を室温にて30分間撹拌した。濾過した後、収集された固体をMeOHおよびEtOAcで洗浄し、EtOAc中で超音波処理し、次いで、濾集することにより、2−(5,6−ジメトキシピリジン−3−イル)−4−メチル−6−(1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−b]ピリジン−5−オン(化合物135,100mg,66%収率)を淡緑色固体として得た:ESMS(Μ+Η)352.4;
スキーム13の工程13−iに示されるように、エチル6−クロロ−2−(クロロメチル)−4−メチルニコチネート(化合物2041,5.11g,20.6mmol;実施例11における化合物2038の調製と同様の様式で2,5−ジメチルニコチン酸から調製される)をメタノール(30.6mL)に溶解させた。7Mアンモニア/MeOH(21.3mL,149mmol)を加えた後、水酸化アンモニウム(18.7g,20.8mL,533mmol)を加えた。その反応混合物を室温で一晩撹拌し、形成した沈殿物を濾集し、高減圧下で乾燥することにより、2−クロロ−4−メチル−6,7−ジヒドロ−5H−ピロロ[3,4−b]ピリジン−5−オンを得た(化合物2042,2.6g,14.2mmol,69%収率):ESMS(M+1)183.29;
スキーム14の工程14−iに示されるように、2−(5,6−ジメトキシ−3−ピリジル)−6,7−ジヒドロピロロ[3,4−b]ピリジン−5−オン(化合物2044,100mg,0.37mmol;実施例13の工程13−iに示されるように化合物2029のアミノ分解によって調製される)、2−ヨード−5−メチル−チオフェン(99mg,54μL,0.44mmol)および炭酸セシウム(240mg,0.737mmol)をねじぶた付きの小チューブに量り入れた。その反応混合物に窒素を15分間流した。CuI(14.0mg,0.074mmol)およびN,N’−ジメチルエタン−1,2−ジアミン(6.5mg,7.8μL,0.073mmol)を加え、さらに5分間、窒素を流し続けた。そのチューブを密閉し、内容物を100℃で18時間加熱した。室温に冷却した後、その反応混合物を20mLの水で希釈し、沈殿物を濾集した。その固体を水で洗浄し、メタノールで洗浄し、次いで、6mLのDMSOに溶かした。逆相HPLCで精製することにより、2−(5,6−ジメトキシピリジン−3−イル)−6−(5−メチルチオフェン−2−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−b]ピリジン−5−オンを得た(化合物252,31.6mg,0.084mmol,23%収率):ESMS(Μ+Η)368.01;
スキーム15の工程15−iに示されるように、DMF(500μL)中の、2−(5,6−ジメトキシピリジン−3−イル)−6−(1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−b]ピリジン−5−オン(化合物115,20mg,0.047mmol,実施例8に示された様式と同様の様式で化合物2029と1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−4−アミンとを反応させることによって調製される)の溶液に、ヨードメタン(17mg,0.119mmol)を加えた後、NaH(6mg,鉱油中60%w/w)を加えた。その反応物を室温で2時間撹拌し、NaHCO3の飽和水溶液(1mL)でクエンチし、DCM(3×2mL)で抽出した。有機相を濃縮し、粗残渣を分取シリカゲル薄層クロマトグラフィー(100%EtOAc)で精製することにより、2−(5,6−ジメトキシピリジン−3−イル)−7,7−ジメチル−6−(1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−b]ピリジン−5−オン(化合物346,11.2mg,50%収率)を白色固体として得た::ESMS(Μ+Η)447.87;
スキーム16の工程16−iに示されるように、0℃のDCM(120mL)中の2,2,2−トリフルオロエタノール(26.54g,19.33mL,265mmol)およびピリジン(20.99g,21.46mL,265mmol)の溶液に、DCM(150mL)中のトリフルオロメチルスルホニルトリフルオロメタンスルホネート(74.85g,44.6mL,265mmol)の溶液を、滴下漏斗を介して45分間にわたって加えた。滴下が完了した後、その反応混合物をさらに15分間撹拌し、次いで、水(400mL)でクエンチした。有機相を水(400mL)で洗浄し、MgSO4で乾燥し、濾過することにより、2,2,2−トリフルオロエチルトリフルオロメタンスルホネート(化合物2045)を得て、それをそのまま使用した。スキーム16の工程16−iiに示されるように、化合物2045の溶液を、氷水浴内で、冷却されたK2CO3(61.11g,442.2mmol)を含むDMF(200mL)中の4−ニトロ−1H−ピラゾール(25g,221.1mmol)の溶液に25分間にわたって加えた。添加が完了したら、冷却浴を除去し、その反応混合物を23℃で16時間撹拌した。有機相を水(500mL)で洗浄し、水性の洗浄液をDCM(150mL)で抽出した。合わせた有機相をMgSO4で乾燥し、濾過し、減圧下で濃縮した。得られたDMF含有濃縮物をEtOAc:ヘキサン類(1:1、500mL)で希釈し、水(3×250mL)、ブライン(200mL)で洗浄し、乾燥し(MgSO4)、濾過し、減圧下で濃縮することにより、4−ニトロ−1−(2,2,2−トリフルオロエチル)ピラゾール(化合物2046,40.4g,207.1mmol,93.65%収率)を黄褐色固体として得た:
スキーム17の工程17−iに示されるように、23℃のAcOH(30mL)中の6−(1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−4−イル)−5H−ピロロ[3,4−b]ピリジン−5,7(6H)−ジオン(化合物2048,2.32g,7.832mmol)に、Zn(2.561g,39.16mmol)を加えた。23℃で20分間撹拌した後、その反応混合物をガラスフリットで濾過し、濾液を濃縮した。残渣を、熱EtOH(40mL)に溶解/懸濁させた。得られた混合物を冷却し、Et2O(50mL)で処理した。得られた沈殿物を濾集し、母液を減圧下で濃縮し、得られた固体を熱EtOH(20mL)およびEt2Oから再結晶させることにより、さらなる7−ヒドロキシ−6−(1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−b]ピリジン−5−オン(化合物2055,合計1.61g)を黄色固体として得た:ESMS(Μ+Η)299.26;
スキーム18の工程18−iに示されるように、CHCl3(80mL)およびMeOH(40mL)中の7−ヒドロキシ−6−(1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−b]ピリジン−5−オン(化合物2055,4.35g,14.6mmol)に、mCPBA(5.39g,21.9mmol)を加えた。24時間撹拌した後、さらなるmCPBA(1.26g,7.30mmol)を加えた。さらに16時間撹拌した後、得られた沈殿物を濾集し、DCM(10mL)およびEt2O(20mL)で洗浄することにより、7−ヒドロキシ−5−オキソ−6−(1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−b]ピリジン1−オキシド(化合物2059,2.49g)を白色固体として得た:ESMS(Μ+Η)315.25;
スキーム19の工程19−iに示されるように、7−ヒドロキシ−6−(1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−b]ピリジン−5−オン(化合物2055,1.75g,5.87mmol)およびメチル2−トリフェニルホスホラニリデンアセテート(2.06g,6.16mmol)に、トルエン(23mL)およびTHF(12mL)を加えた。その反応混合物を加熱還流し、そこで2.5時間保持した。冷却した後、その反応混合物を減圧下で濃縮し、残渣を中圧シリカゲルクロマトグラフィー(DCM中の0〜7.5%EtOH)で精製することにより、メチル2−(5−オキソ−6−(1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−b]ピリジン−7−イル)アセテート(化合物2061,2.25g,6.35mmol)を透明油状物として得た:ESMS(Μ+Η)355.29。その生成物は、少量のトリフェニルホスフィンオキシドを含んでいたが、そのままその後の反応で使用した。
スキーム20の工程20−iに示されるように、2−(5,6−ジメトキシピリジン−3−イル)−6−(1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−b]ピリジン−5−オン[化合物70,100mg,0.2964mmol,実施例12に示されたような化合物135の調製と同様の様式で2−クロロ−6−(1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−b]ピリジン−5−オンおよび2,3−ジメトキシ−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ピリジン(化合物2021)から調製される]および炭酸セシウム(193mg,0.593mmol)を、スターラーバー(stir bar)を備えたコニカルマイクロ波用バイアルに量り入れた。DMF(1.05mL)を加えた後、1−(2−クロロエチル)ピラゾール(77mg,0.593mmol)を加えた。そのバイアルを密閉し、120℃で15分間加熱した。水(3mL)を加え、得られた沈殿物を濾集し、5mLの水で洗浄した。濾液を減圧下で濃縮した。収集した固体および濾液の濃縮からの残渣の各々を、可溶化するまでDMSOで希釈し、逆相HPLCで精製することにより、6−(1−(2−(1H−ピラゾール−1−イル)エチル)−1H−ピラゾール−4−イル)−2−(5,6−ジメトキシピリジン−3−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−b]ピリジン−5−オンを得た(化合物171,22mg,0.05mmol,17%収率):ESMS(Μ+Η)432.0;
スキーム21の工程21−iに示されるように、窒素雰囲気下の1−(2,2,2−トリフルオロエチル)ピラゾール−4−アミン(2.01g,12.2mmol)および炭酸カリウム(3.364g,24.34mmol)が入った丸底フラスコに、DMF(15mL)を加えた後、3−ブロモプロパ−1−イン(1.45g,1.09mL,12.2mmol)を加えた。その反応混合物を室温にて18時間撹拌した。水およびEtOAcを加え、水層をEtOAcで抽出した。合わせた有機相をブライン、水で洗浄し、乾燥し(硫酸ナトリウム)、濾過し、減圧下で濃縮した。シリカゲルクロマトグラフィー(石油エーテル:EtOAc,1:1)で精製することにより、N−(プロパ−2−イニル)−1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−4−アミン(化合物2064,1.19g、48%収率)を橙色固体として得た:
スキーム22の工程22−iに示されるように、冷却器が取り付けられた1L丸底フラスコに、2,6−ジクロロピリジン−3−カルボン酸(10.0g,52.1mmol)、2,3−ジメトキシ−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ピリジン(化合物2021,13.81g,52.1mmol)、Pd(PPh3)4(3.01g,2.60mmol)、Na2CO3(16.56g,156mmol)、ジオキサン(250mL)および水(100mL)を入れた。そのフラスコから1分間空気を抜き、その混合物をN2雰囲気下に置いた。その混合物を110℃で16時間加熱し、その後、沈殿物が形成された。その反応混合物を冷却し、分液漏斗に移した。Na2CO3(200mLの10wt%水溶液)を加えた後、水(100mL)およびEtOAc(500mL)を加えた。沈殿物/エマルジョンはそのまま残り、主に水層に局在化した。その水層を分離し、EtOAc(300mL)で洗浄し、次いで、濃HCl(約50mL)で慎重にpH2に酸性化した。得られた沈殿物を濾集し、水(50mL)で洗浄した。湿固体を、補助のEtOH(200mL)と共に1Lフラスコに移し、次いで、蒸発乾固させた。その固体残渣をEtOAc(120mL)に溶解/懸濁させ、次いで、ヘキサン類(120mL)で処理した。得られた固体を濾集し、ヘキサン類(50mL)で洗浄し、減圧下で乾燥することにより、2−クロロ−6−(5,6−ジメトキシ−3−ピリジル)ピリジン−3−カルボン酸(化合物2068,11.99g,78%収率)をオフホワイトの固体として得た:ESMS(M+H)295.27;
スキーム23の工程23−iに示されるように、1,2−ジブロモエタン(369.3mg,169.4μL,1.966mmol)を、室温でDMF(12mL)中の2−クロロ−4−メチル−6−[1−(2,2,2−トリフルオロエチル)ピラゾール−4−イル]−7H−ピロロ[3,4−b]ピリジン−5−オン(500mg,1.512mmol,1−(2,2,2−トリフルオロエチル)−4−アミノピラゾールと化合物2041との反応から調製される)の撹拌溶液に加えた後、NaH(133mg,3.326mmol,鉱油中60wt%分散液)を加えた。その反応混合物を室温にて30分間撹拌し、0℃に冷却し、飽和NaHCO3(10mL)でクエンチした。その反応混合物をDCM(3×10mL)で抽出し、合わせた有機相をNa2SO4で乾燥し、濾過し、減圧下で濃縮した。粗残渣を中圧シリカゲルクロマトグラフィー(0〜50%EtOAc/ヘキサン類)で精製することにより、2’−クロロ−4’−メチル−6’−(1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−4−イル)スピロ[シクロプロパン−1,7’−ピロロ[3,4−b]ピリジン]−5’(6’H)−オンを得た(化合物2073,250mg,47%収率):ESMS(Μ+Η)358.0。
スキーム24の工程24−iに示されるように、トリメチルシリルシアニド(4.241g,5.700mL,42.75mmol)を、0℃のAcOH(45mL)中の1−(2,2,2−トリフルオロエチル)ピラゾール−4−アミン(7.059g,42.75mmol)およびテトラヒドロフラン−3−オン(3.68g,42.75mmol)の溶液に注射器を介して30秒間にわたって加えた。その反応混合物をゆっくり23℃に温めた。16時間撹拌した後、その混合物を、1:1の水酸化アンモニウム:氷(200mL)に加え、DCM(2×200mL)で抽出した。有機相を乾燥し(硫酸マグネシウム)、濾過し、濃縮した。残渣を中圧シリカゲルクロマトグラフィー(ヘキサン類中0〜100%EtOAc)で精製することにより、3−[[1−(2,2,2−トリフルオロエチル)ピラゾール−4−イル]アミノ]テトラヒドロフラン−3−カルボニトリル(化合物2075,3.66g,14.07mmol,32.91%収率)を茶色油状物として得た:ESMS(M+H)261.32;
表1
実施例25.PI3K阻害アッセイ
Beckman Coulter製のBiomek FXを使用して、100%DMSO中の本発明の化合物の10段階の2.5倍段階希釈物の各々の1.5μLを、96ウェルポリスチレンプレート[Corning,Costar Item No.3697]の個別のウェル(本明細書中以後、「試験ウェル」)に加えた。また、1つの試験ウェルには、化合物を含まない1.5μLのDMSOを入れた。別のウェルに、当該酵素を完全に阻害すると知られている濃度の、DMSO中のインヒビターを入れた(本明細書中以後、「バックグラウンドウェル」)。Titertek Multidropを使用して、50μLのReaction Mix[100mM HEPES pH 7.5、50mM NaCl、10mM DTT、0.2mg/mL BSA、60μΜホスファチジルイノシトール(4,5)二リン酸 ジC16(PI(4,5)P2;Avanti Polar Lipids、Cat.No.840046P)および目的のPI3Kアイソフォーム(アイソフォーム濃度については表3を参照のこと)]を各ウェルに加えた。反応を開始するために、50μLのATP Mix[20mM MgCl2、6μΜ ATP(100μCi/μモル33P−ATP)]を各ウェルに加えた後、それらのウェルを25℃で30分間インキュベートした。各ウェル内の最終濃度は、50mM HEPES 7.5、10mM MgCl2、25mM NaCl、5mM DTT、0.1mg/mL BSA、30μΜ PI(4,5)P2、3μΜ ATPおよび目的のPI3Kアイソフォーム(表2を参照のこと)だった。各ウェル内の化合物の最終濃度は、10μΜ〜1nMの範囲だった。
雌C57Bl/6Jマウス(7週齢)をJackson Laboratory(Maine,US)から購入した。動物を、げっ歯類用の固形飼料および水を自由に摂取できる状態で1週間、標準的な実験室条件(12時間明期)に順応させた。すべての手順は、National Institute of Health Guidelines for the care and Use of Laboratory Animalsに従い、IACUCCによって承認されたものだった。エンドトキシンであるリポ多糖(LPS)(大腸菌011:B4,cat#437627)をCalbiochemから購入した。LPSを0.05mg/mlの濃度でPBS緩衝液に溶解させ、凍結アリコートとして保存した。研究の開始時に、3日間連続でマウスにLPS(0.5mg/kg)を腹腔内(i.p.)注射した。VRT化合物による治療的処置を、2回目のLPS投与とともに開始し、この研究中ずっと維持した。化合物を1日に2回で合計4回、胃管栄養法により経口的に投薬した。最後のLPSの注射の24時間後かつ最後のVRT投薬の2時間後に、動物をCO2窒息により屠殺した。
Claims (39)
- 式:
X1は、NまたはCHであり;
X2は、N、CHまたはC−CH3であり;
R1は、フェニル環、5〜6員ヘテロアリール環、ピリドン環、または9〜10員縮合二環式のヘテロアリールもしくは複素環式環系から選択され、ここで、前記環または環系の各々は、独立して存在する1個または2個のR1aで必要に応じて置換され、前記ヘテロアリールまたは複素環式環の各々は、窒素、酸素または硫黄から選択される1個、2個または3個のヘテロ原子を有し;
R1aは、クロロ、フルオロ、C1−8脂肪族、−(CH2)0−2C3−6脂環式、窒素、酸素もしくは硫黄から選択される最大2個のヘテロ原子を有する−(CH2)0−2−5〜6員複素環式、−CN、−C(O)C1−4脂肪族、−C(O)NH(C1−4脂肪族)、−C(O)N(C1−4脂肪族)2、−C(O)OC1−4脂肪族、−S(O)2NH(C1−4脂肪族)、−S(O)2N(C1−4脂肪族)2または−S(O)2C1−4脂肪族であり、ここで、R1aの前記脂肪族または脂環式の最大3個の隣接していない炭素原子は、−O−、−S−または−N(R1b)−で置換され得、R1aの前記脂肪族、脂環式または複素環式の各々は、必要に応じてかつ独立して、最大4個のJRで置換され;
各JRは、独立して、フルオロ、オキソ、−(CH2)0−2CN、−(CH2)0−2CF3、−C(O)R1b、−C(O)N(R1b)2、−C(O)O(R1b)、−N(R1b)2、−N(R1b)C(O)R1b、−(CH2)0−2OR1b、フェニルもしくは5〜6員ヘテロアリール、4−6ヘテロシクリルまたは9−11縮合二環式のヘテロアリールもしくはヘテロシクリルであり、前記ヘテロアリールまたはヘテロシクリル環の各々は、窒素、酸素または硫黄から選択される最大3個の原子を有し、前記脂環式、フェニル、ヘテロアリールまたはヘテロシクリルの各々は、最大2個のR1cで必要に応じて置換され;
各R1bは、独立して、水素、C1−8脂肪族、−(CH2)0−1C3−6脂環式、またはNもしくはOから選択される最大2個のヘテロ原子を有する−(CH2)0−1C4−6複素環式から選択されるか、または2つのR1bが、それらが結合している原子と一体となって、5〜6員複素環式環を形成し、ここで、脂肪族、脂環式または複素環式の各々は、最大3個のF原子または最大2個の−OH、−C1−2アルキルもしくは−OC1−2アルキル基で必要に応じて置換され;
各R1cは、独立して、フルオロ、クロロ、C1−4脂肪族、−(CH2)0−2OH、−CN、−C(O)C1−4脂肪族または−C(O)OC1−4脂肪族であり;
R2は、水素、F、Cl、CF3、C1−2脂肪族、C3−4脂環式、−N(CH3)2、−N(CH2)3、−OCF3、−OCHF2または−OC1−2脂肪族であり;
R3は、水素、C1−6脂肪族、C3−6脂環式、NもしくはOから選択される1個もしくは2個の原子を有するC4−7ヘテロシクリル、−(CH2)0−1CF3、−OH、−OC1−6脂肪族、−OC3−6脂環式、1つの酸素原子を有する−OC3−6ヘテロシクリル、−O(CH2)2OC1−2脂肪族もしくは−OC1−2アルキルC(O)OC1−3脂肪族、またはベンジルであり;そして
R4は、水素またはC1−6アルキルであるか;またはR3およびR4は、それらが結合している炭素と一体となって、3〜6員脂環式環、NもしくはOから選択される最大2個の原子を有する3〜6員複素環式環、またはC2アルケニルを形成し、ここで、R3、R4、またはR3とR4とが一体となったときの前記脂肪族、脂環式もしくはヘテロシクリルの各々は、最大3個のF原子、または最大2個のC1−2アルキル、−C(O)C1−4アルキル、−C(O)OC1−4アルキル、−OHもしくは−OC1−2アルキル基で必要に応じて置換され;
Aは、NまたはCRAであり;
Bは、NもしくはCRBであるか、またはA=Bは、硫黄原子であり;
Cは、NまたはCRCであり;
Dは、NまたはCRDであり;
Eは、NまたはCREであり、ここで、A、B、C、DまたはEのうちの2個以下が、Nであり;
RAは、水素、CH3またはOCH3であり;
RBは、水素、F、Cl、C1−3脂肪族、−(CH2)0−1CF3、−(CH2)0−1CHF2または−O(CH2)0−1CF3であり;
RCは、水素、F、Cl、C1−3脂肪族、−(CH2)0−1CF3、−(CH2)0−1CHF2、N(R1b)2、−OH、−O(CH2)0−1CF3または−OC1−8脂肪族であり、ここで、前記脂肪族の最大2個の隣接していない炭素原子は、−O−で置換され得;
RDは、水素、フルオロ、クロロ、C1−4脂肪族、−C(O)OH、−C(O)OC1−4脂肪族、−C(O)N(R1b)2、−CN、−C(RD1)=N−OR1b、−N(R1b)2、−N(RD1)C(O)C1−4脂肪族、−N(RD1)C(O)フェニル、−N(RD1)S(O)2C1−4脂肪族、−N(RD1)S(O)2N(R1b)2、−N(RD1)S(O)2フェニル−OH、−OC1−8脂肪族、−O(CH2)0−1C3−6脂環式、−SC1−4脂肪族、−S(O)C1−4脂肪族、−S(O)2C1−4脂肪族または−S(O)2N(R1b)2であり;ここで、RDの前記脂肪族、脂環式または複素環式の最大2個の隣接していない炭素原子は、−O−で置換され得、RDの前記脂肪族、脂環式またはフェニルの各々は、最大5個のフッ素原子で置換され得るか;またはRDおよびRCは、それらが結合している原子と一体となって、フェニル環またはピリジル環を形成し;
各RD1は、独立して、水素またはC1−2アルキルであり;そして
REは、水素、F、Cl、−NHC(O)C1−8脂肪族、−OH、−OC1−2脂肪族、−(CH2)0−1CF3、−(CH2)0−1CHF2、C1−3脂肪族、C3−4脂環式、N(R1b)2、アゼチジン−1−イルである、
化合物またはその薬学的に許容され得る塩。 - RDが、水素、フルオロ、クロロ、C1−4脂肪族、−(CH2)0−1CF3、−C(O)N(R1b)2、−CN、−N(R1b)2、−NHC(O)C1−8脂肪族、−OH、−O(CH2)0−1CF3、−O(CH2)0−1CHF2、−O(CH2)0−1CH2F、−OC1−8脂肪族、−O(CH2)0−1C3−6脂環式、−SC1−8脂肪族、−S(O)2C1−8脂肪族、−S(O)2N(R1b)2であり;ここで、RDの前記脂肪族、脂環式または複素環式の最大2個の隣接していない炭素原子は、−O−で置換され得るか、またはRDおよびRCは、それらが結合している原子と一体となって、フェニル環またはピリジル環を形成し;
R3が、水素、C1−6アルキル、C3−6シクロアルキル、−(CH2)0−1CF3、−OH、−OC1−6アルキル、−OC3−6シクロアルキル、1つの酸素原子を有する−OC3−6ヘテロシクリル、−O(CH2)2OC1−2アルキルもしくは−OC1−2アルキルC(O)OC1−3アルキルまたはベンジルであり;そして
R4が、水素またはC1−6アルキルであるか;またはR3およびR4が、それらが結合している炭素と一体となって、3〜6員シクロアルキル環、1つの酸素原子を有する3〜6員複素環式環を形成し、ここで、R3、R4、またはR3とR4とが一体となったときの前記アルキル、シクロアルキルもしくはヘテロシクリルの各々は、最大2個のF、C1−2アルキルまたは−OC1−2アルキルで必要に応じて置換される、
請求項1に記載の化合物またはその薬学的に許容され得る塩。 - 各R1bが、独立して、水素、C1−4脂肪族またはC3−6脂環式から選択され;
RBが、水素、F、Cl、−OCF3、−OC1−2脂肪族、−CF3またはC1−2脂肪族であり;
RCが、水素、F、Cl、C1−3脂肪族、−(CH2)0−1CF3、−N(R1b)2、−OH、−OCF3または−OC1−8脂肪族であり;
RDが、水素、フルオロ、クロロ、C1−4脂肪族、(CH2)0−1CF3、−C(O)NHC1−8脂肪族、−CN、−N(R1b)2、−NHC(O)C1−8脂肪族、−OH、−OCF3、−OCHF2、−OC1−8脂肪族、−O(CH2)0−1C3−6脂環式、−SC1−8脂肪族、−S(O)2C1−8脂肪族、−S(O)2N(R1b)2であり;ここで、RDの前記脂肪族または脂環式の最大2個の隣接していない炭素原子は、−O−で置換され得るか、またはRDおよびRCは、それらが結合している原子と一体となって、フェニル環またはピリジル環を形成し;
REが、水素、F、Cl、−NHC(O)C1−8脂肪族、−OH、−OCF3、−OC1−2脂肪族、CF3、C1−2脂肪族、C3−4脂環式、N(CH3)2、アゼチジン−1−イルであり;
R2が、水素、F、Cl、CF3、C1−2脂肪族、C3−4脂環式、−N(CH3)2、−N(CH2)3、−OCF3または−OC1−2脂肪族であり;
R3が、水素、C1−2アルキル、−OH、−OC1−2アルキル、−O(CH2)2OC1−2アルキルまたは−OC1−2アルキルC(O)OC1−2アルキルであり;そして
R4が、水素またはC1−2アルキルである、
請求項1に記載の化合物またはその薬学的に許容され得る塩。 - 式:
X1は、CHまたはNであり;
R1は、フェニル環、5員ヘテロアリール環、6員ヘテロアリール環または9もしくは10員縮合二環式のヘテロアリールもしくは複素環式環系から選択され、ここで、前記環または環系の各々は、独立して存在する1個または2個のR1aで必要に応じて置換され、前記ヘテロアリールまたは複素環式環の各々は、窒素、酸素または硫黄から選択される1個、2個または3個のヘテロ原子を有し;
R1aは、クロロ、フルオロ、C1−6脂肪族、C3−6脂環式、−CN、−C(O)R1b、−C(O)N(R1b)2、−C(O)O(R1b)または−OR1bであり、ここで、前記脂肪族または脂環式の各々は、最大3個のJRで必要に応じて置換され;
各JRは、独立して、フルオロ、オキソ、−CN、−C(O)R1b、−C(O)N(R1b)2、−C(O)O(R1b)、−N(R1b)2、−N(R1b)C(O)R1b、−OR1b、または窒素、酸素もしくは硫黄から選択される最大3個の原子を有する5員のヘテロアリールもしくはヘテロシクリルであり;
各R1bは、独立して、水素、C1−4脂肪族またはC3−6脂環式から選択され;
R2は、水素、F、Cl、CF3またはCH3であり;
Bは、Nであり;
Cは、CRCであり、ここで、RCは、水素、フルオロ、クロロ、C1−3脂肪族、CF3、−OCF3または−OC1−2脂肪族であり;そして
Dは、CRDであり、ここで、RDは、フルオロ、クロロ、C1−3脂肪族、CF3、−OCF3または−OC1−2脂肪族である、
請求項1に記載の化合物またはその薬学的に許容され得る塩。 - X1がNである、請求項4に記載の化合物またはその薬学的に許容され得る塩。
- R2がCH3である、請求項5に記載の化合物またはその薬学的に許容され得る塩。
-
- 式:
R1は、
R1aは、−CNもしくは最大3個のF原子もしくは最大2個のCH3で必要に応じてかつ独立して置換される−C1−4アルキル、−OC1−2アルキルまたは−OH基であり;
R2は、C1−2アルキルであり;
R3は、水素、−OH、−OC1−4アルキル、または最大2個の−OH基で必要に応じて置換されるC1−4アルキルであり;
R4は、水素もしくはCH3であるか、またはR3およびR4は一体となって、最大2個のOH基で必要に応じて置換されるC3−6シクロアルキル環、またはC1−4アルキル、−C(O)C1−4アルキルもしくはC(O)OC1−4アルキルで必要に応じて置換される1つの酸素原子または窒素原子を有する4〜6員複素環式環を形成し;
RCは、水素、F、C1−2アルキルまたは−OC1−2アルキルであり;そして
RDは、−ORD1、−C(O)N(RD1)RD2、−S(O)2N(RD1)RD2、−S(O)1−2RD2、−N(RD1)S(O)2RD2または−N(RD1)S(O)2N(RD1)RD2であり、ここで、
RD1は、水素またはC1−2アルキルであり、RD2は、C1−4アルキル、−(CH2)0−1C3−6シクロアルキル、または最大2個の酸素原子もしくは窒素原子を有する−(CH2)0−1C4−6ヘテロシクリルであり、アルキル、シクロアルキルまたはヘテロシクリルの各々は、最大3個のF原子または最大2個の−OH基で必要に応じて置換される、
請求項1に記載の化合物またはその薬学的に許容され得る塩。 - R1aが、最大3個のフッ素原子で必要に応じて置換されるC1−2アルキルである、請求項8に記載の化合物またはその薬学的に許容され得る塩。
- R1aが、CNで必要に応じて置換されるC1−4アルキルである、請求項8に記載の化合物またはその薬学的に許容され得る塩。
- R2がCH3である、請求項8に記載の化合物またはその薬学的に許容され得る塩。
- R3およびR4の少なくとも1つが水素でない、請求項8に記載の化合物またはその薬学的な許容され得る塩。
- R3およびR4の各々がCH3である、請求項12に記載の化合物またはその薬学的な許容され得る塩。
- R3およびR4が一体となって、C1−4アルキル、−C(O)C1−4アルキルまたは−C(O)OC1−4アルキルで必要に応じて置換される1つの酸素原子または窒素原子を有する4〜6員複素環式環を形成する、請求項12に記載の化合物またはその薬学的な許容され得る塩。
- R1が、N、OまたはSから選択される1〜3個のヘテロ原子を有し、かつ1個または2個のR1a基で必要に応じて置換される、5員ヘテロアリール環である、請求項1から14のいずれか1項に記載の化合物またはその薬学的に許容され得る塩。
- R1が、必要に応じて置換されるピラゾール−4−イル、ピラゾール−3−イル、イミダゾール−4−イル、1,2,3−トリアゾール−4−イル、1,2,4−トリアゾール−3−イル、1,2,5−トリアゾール−3−イル、1,3−チアゾール−4−イル、1,3−チアゾール−2−イル、1,2−チアゾール−5−イル、1,2−イソオキサゾール−3−イルである、請求項15に記載の化合物またはその薬学的に許容され得る塩。
- R1が、
- R1が、
- R1が、
- R1が、
R2が、CH3であり;
R3が、水素、C1−2アルキル、OHまたはOCH3であり;
R4が、水素またはCH3であり;
RCが、水素であり;そして
RDが、−OC1−2アルキルまたは−OC3−5シクロアルキルであり、各々は、最大3個のフッ素原子で必要に応じて置換される、
請求項16に記載の化合物またはその薬学的に許容され得る塩。 - R1が、1−(2,2−ジフルオロエチル)−1H−ピラゾール−4−イルまたは1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−4−イルである、請求項20に記載の化合物またはその薬学的に許容され得る塩。
- R1が、1〜3個の窒素を有し、かつ1個または2個のR1a基で必要に応じて置換される、6員ヘテロアリール環である、請求項1から14のいずれか1項に記載の化合物またはその薬学的に許容され得る塩。
- R1が、必要に応じて置換されるピリジニル基である、請求項22に記載の化合物またはその薬学的に許容され得る塩。
- R1が、
R2が、CH3であり;
R3が、水素、C1−2アルキル、OHまたはOCH3であり;
R4が、水素またはCH3であり;
RCが、水素、F、Cl、C1−3脂肪族、(CH2)0−1CF3、−OCF3または−OC1−8脂肪族であり;そして
RDが、−C(O)NHC1−8脂肪族である、
請求項23に記載の化合物またはその薬学的に許容され得る塩。 - R1が、
- RCおよびRDの各々が、−OCH3である、請求項6から14のいずれか1項に記載の化合物またはその薬学的に許容され得る塩。
- RDが、−C(O)OH、−C(O)N(R1b)2、−CN、−S(O)2C1−8脂肪族または−S(O)2N(R1b)2である、請求項8から14のいずれか1項に記載の化合物またはその薬学的な許容され得る塩。
- RCおよびRDの各々が、独立して、水素、フルオロ、クロロ、C1−3脂肪族、CF3、−OCF3、−OCHF2または−OC1−2脂肪族であり、ここで、RCおよびRDの少なくとも1つは、水素でない、請求項8から14のいずれか1項に記載の化合物またはその薬学的に許容され得る塩。
- RCが、水素であり、RDが、最大3個のF原子で必要に応じて置換される−OC1−3アルキルである、請求項28に記載の化合物またはその薬学的な許容され得る塩。
-
- 前記化合物が、表1から選択される化合物である、請求項1に記載の化合物またはその薬学的に許容され得る塩。
- 請求項1に記載の化合物および薬学的に許容され得るキャリア、佐剤またはビヒクルを含む、薬学的組成物。
- 多発性硬化症を処置するための薬剤、抗炎症剤、免疫調節剤または免疫抑制剤から選択される治療薬をさらに含む、請求項32に記載の組成物。
- 前記治療薬が、ベータインターフェロン、グラチラマー、ナタリズマブまたはミトキサントロンである、請求項33に記載の組成物。
- 多発性硬化症、癲癇、パーキンソン病、アルツハイマー病、ハンチントン病または筋萎縮性側索硬化症から選択される脳または脊髄の自己免疫疾患または炎症性疾患から選択される疾患または状態を処置するかまたはその重症度を下げる方法であって、該方法は、請求項1から14もしくは31のいずれか1項に記載の化合物またはその塩あるいはそれらの薬学的組成物を前記患者に投与する工程を包含する、方法。
- 前記疾患または障害が、多発性硬化症である、請求項35に記載の方法。
- 前記患者に追加の治療薬を投与する追加の工程を包含する、請求項35に記載の方法であって、ここで、前記追加の治療薬は、処置される疾患に対して適切であり、前記追加の治療薬は、単回投与形態として前記化合物もしくは組成物とともに投与されるか、または複数回投与形態の一部として前記化合物もしくは組成物とは別個に投与される、請求項35に記載の方法。
- 前記追加の治療薬が、多発性硬化症を処置するのに有用であり、ベータインターフェロン、グラチラマー、ナタリズマブまたはミトキサントロンから選択される、請求項37に記載の方法。
- 生物学的サンプルにおいてPI3Kγキナーゼ活性を阻害する方法であって、該方法は、前記生物学的サンプルを、請求項1から14もしくは31のいずれか1項に記載の化合物または前記化合物を含む組成物と接触させる工程を包含する、方法。
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JP2019507788A (ja) * | 2016-03-10 | 2019-03-22 | アストラゼネカ・アクチエボラーグAstrazeneca Aktiebolag | ホスファチジルイノシトール3−キナーゼガンマの新規の阻害剤 |
JP2021521271A (ja) * | 2018-04-06 | 2021-08-26 | ブラック ベルト ティーエックス リミテッド | Atf6阻害剤およびその使用 |
JP7476167B2 (ja) | 2018-04-06 | 2024-04-30 | アルトス ラブス,インコーポレーテッド | Atf6阻害剤およびその使用 |
JP7508584B2 (ja) | 2020-04-29 | 2024-07-01 | リレー セラピューティクス, インコーポレイテッド | PI3Kα阻害剤およびそれらの使用 |
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