JPWO2019217250A5 - - Google Patents

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JPWO2019217250A5
JPWO2019217250A5 JP2020563505A JP2020563505A JPWO2019217250A5 JP WO2019217250 A5 JPWO2019217250 A5 JP WO2019217250A5 JP 2020563505 A JP2020563505 A JP 2020563505A JP 2020563505 A JP2020563505 A JP 2020563505A JP WO2019217250 A5 JPWO2019217250 A5 JP WO2019217250A5
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cyclopropyl
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Priority claimed from PCT/US2019/030771 external-priority patent/WO2019217250A1/en
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ＣＤＫ４／６阻害剤、ソラフェニブ、レゴラフェニブ、ベンクレクスタ、ボリノスタット、またはこれらの組み合わせを含む組成物と組み合わせて、式（Ｉ）の構造によって表される１つ以上の化合物および／またはその少なくとも１つの塩を含む組成物。
Figure 2019217250000001
 式中、
Ｒ１は、－ＣＨ２ＣＦ３または－ＣＨ２ＣＨ２ＣＦ３であり、
Ｒ２は、－ＣＨ２ＣＦ３、－ＣＨ２ＣＨ２ＣＦ３、または－ＣＨ２ＣＨ２ＣＨ２ＣＦ３であり、
Ｒ３は、Ｈ、－ＣＨ３またはＲｘであり、
Ｒ４は、ＨまたはＲｙであり、
Ｒｘは、－ＣＨ２ＯＣ（Ｏ）ＣＨ（ＣＨ３）ＮＨ２、－ＣＨ２ＯＣ（Ｏ）ＣＨ（ＮＨ２）ＣＨ（ＣＨ３）２、－ＣＨ２ＯＣ（Ｏ）ＣＨ（（ＣＨ（ＣＨ３）２）ＮＨＣ（Ｏ）ＣＨ（ＮＨ２）ＣＨ（ＣＨ３）２、
Figure 2019217250000002
 であり、
Ｒｙは、－ＳＣＨ２ＣＨ（ＮＨ２）Ｃ（Ｏ）ＯＨ、－ＳＣＨ２ＣＨ（ＮＨ２）Ｃ（Ｏ）ＯＨ３、または－ＳＣＨ２ＣＨ（ＮＨ２）Ｃ（Ｏ）ＯＣ（ＣＨ３）３であり、
環Ａは、フェニルまたはピリジニルであり、
各Ｒａは独立して、Ｆ、Ｃｌ、－ＣＮ、－ＯＣＨ３、Ｃ１～３アルキル、－ＣＨ２ＯＨ、－ＣＦ３、シクロプロピル、－ＯＣＨ３、－Ｏ（シクロプロピル）および／または－ＮＨＣＨ２ＣＨ２ＯＣＨ３であり、
各Ｒｂは独立して、Ｆ、Ｃｌ、－ＣＨ３、－ＣＨ２ＯＨ、－ＣＦ３、シクロプロピル、および／または－ＯＣＨ３であり、
ｙは、ゼロ、１、または２であり、
ｚは、ゼロ、１、または２である。 One or more compounds represented by the structure of formula (I) and / or at least one salt thereof in combination with a CDK4 / 6 inhibitor, sorafenib, regorafenib, Bencrexta, vorinostat, or a composition comprising a combination thereof. Composition containing.
Figure 2019217250000001
 During the ceremony
R 1 is -CH 2 CF 3 or -CH 2 CH 2 CF 3 .
R 2 is -CH 2 CF 3 , -CH 2 CH 2 CF 3 , or -CH 2 CH 2 CH 2 CF 3 .
R 3 is H, -CH 3 or Rx,
R 4 is H or R y ,
R x is -CH 2 OC (O) CH (CH 3 ) NH 2 , -CH 2 OC (O) CH (NH 2 ) CH (CH 3 ) 2 , -CH 2 OC (O) CH ((CH (O) CH 3 ) 2 ) NHC (O) CH (NH 2 ) CH (CH 3 ) 2 ,
Figure 2019217250000002
 And
Ry is -SCH 2 CH (NH 2 ) C (O) OH, -SCH 2 CH (NH 2 ) C (O) OH 3 , or -SCH 2 CH (NH 2 ) C (O) OC (CH 3 ). ) 3
Ring A is phenyl or pyridinyl and
Each Ra independently has F, Cl, -CN, -OCH 3 , C 1-3 alkyl, -CH 2 OH, -CF 3 , cyclopropyl, -OCH 3 , -O (cyclopropyl) and / or -NHCH 2 CH 2 OCH 3
Each Rb is independently F, Cl, -CH 3 , -CH 2 OH, -CF 3 , cyclopropyl, and / or -OCH 3 .
y is zero, 1, or 2,
z is zero, one, or two. 前記式（Ｉ）の化合物のうちの１つが、以下によって表される、請求項１に記載の組成物。
Figure 2019217250000003
 The composition according to claim 1, wherein one of the compounds of the formula (I) is represented by the following .
Figure 2019217250000003
 前記ＣＤＫ４／６阻害剤が、イブランス、リボシクリブ、アベマシクリブ、またはこれらの組み合わせを含む、請求項１～２のいずれか一項に記載の組成物。 The composition according to any one of claims 1 to 2, wherein the CDK4 / 6 inhibitor comprises ibrans, ribociclib, abemaciclib, or a combination thereof. 対象の増殖性疾患を治療、抑制、または阻害する方法で使用するための、式（Ｉ）の構造によって表される１つ以上の化合物および／またはその少なくとも１つの塩を含む、第１の組成物と、ＣＤＫ４／６阻害剤、ソラフェニブ、レゴラフェニブ、ベンクレクスタ、ボリノスタット、またはこれらの組み合わせを含む第２の組成物と、を含む医薬組成物。
Figure 2019217250000004
 式中、
Ｒ１は、－ＣＨ２ＣＦ３または－ＣＨ２ＣＨ２ＣＦ３であり、
Ｒ２は、－ＣＨ２ＣＦ３、－ＣＨ２ＣＨ２ＣＦ３、または－ＣＨ２ＣＨ２ＣＨ２ＣＦ３であり、
Ｒ３は、Ｈ、－ＣＨ３またはＲｘであり、
Ｒ４は、ＨまたはＲｙであり、
Ｒｘは、－ＣＨ２ＯＣ（Ｏ）ＣＨ（ＣＨ３）ＮＨ２、－ＣＨ２ＯＣ（Ｏ）ＣＨ（ＮＨ２）ＣＨ（ＣＨ３）２、－ＣＨ２ＯＣ（Ｏ）ＣＨ（（ＣＨ（ＣＨ３）２）ＮＨＣ（Ｏ）ＣＨ（ＮＨ２）ＣＨ（ＣＨ３）２、
Figure 2019217250000005
 であり、
Ｒｙは、－ＳＣＨ２ＣＨ（ＮＨ２）Ｃ（Ｏ）ＯＨ、－ＳＣＨ２ＣＨ（ＮＨ２）Ｃ（Ｏ）ＯＨ３、または－ＳＣＨ２ＣＨ（ＮＨ２）Ｃ（Ｏ）ＯＣ（ＣＨ３）３であり、
環Ａは、フェニルまたはピリジニルであり、
各Ｒａは独立して、Ｆ、Ｃｌ、－ＣＮ、－ＯＣＨ３、Ｃ１～３アルキル、－ＣＨ２ＯＨ、－ＣＦ３、シクロプロピル、－ＯＣＨ３、－Ｏ（シクロプロピル）および／または－ＮＨＣＨ２ＣＨ２ＯＣＨ３であり、
各Ｒｂは独立して、Ｆ、Ｃｌ、－ＣＨ３、－ＣＨ２ＯＨ、－ＣＦ３、シクロプロピル、および／または－ＯＣＨ３であり、
ｙは、ゼロ、１、または２であり、
ｚは、ゼロ、１、または２である。 A first composition comprising one or more compounds represented by the structure of formula (I) and / or at least one salt thereof for use in a method of treating, suppressing, or inhibiting a proliferative disorder of interest. A pharmaceutical composition comprising a product and a second composition comprising a CDK4 / 6 inhibitor, sorafenib, regorafenib, Bencrexta, vorinostat , or a combination thereof.
Figure 2019217250000004
 During the ceremony
R 1 is -CH 2 CF 3 or -CH 2 CH 2 CF 3 .
R 2 is -CH 2 CF 3 , -CH 2 CH 2 CF 3 , or -CH 2 CH 2 CH 2 CF 3 .
R 3 is H, -CH 3 or Rx,
R 4 is H or R y ,
R x is -CH 2 OC (O) CH (CH 3 ) NH 2 , -CH 2 OC (O) CH (NH 2 ) CH (CH 3 ) 2 , -CH 2 OC (O) CH ((CH (O) CH 3 ) 2 ) NHC (O) CH (NH 2 ) CH (CH 3 ) 2 ,
Figure 2019217250000005
 And
Ry is -SCH 2 CH (NH 2 ) C (O) OH, -SCH 2 CH (NH 2 ) C (O) OH 3 , or -SCH 2 CH (NH 2 ) C (O) OC (CH 3 ). ) 3
Ring A is phenyl or pyridinyl and
Each Ra independently has F, Cl, -CN, -OCH 3 , C 1-3 alkyl, -CH 2 OH, -CF 3 , cyclopropyl, -OCH 3 , -O (cyclopropyl) and / or -NHCH 2 CH 2 OCH 3
Each Rb is independently F, Cl, -CH 3 , -CH 2 OH, -CF 3 , cyclopropyl, and / or -OCH 3 .
y is zero, 1, or 2,
z is zero, one, or two. 前記ＣＤＫ４／６阻害剤が、イブランス、リボシクリブ、アベマシクリブ、またはこれらの組み合わせを含む、請求項４に記載の組成物。The composition of claim 4, wherein the CDK4 / 6 inhibitor comprises ibrans, ribociclib, abemaciclib, or a combination thereof. 前記増殖性疾患が前癌状態または良性増殖性障害である、請求項４または５に記載の組成物。The composition according to claim 4 or 5, wherein the proliferative disease is a precancerous state or a benign proliferative disorder. 前記増殖性疾患が癌である、請求項４～６のいずれか一項に記載の組成物。The composition according to any one of claims 4 to 6, wherein the proliferative disease is cancer. 前記癌が、腺様嚢胞癌（ＡＣＣ）、デスモイド腫瘍、乳癌、子宮内膜癌、非小細胞肺癌、多発性骨髄腫、リンパ腫、または白血病を含む、請求項７に記載の組成物。The composition of claim 7, wherein the cancer comprises adenoid cystic carcinoma (ACC), aggressive fibromatism, breast cancer, endometrial cancer, non-small cell lung cancer, multiple myeloma, lymphoma, or leukemia. 前記乳癌が、トリプルネガティブ乳癌を含む、請求項８に記載の組成物。The composition of claim 8, wherein the breast cancer comprises triple negative breast cancer. 前記白血病が、Ｔ細胞急性リンパ芽球性白血病またはＴリンパ芽球性白血病／リンパ腫を含む、請求項８に記載の組成物。The composition according to claim 8, wherein the leukemia comprises T-cell acute lymphoblastic leukemia or T-lymphoblastic leukemia / lymphoma. 前記癌が、Ｎｏｔｃｈ活性化突然変異を含む、請求項７～１０のいずれか一項に記載の組成物。The composition according to any one of claims 7 to 10, wherein the cancer comprises a Notch-activating mutation. 前記第１の組成物および／または前記第２の組成物が、静脈内または経口投与用に処方される、請求項４～１１のいずれか一項に記載の組成物。The composition according to any one of claims 4 to 11, wherein the first composition and / or the second composition is formulated for intravenous or oral administration. 前記式（Ｉ）の化合物が以下のうちいずれか１つを含む、請求項４～１２のいずれか一項に記載の組成物。
Figure 2019217250000006
 The composition according to any one of claims 4 to 12 , wherein the compound of the formula (I) contains any one of the following .
Figure 2019217250000006
JP2020563505A 2018-05-06 2019-05-05 Combination composition containing bisfluoroalkyl-1,4-benzodiazepinone compound and method of use thereof Pending JP2021523169A (en)

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US201862667540P 2018-05-06 2018-05-06
US62/667,540 2018-05-06
PCT/US2019/030771 WO2019217250A1 (en) 2018-05-06 2019-05-05 Combination compositions comprising bisfluoroalkyl-1,4- benzodiazepinone compounds and methods of use thereof

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JP2021523169A JP2021523169A (en) 2021-09-02
JPWO2019217250A5 true JPWO2019217250A5 (en) 2022-04-19

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CN (1) CN112218639A (en)
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CN113939297A (en) * 2019-05-15 2022-01-14 艾雅拉制药公司 Bifluoroalkyl-1, 4-benzodiazepinone compounds for the treatment of Notch activated breast cancer

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