JP2021521179A - Vps34の阻害剤としてのモルホリン誘導体 - Google Patents
Vps34の阻害剤としてのモルホリン誘導体 Download PDFInfo
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- JP2021521179A JP2021521179A JP2020555504A JP2020555504A JP2021521179A JP 2021521179 A JP2021521179 A JP 2021521179A JP 2020555504 A JP2020555504 A JP 2020555504A JP 2020555504 A JP2020555504 A JP 2020555504A JP 2021521179 A JP2021521179 A JP 2021521179A
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- Prior art keywords
- substituted
- unsubstituted
- pharmaceutically acceptable
- alkyl
- acceptable salt
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
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Abstract
Description
本出願は、2018年4月10日に出願された「THIAZOLE OR THIADIAZOLE SUBSTITUTED ARYL AND HETEROARYL DERIVATIVES AS INHIBITORS OF VPS34」と題する米国仮出願第62/655,723号の優先権を主張し、その内容は、あらゆる目的のためにその全体が参照により本明細書に組み込まれる。
本開示は、チアゾール置換またはジアチアゾール置換アリールおよびヘテロアリール化合物、それらを含む医薬組成物、ならびにそれらの使用方法に関し、本方法は、Vps34/PI3K IIIシグナル伝達経路の調節に関連する障害または疾患の処置を含む。
Vps34(液胞タンパク質選別34(vascular protein sorting 34))は、脂質キナーゼのPI3K(ホスファチジルイノシトール3−キナーゼ)ファミリーのクラスIIIメンバーであり、多数の細胞機能の調節に関与する。Vps34は、全ての真核生物細胞において発現される唯一のPI3キナーゼである。最初は酵母中で同定され、哺乳動物を介して進化的に保存されていることが見出された。ヒトにおいて、hVPS34は、PIK3C3遺伝子によってコードされる。Vps34は、ホスファチジルイノシトール(PI)をリン酸化して、プレオートフアゴソーム(pre−autophagosome)またはエンドソームにおいてホスファチジルイノシトール3−リン酸塩(PI3P)を形成し、FYVEおよびPXドメイン含有タンパク質の動員をもたらす(Hawkins P.T.,Stephens L.R.PI3K signaling in inflammation.Biochim.Biophys.Acta.2015;1851:882−897(非特許文献1);Okkenhaug K.Signaling by the phosphoinositide 3−kinase family in immune cells.Annu.Rev.Immunol.2013;31:675−704(非特許文献2);Backer J.M.Biochem.J.2008;410:1−17(非特許文献3))。Vps34は、異なるタンパク質複合体中のタンパク質キナーゼVps15と会合し、膜輸送(membrane trafficking)およびタンパク質選別経路において重要な役割を果たす。他のPI3Kとは異なり、Vps34の基質特異性はホスファチジルイノシトールに限定される。この特性により、それは、アイソフォームに応じてより広範囲にリン酸化することができるクラスIおよびクラスII酵素と区別される。Vps34によって産生されるPI3Pは、オートファゴソームおよびファゴソーム成熟、ならびにNOX2媒介性ROS産生に重要であり、それにより、オートファジー、ならびに自然免疫細胞による病原体取り込みおよび殺傷において重要な役割を果たす。
一態様では、式Iの化合物またはその薬学的に許容される塩が提供される:
式中、
R1は、C6〜C14アリール、5〜10員ヘテロアリール、C3〜C6シクロアルキル、または4〜10員ヘテロシクロアルキルであり、R1のC6〜C14アリール、5〜10員ヘテロアリール、C3〜C6シクロアルキル、または4〜10員ヘテロシクロアルキルは、それぞれ、非置換であるか、またはハロゲン、−CN、−NO2、置換もしくは非置換C1〜C6アルキル、置換もしくは非置換C2〜C6アルケニル、置換もしくは非置換C2〜C6アルキニル、C1〜C6ハロアルキル、−ORa、−SRa、−S(O)2Ra、−NRbRc、−C(O)Ra、−OC(O)Ra、−C(O)ORa、−C(O)NRbRc、−OC(O)NRbRc、−NRaC(O)Rb、−NRaC(O)ORb、置換もしくは非置換C3〜C6シクロアルキル、置換もしくは非置換C3〜C6シクロアルケニル、置換もしくは非置換C6〜C14アリール、置換もしくは非置換5〜10員ヘテロアリール、および置換もしくは非置換4〜10員ヘテロシクロアルキルからなる群から選択される1つ以上の置換基で置換され;
Lは、−S(O)2−、−O−、−C(O)−、または−CH2−であり;
Y1は、CHまたはNであり;
R2は、5員ヘテロアリールまたは5員ヘテロシクロアルキルであり、R2の5員ヘテロアリールおよび5員ヘテロシクロアルキルは、それぞれ、非置換であるか、またはハロゲン、−CN、−NO2、置換もしくは非置換C1〜C6アルキル、置換もしくは非置換C2〜C6アルケニル、置換もしくは非置換C2〜C6アルキニル、C1〜C6ハロアルキル、−ORd、−SRd、−S(O)2Rd、−NReRf、−C(O)Rd、−OC(O)Rd、−C(O)ORd、−C(O)NReRf、−OC(O)NReRf、−NRdC(O)Re、−NRdC(O)ORe、置換もしくは非置換C3〜C6シクロアルキル、置換もしくは非置換C3〜C6シクロアルケニル、置換もしくは非置換C6〜C14アリール、置換もしくは非置換5〜10員ヘテロアリール、および置換もしくは非置換4〜10員ヘテロシクロアルキルからなる群から選択される1つ以上の置換基で置換され;かつ
Ra、Rb、Rc、Rd、Re、およびRfは、それぞれ独立して、HまたはC1〜4アルキルであり;
Lが−S(O)2−であり、かつY1がNである場合、R1は、4,4−ジフルオロ−ピペリジン1−イルではない。
式中、
G1は、SまたはNであり;
G2は、CR3、S、またはNであり;
R3は、H、C1〜6アルキル、またはC1〜6ハロアルキルであり;かつ
ReおよびRfは、独立して、HまたはC1〜4アルキルである。
本開示は、チアゾール置換またはジアチアゾール置換アリールおよびヘテロアリール化合物、それらを含む医薬組成物、ならびにVps34/PI3K IIIシグナル伝達経路の調節に関連する障害または疾患の処置を含むそれらの使用方法に関する。
以下の用語は、別段で指示がない限り、以下の意味を有する。定義されていない任意の用語は、当該技術分野で認識されている意味を有する。
化合物およびその塩(薬学的に許容される塩等)は、要約および付随する特許請求の範囲を含む本明細書に詳述される。本明細書に記載の化合物の塩および溶媒和物を含む本明細書に記載の化合物の全ての使用、ならびにそのような化合物の製造方法も提供される。本明細書に記載の任意の化合物は、薬物とも称される。
式中、
R1は、C6〜C14アリール、5〜10員ヘテロアリール、C3〜C6シクロアルキル、または4〜10員ヘテロシクロアルキルであり、R1のC6〜C14アリール、5〜10員ヘテロアリール、C3〜C6シクロアルキル、または4〜10員ヘテロシクロアルキルは、それぞれ、非置換であるか、またはハロゲン、−CN、−NO2、置換もしくは非置換C1〜C6アルキル、置換もしくは非置換C2〜C6アルケニル、置換もしくは非置換C2〜C6アルキニル、C1〜C6ハロアルキル、−ORa、−SRa、−S(O)2Ra、−NRbRc、−C(O)Ra、−OC(O)Ra、−C(O)ORa、−C(O)NRbRc、−OC(O)NRbRc、−NRaC(O)Rb、−NRaC(O)ORb、置換もしくは非置換C3〜C6シクロアルキル、置換もしくは非置換C3〜C6シクロアルケニル、置換もしくは非置換C6〜C14アリール、置換もしくは非置換5〜10員ヘテロアリール、および置換もしくは非置換4〜10員ヘテロシクロアルキルからなる群から選択される1つ以上の置換基で置換され、
Lは、−S(O)2−、−O−、−C(O)−、または−CH2−であり、
Y1は、CHまたはNであり、
R2は、5員ヘテロアリールまたは5員ヘテロシクロアルキルであり、R2の5員ヘテロアリールおよび5員ヘテロシクロアルキルは、それぞれ、非置換であるか、またはハロゲン、−CN、−NO2、置換もしくは非置換C1〜C6アルキル、置換もしくは非置換C2〜C6アルケニル、置換もしくは非置換C2〜C6アルキニル、C1〜C6ハロアルキル、−ORd、−SRd、−S(O)2Rd、−NReRf、−C(O)Rd、−OC(O)Rd、−C(O)ORd、−C(O)NReRf、−OC(O)NReRf、−NRdC(O)Re、−NRdC(O)ORe、置換もしくは非置換C3〜C6シクロアルキル、置換もしくは非置換C3〜C6シクロアルケニル、置換もしくは非置換C6〜C14アリール、置換もしくは非置換5〜10員ヘテロアリール、および置換もしくは非置換4〜10員ヘテロシクロアルキルからなる群から選択される1つ以上の置換基で置換され、
Ra、Rb、Rc、Rd、Re、およびRfは、それぞれ独立して、HまたはC1〜4アルキルであり、
Lが−S(O)2−であり、かつY1がNである場合、R1は、4,4−ジフルオロ−ピペリジン1−イルではない。
であり、式中、G1は、SまたはNであり;G2は、CR3、S、またはNであり;R3は、H、C1〜6アルキル、またはC1〜6ハロアルキルであり;かつReおよびRfは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、G1はSである。いくつかの実施形態では、G1はNである。いくつかの実施形態では、G2はCR3であり、R3は、C1〜6アルキルまたはC1〜6ハロアルキルである。いくつかの実施形態では、G2はCHである。他の実施形態では、G2はCR3であり、R3はC1〜6アルキルである。他の実施形態では、G2はCR3であり、R3はC1〜6ハロアルキルである。いくつかの実施形態では、G2はSである。いくつかの実施形態では、G2はNである。
であり、式中、ReおよびRfの一方はHであり、他方はC1〜4アルキルである。いくつかの実施形態では、ReおよびRfは両方ともC1〜4アルキルである。いくつかの実施形態では、ReおよびRfは両方ともHである。
であり、式中、G1はSであり、G2は、CR3、S、またはNであり、R3は、H、C1〜6アルキル、またはC1〜6ハロアルキルであり、RaおよびRbは両方とも、Hである。いくつかの実施形態では、G1はNであり、G2は、CR3、S、またはNであり、R3は、H、C1〜6アルキル、またはC1〜6ハロアルキルであり、RaおよびRbは両方とも、Hである。いくつかの実施形態では、R2は、
であり、R3は、H、C1〜6アルキル、またはC1〜6ハロアルキルであり、ReおよびRfは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R2は、
である。
であり、式中、G1は、SまたはNであり、G2は、CR3であり、R3は、H、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつReおよびRfは両方ともHである。いくつかの実施形態では、G1は、SまたはNであり、G2は、Sであり、かつReおよびRfは、それぞれ独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、G1は、SまたはNであり、G2は、Nであり、かつReおよびRfは、それぞれ独立して、HまたはC1〜4アルキルである。
であり、式中、G1は、SまたはNであり、G2は、CR3であり、R3は、Hであり、RaおよびRbは、それぞれ独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、G1は、SまたはNであり、G2は、CR3であり、R3は、C1〜6アルキルであり、ReおよびRfは、それぞれ独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、G1は、SまたはNであり、G2は、CR3であり、R3は、C1〜6ハロアルキルであり、ReおよびRfは、それぞれ独立して、HまたはC1〜4アルキルである。
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はH、C1〜6アルキルまたはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R1はフェニルまたはナプチルであり、Lは−O−であり、Y1はCHであり、R2は、
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はH、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R1はフェニルまたはナプチルであり、Lは−C(O)−であり、Y1はCHであり、R2は、
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はH、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R1はフェニルまたはナプチルであり、Lは−CH2−、Y1はCHであり、R2は、
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はH、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R1はフェニルまたはナプチルであり、Lは−S(O)2−であり、Y1はNであり、R2は、
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はH、C1〜6アルキルまたはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R1はフェニルまたはナプチルであり、Lは−O−であり、Y1はNであり、R2は、
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はH、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R1はフェニルまたはナプチルであり、Lは−C(O)−であり、Y1はNであり、R2は、
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はH、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R1はフェニルまたはナプチルであり、Lは−CH2−であり、Y1はNであり、R2は、
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はH、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はH、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R1は5員または6員ヘテロシクロアルキルであり、Lは−O−であり、Y1はCHであり、R2は、
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はH、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R1は5員または6員ヘテロシクロアルキルであり、Lは−C(O)−であり、Y1はCHであり、R2は、
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はH、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R1は5員または6員ヘテロシクロアルキルであり、Lは−CH2−であり、Y1はCHであり、R2は、
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はHであり、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R1は5員または6員ヘテロシクロアルキルであり、Lは−S(O)2−であり、Y1はNであり、R2は、
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はH、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R1は5員または6員のヘテロシクロアルキルであり、Lは−O−であり、Y1はNであり、R2は、
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はH、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R1は5員または6員ヘテロシクロアルキルであり、Lは−C(O)−であり、Y1はNであり、R2は、
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はH、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。いくつかの実施形態では、R1は5員または6員ヘテロシクロアルキルであり、Lは−CH2−であり、Y1はNであり、R2は、
であり、式中、G1はSまたはNであり、G2はCR3、S、またはNであり、R3はHであり、C1〜6アルキル、またはC1〜6ハロアルキルであり、かつRaおよびRbは、独立して、HまたはC1〜4アルキルである。
R1は、C6〜C14アリールまたは4〜10員ヘテロシクロアルキルであり、
Lは、−S(O)2−または−O−であり、
Y1は、CHまたはNであり、
R2は、C1〜6アルキル、C1〜6ハロアルキル、およびNReRfからなる群から選択される1つ以上の置換基で置換された5員ヘテロアリール環であり、
ReおよびRfは、独立して、HまたはC1〜4アルキルであり、
またはその薬学的に許容される塩である。
処置目的のために、本開示による医薬組成物は、少なくとも1つの式(I)の化合物、またはその薬学的に許容される塩を含む。医薬組成物は、1つ以上の薬学的に許容される賦形剤をさらに含み得る。薬学的に許容される賦形剤は、非毒性であり、その他では対象への投与に対して生物学的に好適である物質である。そのような賦形剤は、本明細書に記載の化合物の投与を容易にし、活性成分と適合性がある。薬学的に許容される賦形剤の例には、安定剤、潤滑剤、界面活性剤、希釈剤、抗酸化剤、結合剤、着色剤、増量剤、乳化剤、または味覚改変剤が含まれる。好ましい実施形態では、実施形態による医薬組成物は、滅菌組成物である。医薬組成物は、当業者に既知であるかまたは利用可能になる配合技術を使用して調製され得る。
本明細書に記載の本発明の化合物は、Vps34/PI3K IIIシグナル伝達経路の調節に関連する疾患または医学的状態の処置において、1つ以上の追加の活性成分と組み合わせて、医薬組成物または方法に使用し得る。例えば、追加の活性成分は、Vps34/PI3K IIIシグナル伝達経路の調節に関連する疾患または医学的状態の処置に有効であることが既知であるかまたは発見されているものであり、疾患に関連する別の標的に対して活性であるもの、例えば、限定されないが、相乗的作用機序を有する抗癌剤、そのような障害の症状を処置する化合物、および抗酸化剤を含む。
本明細書の化合物および医薬組成物は、個体における疾患または状態を処置または予防するために使用され得る。いくつかの実施形態では、Vps34/PI3K IIIシグナル伝達経路の調節に関連する疾患または医学的状態を処置する方法であって、そのような処置を必要とする対象に、有効量の、少なくとも1つの式(I)の化合物、もしくは表1の化合物、もしくはその薬学的に許容される塩、または(a)少なくとも1つの式(I)の化合物、もしくは表1の化合物、もしくはその薬学的に許容される塩、および(b)薬学的に許容される賦形剤を含む医薬組成物を投与することを含む、方法が提供される。
本明細書で提供される化合物または医薬組成物のいずれかを含む製造物品およびキットも提供される。製品は、ラベルを有する容器を含み得る。好適な容器には、例えば、ボトル、バイアル、および試験管が含まれる。容器は、ガラスまたはプラスチック等の様々な材料から形成され得る。容器は、本明細書で提供される医薬組成物を保持し得る。容器上のラベルは、医薬組成物が本明細書に記載の疾患または医学的状態を予防、処置、または抑制するために使用されることを示してもよく、インビボまたはインビトロでのいずれかの使用の指示を示してもよい。
本開示の化合物は、以下に一般的に記載される、より具体的には後述の実施例(以下の実施例に提供されるスキーム等)に記載される多くのプロセスによって調製され得る。以下のプロセスの記載では、示される式で使用されるときの記号は、本明細書の式に関連して上述したそれらの基を表すと理解されるべきである。
スキームA
R1、R2、およびY1は、本明細書に詳述される式(I)またはその任意の変形について定義される通りであり、Xはハロゲンである。
スキームB
R1、R2、およびY1は、本明細書に詳述される式(I)またはその任意の変形について定義される通りであり、Xはハロゲンである。
スキームC
R1、Y1、Ra、およびRbは、本明細書に詳述される式(I)またはその任意の変形について定義される通りであり、Xはハロゲンである。
本開示の方法に有用な例示的な化学物質を、後に続く特定の実施例を参照することによって記載する。当業者は、本明細書の様々な化合物を得るために、出発物質が好適に選択されてもよく、その結果、最終的に所望される置換基が、所望の生成物を得るために、必要に応じて保護されてまたは保護されずに反応スキームを通して担持されることを認識するであろう。あるいは、最終的に所望される置換基の代わりに、反応スキームを通して担持され、かつ、所望される置換基に必要に応じて置き換えられ得る好適な基を用いることが必要であるかまたは望ましいものであり得る。さらに、当業者は、以下のスキームに示される変換が、特定のペンダント基の官能基と適合する任意の順序で行われ得ることを認識するであろう。一般的なスキームに示される各反応は、好ましくは、使用される有機溶媒の約0℃〜還流温度で行われる。
スキーム1:
工程1:フェニルメタンチオール(19.8g、0.16mol)を、DMF(300mL)中の水素化ナトリウム(7.04g、0.18mol、鉱油中の純度60%)の溶液に0℃で添加した。反応物を室温で15分間撹拌し、1,3,5−トリブロモベンゼン(50g、0.16mol)を添加した。反応物を室温(rt)でさらに2時間撹拌した。溶液を氷水(500mL)に注ぎ、酢酸エチル(300mL×3)で抽出した。有機抽出物を合わせ、食塩水(300mL×2)で洗浄し、無水硫酸ナトリウムで乾燥させ、濃縮した。残渣をシリカゲルカラムクロマトグラフィー(石油エーテル)によって精製して、ベンジル(3,5−ジブロモフェニル)スルファン(50.1g、収率88%)を得た。化合物をLC−MSのみで確認した:379.10(M+Na)+、C13H10Br2S。
実施例2をスキーム1の実施例1に記載したのと同様に合成したが、工程7において5−ブロモ−4−(トリフルオロメチル)チアゾール−2−アミン(133mg、0.54mmol)を使用して、(R)−5−(3−モルホリノ−5−((テトラヒドロフラン−3−イル)スルホニル)フェニル)−4−(トリフルオロメチル)チアゾール−2−アミン(71mg、収率28%)をオフホワイト色の固体として得た。
スキーム2:
工程1:水(100mL)中のベンゼンスルホニルクロリド(10g、56.7mmol)、亜硫酸ナトリウム(14.3g、0.11mol)、および重炭酸ナトリウム(9.5g、0.11mol)の混合物を30℃で2時間撹拌した。水を真空中で除去した。残渣をメタノール(30mL×3)で抽出した。有機抽出物を合わせ、濃縮し、ジクロロメタンと共に2回共蒸発させて、粗ベンゼンスルフィン酸ナトリウム(11g、定量的収率)を白色固体として得た。化合物をLC−MSのみで確認した:141.36(M−Na)−、C6H5NaO2S。
スキーム3:
工程1:ジオキサン/DMSO(5mL/0.05mL)中の酢酸カリウム(82mg、2.49mmol)、4,4,4’,4’,5,5,5’,5’−オクタメチル−2,2’−ビ(1,3,2−ジオキサボロラン)(318mg、1.25mmol)、Pd(dppf)Cl2(68mg、0.08mmol)、および4−(3−ブロモ−5−(フェニルスルホニル)フェニル)モルホリン(300mg、0.83mmol、調製用、スキーム2を参照のこと)の混合物を100℃で1時間加熱した。反応混合物を水(50mL)に注ぎ、酢酸エチル(50mL×3)で抽出した。有機抽出物を合わせ、食塩水(20mL)で洗浄し、無水硫酸ナトリウムで乾燥させ、濃縮した。残渣をシリカゲルカラムクロマトグラフィー(石油エーテル/酢酸エチル=5:1)によって精製して、4−(3−(フェニルスルホニル)−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)フェニル)モルホリン(250mg、収率70%)を得た。化合物をLC−MSのみで確認した:429.90(M+H)+、C22H28BNO5S。
スキーム4:
工程1:Pd2(dba)3(0.17g、0.18mmol)を、ジオキサン(20mL)中の2,6−ジクロロ−4−ヨードピリジン(1g、3.66mmol)、チオフェノール(0.44g、4.03mmol)、キサントホス(0.21g、0.37mmol)、およびDIPEA(0.94g、7.32mmol)の混合物にN2下で添加した。反応物を110℃で2時間加熱した。混合物を室温に冷却し、水(20mL)に注ぎ、酢酸エチル(20mL×3)で抽出した。合わせた有機物を食塩水(20mL)で洗浄し、硫酸ナトリウムで乾燥させ、濃縮した。残渣をシリカゲルカラムクロマトグラフィー(石油エーテル)によって精製し、2,6−ジクロロ−4−(フェニルチオ)ピリジン(0.78g、収率83%)をオフホワイト色の固体として得た。化合物を、LC−MSのみで確認した:256.16(M+H)+、C11H7Cl2NS。
5−(6−モルホリノ−4−(フェニルスルホニル)ピリジン−2−イル)−4−(トリフルオロメチル)チアゾール−2−アミン(5mg、収率2%)を、実施例5(スキーム4、工程4)と同じ手順に従って、4−(6−クロロ−4−(フェニルスルホニル)ピリジン−2−イル)モルホリン(203mg、0.60mmol)および5−ブロモ−4−(トリフルオロメチル)チアゾール−2−アミン(148mg、0.60mmol)から得た。
4−メチル−5−(6−モルホリノ−4−(フェニルスルホニル)ピリジン−2−イル)チアゾール−2−アミン(31mg、収率7%)を、実施例5(スキーム4、工程4)と同じ手順に従って、4−(6−クロロ−4−(フェニルスルホニル)ピリジン−2−イル)モルホリン(338mg、1.0mmol)および5−ブロモ−4−メチルチアゾール−2−アミン(384mg、2.0mmol)から得た。
スキーム5:
工程1:DMSO(20mL)中の2,6−ジクロロ−4−ヨードピリジン(600mg、2.20mmol)、フェノール(207mg、2.20mmol)、および炭酸カリウム(455mg、3.30mmol)の混合物を、N2下で100℃で3時間撹拌した。反応混合物を水(100mL)に注ぎ、酢酸エチル(100mL×3)で抽出した。合わせた有機物を食塩水(50mL×2)で洗浄し、硫酸ナトリウムで乾燥させ、濃縮した。残渣をシリカゲルカラムクロマトグラフィー(石油エーテル)によって精製して、2,6−ジクロロ−4−フェノキシピリジン(210mg、収率40%)を得た。化合物を、LC−MSのみで確認した:239.86(M+H)+、C11H7Cl2NO。
アッセイ実施例1:VPS34プロトコル
PI3KC3(hVPS34)キナーゼ反応は、ATPを利用し、副産物としてADPを産生する。ADP産生は、ADP−Glo発光検出によって定量化される。PI3KC3(hVPS34)キナーゼアッセイは、Reaction Biology Corp .(Malvern,PA)によって行われた。
PI3Kαの阻害−PI3Kα活性の尺度としてのATPからADPへの変換の定量化。活性PI3Kα(Life Technologies)を、PI3Kα阻害剤の存在下または非存在下で、クラスI PI3キナーゼとの使用のために特に最適化された基質であるPIP2:PS(Life Technologies)、および超高純度ATP(Promega)と反応させた。PI3KαによるATPのADPへの変換を、Promega ADP−Gloキナーゼ活性アッセイによって発光シグナルとして測定した。公開されているPI3Ka阻害剤LY294002、PI−103、BYL719、およびGDC0198、ならびにDMSOビヒクル対照を使用して、アッセイを検証した。
Claims (40)
- 式Iの化合物またはその薬学的に許容される塩:
式中、
R1は、C6〜C14アリール、5〜10員ヘテロアリール、C3〜C6シクロアルキル、または4〜10員ヘテロシクロアルキルであり、R1の前記C6〜C14アリール、5〜10員ヘテロアリール、C3〜C6シクロアルキル、または4〜10員ヘテロシクロアルキルは、それぞれ、非置換であるか、またはハロゲン、−CN、−NO2、置換もしくは非置換C1〜C6アルキル、置換もしくは非置換C2〜C6アルケニル、置換もしくは非置換C2〜C6アルキニル、C1〜C6ハロアルキル、−ORa、−SRa、−S(O)2Ra、−NRbRc、−C(O)Ra、−OC(O)Ra、−C(O)ORa、−C(O)NRbRc、−OC(O)NRbRc、−NRaC(O)Rb、−NRaC(O)ORb、置換もしくは非置換C3〜C6シクロアルキル、置換もしくは非置換C3〜C6シクロアルケニル、置換もしくは非置換C6〜C14アリール、置換もしくは非置換5〜10員ヘテロアリール、および置換もしくは非置換4〜10員ヘテロシクロアルキルからなる群から選択される1つ以上の置換基で置換され;
Lは、−S(O)2−、−O−、−C(O)−、または−CH2−であり;
Y1は、CHまたはNであり;
R2は、5員ヘテロアリールまたは5員ヘテロシクロアルキルであり、R2の前記5員ヘテロアリールおよび5員ヘテロシクロアルキルは、それぞれ、非置換であるか、またはハロゲン、−CN、−NO2、置換もしくは非置換C1〜C6アルキル、置換もしくは非置換C2〜C6アルケニル、置換もしくは非置換C2〜C6アルキニル、C1〜C6ハロアルキル、−ORd、−SRd、−S(O)2Rd、−NReRf、−C(O)Rd、−OC(O)Rd、−C(O)ORd、−C(O)NReRf、−OC(O)NReRf、−NRdC(O)Re、−NRdC(O)ORe、置換もしくは非置換C3〜C6シクロアルキル、置換もしくは非置換C3〜C6シクロアルケニル、置換もしくは非置換C6〜C14アリール、置換もしくは非置換5〜10員ヘテロアリール、および置換もしくは非置換4〜10員ヘテロシクロアルキルからなる群から選択される1つ以上の置換基で置換され;かつ
Ra、Rb、Rc、Rd、Re、およびRfは、それぞれ独立して、HまたはC1〜4アルキルであり;
Lが−S(O)2−であり、かつY1がNである場合、R1は、4,4−ジフルオロ−ピペリジン1−イルではない。 - R1が、C6〜C14アリールまたは4〜10員ヘテロシクロアルキルである、請求項1に記載の化合物またはその薬学的に許容される塩。
- R1が、フェニルである、請求項1に記載の化合物またはその薬学的に許容される塩。
- R1が、5員または6員ヘテロシクロアルキルである、請求項1に記載の化合物またはその薬学的に許容される塩。
- R1が、テトラヒドロフラニル、テトラヒドロピラニル、ピロリジニル、ピペリジニル、ピペラジニル、またはモルホリニルである、請求項1に記載の化合物またはその薬学的に許容される塩。
- R1が、テトラヒドロフラン−3−イルである、請求項5に記載の化合物またはその薬学的に許容される塩。
- R1が、テトラヒドロピラン−4−イルである、請求項5に記載の化合物またはその薬学的に許容される塩。
- Lが、−S(O)2−である、請求項1〜7のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- Lが、−O−である、請求項1〜7のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- Lが、−C(O)−である、請求項1〜7のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- Lが、−CH2−である、請求項1〜7のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- Y1が、CHである、請求項1〜11のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- Y1が、Nである、請求項1〜11のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- R2が、5員ヘテロアリール環である、請求項1〜13のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- R2が、C1〜6アルキル、C1〜6ハロアルキル、およびNReRfからなる群から選択される1つ以上の置換基で置換された5員ヘテロアリール環であり、ReおよびRfが、独立して、HまたはC1〜4アルキルである、請求項1〜14のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- R2が、C1〜6アルキル、C1〜6ハロアルキル、およびNReRfからなる群から選択される1つ以上の置換基で置換されたチアゾリルまたはチアジアゾリルであり、ReおよびRfが、独立して、HまたはC1〜4アルキルである、請求項1〜15のいずれか一項に記載の化合物。
- R2が、メチル、CF3、およびNH2からなる群から選択される1つ以上の置換基で置換されたチアゾリルまたはチアジアゾリルである、請求項1〜16のいずれか一項に記載の化合物。
- G1が、Sであり、かつG2が、CR3である、請求項18に記載の化合物またはその薬学的に許容される塩。
- R3が、Hである、請求項19に記載の化合物またはその薬学的に許容される塩。
- R3が、C1〜6アルキルである、請求項19に記載の化合物またはその薬学的に許容される塩。
- R3が、C1〜6ハロアルキルである、請求項19に記載の化合物またはその薬学的に許容される塩。
- G1が、Nであり、かつG2が、Sである、請求項18に記載の化合物またはその薬学的に許容される塩。
- G1が、Sであり、かつG2が、Nである、請求項18に記載の化合物またはその薬学的に許容される塩。
- ReおよびRfが両方とも、Hである、請求項1〜24のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- (a)請求項1〜29のいずれか一項に記載の少なくとも1つの化合物またはその薬学的に許容される塩、および(b)薬学的に許容される賦形剤を含む、医薬組成物。
- Vps34/PI3K IIIシグナル伝達経路の調節に関連する疾患または医学的状態を処置する方法であって、有効量の、請求項1〜29のいずれか一項に記載の少なくとも1つの化合物もしくはその薬学的に許容される塩または請求項30に記載の医薬組成物を、そのような処置を必要とする対象に投与することを含む、方法。
- 前記疾患または医学的状態が、糖尿病、多嚢胞性卵巣症候群、糖尿病関連心血管疾患、癌、神経炎症、または虚血性脳卒中である、請求項31に記載の方法。
- 前記疾患または医学的状態が、癌であり、前記癌が、膠芽腫、腎細胞癌、または黒色腫である、請求項32に記載の方法。
- Vps34/PI3K IIIシグナル伝達経路の調節に関連する疾患または医学的状態の処置に使用するための、請求項1〜29のいずれか一項に記載の化合物もしくはその薬学的に許容される塩または請求項30に記載の医薬組成物。
- 前記疾患または医学的状態が、糖尿病、多嚢胞性卵巣症候群、糖尿病関連心血管疾患、癌、神経炎症、または虚血性脳卒中である、請求項34に記載の化合物または医薬組成物。
- 前記疾患または医学的状態が、癌であり、前記癌が、膠芽腫、腎細胞癌、または黒色腫である、請求項35に記載の化合物または医薬組成物。
- Vps34/PI3K IIIシグナル伝達経路の調節に関連する疾患または医学的状態の処置のための医薬の製造における、請求項1〜29のいずれか一項に記載の少なくとも1つの化合物もしくはその薬学的に許容される塩または請求項30に記載の医薬組成物の使用。
- 前記疾患または医学的状態が、糖尿病、多嚢胞性卵巣症候群、糖尿病関連心血管疾患、癌、神経炎症、または虚血性脳卒中である、請求項37に記載の使用。
- 前記疾患または医学的状態が、癌であり、前記癌が、膠芽腫、腎細胞癌、または黒色腫である、請求項38に記載の使用。
- 細胞を、有効量の、請求項1〜29のいずれか一項に記載の少なくとも1つの化合物もしくはその塩および/または請求項30に記載の少なくとも1つの医薬組成物と接触させることを含む、細胞中のVps34/PI3K IIIシグナル伝達経路を妨げるか、または細胞中のVps34/PI3K IIIシグナル伝達経路を調節し、防止し、遅延させ、反転し、もしくは阻害する方法であって、前記接触がインビトロ、エクスビボ、またはインビボである、方法。
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JP2013504325A (ja) * | 2009-09-09 | 2013-02-07 | アビラ セラピューティクス, インコーポレイテッド | Pi3キナーゼインヒビターおよびその使用 |
JP2014509647A (ja) * | 2011-03-28 | 2014-04-21 | メイ プハルマ,インコーポレーテッド | (α−置換アラルキルアミノ及びヘテロアリールアルキルアミノ)ピリミジニル及び1,3,5−トリアジニルベンズイミダゾール、それらを含む医薬組成物、並びに増殖性疾患の治療で使用するためのこれらの化合物 |
WO2017140843A1 (en) * | 2016-02-19 | 2017-08-24 | Sprint Bioscience Ab | 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes |
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AU2019251363B2 (en) | 2018-04-10 | 2024-03-07 | Neuropore Therapies, Inc. | Morpholine derivates as inhibitors of Vps34 |
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JP2013504325A (ja) * | 2009-09-09 | 2013-02-07 | アビラ セラピューティクス, インコーポレイテッド | Pi3キナーゼインヒビターおよびその使用 |
JP2014509647A (ja) * | 2011-03-28 | 2014-04-21 | メイ プハルマ,インコーポレーテッド | (α−置換アラルキルアミノ及びヘテロアリールアルキルアミノ)ピリミジニル及び1,3,5−トリアジニルベンズイミダゾール、それらを含む医薬組成物、並びに増殖性疾患の治療で使用するためのこれらの化合物 |
WO2017140843A1 (en) * | 2016-02-19 | 2017-08-24 | Sprint Bioscience Ab | 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes |
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