JP7450541B2 - 置換アミノピリミジン化合物及び使用方法 - Google Patents
置換アミノピリミジン化合物及び使用方法 Download PDFInfo
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- JP7450541B2 JP7450541B2 JP2020538684A JP2020538684A JP7450541B2 JP 7450541 B2 JP7450541 B2 JP 7450541B2 JP 2020538684 A JP2020538684 A JP 2020538684A JP 2020538684 A JP2020538684 A JP 2020538684A JP 7450541 B2 JP7450541 B2 JP 7450541B2
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- alkylene
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- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
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- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
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- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
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- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
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- RZFHLOLGZPDCHJ-XZXLULOTSA-N α-Tocotrienol Chemical compound OC1=C(C)C(C)=C2O[C@@](CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1C RZFHLOLGZPDCHJ-XZXLULOTSA-N 0.000 description 1
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- OTXNTMVVOOBZCV-WAZJVIJMSA-N γ-tocotrienol Chemical compound OC1=C(C)C(C)=C2O[C@@](CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1 OTXNTMVVOOBZCV-WAZJVIJMSA-N 0.000 description 1
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Classifications
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Engineering & Computer Science (AREA)
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- Hematology (AREA)
- Immunology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本出願は、2018年1月20日に出願された米国仮出願第62/619,741号の利益を主張するものであり、これは参照によりその全体が本明細書に組み込まれる。
本発明は、キナーゼ活性の阻害剤である、ある特定の新規化合物、それらの調製のための方法、化合物を含む医薬組成物、及び様々な障害の処置における化合物又は組成物の使用を対象とする。より具体的には、本明細書に開示される化合物は、ホスファチジルイノシトール3-キナーゼキナーゼファミリー(以下、PI3-キナーゼ、PI3K)、例えばPI3Kδ、PI3Kα、PI3Kβ及び/又はPI3Kγの活性又は機能の阻害剤である。
Xは、3~8員ヘテロシクリル、(C6~C10)アリール又は5~10員ヘテロアリールであり、ここで、Xは、1、2、3、4又は5個のR3基により場合により置換されており、
mは、1、2又は3であり、
Wは、N又はCR5であり、
Aは、H、D、(C1~C6)アルキル、(C1~C6)ハロアルキル、(C1~C6)ヒドロキシアルキル、(C1~C6)アミノアルキル、(C3~C8)シクロアルキル又は3~8員ヘテロシクリルであり、ここで、各(C1~C6)アルキル、((C1~C6)ハロアルキル、(C1~C6)ヒドロキシアルキル、(C1~C6)アミノアルキル、(C3~C8)シクロアルキル及び3~8員ヘテロシクリルは、D、オキソ、F、Cl、Br、OH、NH2、CN、NO2、(C1~C6)アルキル及び(C1~C6)アルコキシから独立して選択される1、2、3、又は4個の置換基で場合により置換されており、
Bは、(C3~C8)シクロアルキル、3~8員ヘテロシクリル、(C6~C10)アリール又は5~10員ヘテロアリールであり、ここで、(C3~C8)シクロアルキル、3~8員ヘテロシクリル、(C6~C10)アリール及び5~10員ヘテロアリールのそれぞれは、D、オキソ(=O)、F、Cl、Br、CN、Ra、ORa、NRaRb、(C1~C6)アルキル、-(C1~C4)アルキレン-ORa及び-(C1~C4)アルキレン-NRaRbから独立して選択される1、2、3、又は4個の置換基で場合により置換されており、
各R3、R4及びR5は、独立して、H、D、F、Cl、Br、CN、NO2、オキソ(=O)、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRb、-OC(=O)NRaRb、-OC(=O)ORa、-N(Rc)C(=O)NRaRb、-N(Rc)C(=O)ORa、-N(Rc)C(=O)Ra、-S(=O)2NRaRb、-S(=O)2Ra、-N(Rc)S(=O)2Ra、-N(Rc)-(C1~C4)アルキレン-S(=O)2Ra、-(C1~C4)アルキレン-C(=O)NRaRb、-(C1~C4)アルキレン-N(Rc)C(=O)NRaRb、-(C1~C4)アルキレン-N(Rc)C(=O)ORa、-(C1~C4)アルキレン-OC(=O)NRaRb、-(C1~C4)アルキレン-S(=O)2NRaRb、-(C1~C4)アルキレン-N(Rc)S(=O)2Ra、ORa、NRaRb、-(C1~C4)アルキレン-ORa、-(C1~C4)アルキレン-NRaRb、(C1~C6)アルキル、(C2~C6)アルケニル、(C2~C6)アルキニル、(C3~C8)シクロアルキル、-(C1~C4)アルキレン-(C3~C8)シクロアルキル、3~8員ヘテロシクリル、-(C1~C4)アルキレン-(3~8員ヘテロシクリル)、(C6~C10)アリール、-(C1~C4)アルキレン-(C6~C10)アリール、5~10員ヘテロアリール、又は-(C1~C4)アルキレン-(5~10員ヘテロアリール)であり、ここで、(C1~C6)アルキル、(C2~C6)アルケニル、(C2~C6)アルキニル、(C3~C8)シクロアルキル、-(C1~C4)アルキレン-(C3~C8)シクロアルキル、3~8員ヘテロシクリル、-(C1~C4)アルキレン-(3~8員ヘテロシクリル)、(C6~C10)アリール、-(C1~C4)アルキレン-(C6~C10)アリール、5~10員ヘテロアリール及び-(C1~C4)アルキレン-(5~10員ヘテロアリール)のそれぞれは、D、F、Cl、Br、CN、オキソ(=O)、Ra、ORa、NRaRb、(C1~C6)アルキル、-(C1~C4)アルキレン-ORa及び-(C1~C4)アルキレン-NRaRbから独立して選択される1、2、3、又は4個の置換基で場合により置換されており、
各Ra、Rb及びRcは、独立して、H、(C1~C6)アルキル、(C2~C6)アルケニル、(C2~C6)アルキニル、(C3~C6)シクロアルキル、-(C1~C4)アルキレン-(C3~C6)シクロアルキル、3~6員ヘテロシクリル、-(C1~C4)アルキレン-(3~6員ヘテロシクリル)、(C6~C10)アリール、-(C1~C4)アルキレン-(C6~C10)アリール、5~10員ヘテロアリール、若しくは-(C1~C4)アルキレン-(5~10員ヘテロアリール)であり、ここで、(C1~C6)アルキル、(C2~C6)アルケニル、(C2~C6)アルキニル、(C3~C6)シクロアルキル、-(C1~C4)アルキレン-(C3~C6)シクロアルキル、3~6員ヘテロシクリル、-(C1~C4)アルキレン-(3~6員ヘテロシクリル)、(C6~C10)アリール、-(C1~C4)アルキレン-(C6~C10)アリール、5~10員ヘテロアリール及び-(C1~C4)アルキレン-(5~10員ヘテロアリール)のそれぞれは、D、F、Cl、Br、CN、NO2、N3、OH、NH2、(C1~C6)アルキル、(C1~C6)ハロアルキル、(C1~C6)アルコキシ及び(C1~C6)アルキルアミノから独立して選択される1、2、3若しくは4個の置換基で場合により置換されており;又はRa及びRbは、それらが結合している窒素原子と一緒になって、場合により置換されている3~8員の複素環式環を形成する。
ここで、本発明のある特定の実施形態に詳細に言及し、その例を、付随する構造及び式において例証する。本発明は、特許請求の範囲により定義される通りの本発明の範囲内に含まれ得る、すべての代替物、修正物、及び均等物を網羅することが意図されている。当業者であれば、本発明の実践において使用され得る、本明細書に記載されるものと同様又は同等の多くの方法及び物質を認識するであろう。本発明は、本明細書に記載される方法及び物質に決して限定されない。組み込まれる文献、特許及び同様の資料の1つ又は複数が、定義される用語、用語の用法、記載される技術等を含むがこれらに限定されない本出願と異なるか、又は矛盾する場合、本出願が優先する。
本発明者らは、キナーゼ活性、特にPI3-キナーゼ活性の阻害剤である新規化合物を発見した。PI3-キナーゼ阻害剤である化合物は、不適当なキナーゼ活性、特に不適当なPI3-キナーゼ活性に関連する障害の処置、例えば、PI3-キナーゼ機序により媒介される障害の処置及び予防において有用であり得る。そのような障害には、喘息、慢性閉塞性肺疾患(COPD)及び特発性肺線維症(IPF)を含む呼吸器疾患;ウイルス性呼吸器感染症、並びに喘息及びCOPD等の呼吸器疾患のウイルス増悪を含む、ウイルス感染症;アスペルギルス症及びリーシュマニア症を含む非ウイルス性呼吸器感染症;アレルギー性鼻炎及びアトピー性皮膚炎を含むアレルギー性疾患;関節リウマチ及び多発性硬化症を含む自己免疫疾患;炎症性腸疾患を含む炎症性障害;血栓症及びアテローム性動脈硬化症を含む心血管疾患;血液学的悪性腫瘍;神経変性疾患;膵炎;多臓器不全;腎臓疾患;血小板凝集;がん;精子運動性;移植拒絶;移植片拒絶;肺損傷;並びに関節リウマチ又は変形性関節症に関連する疼痛、背痛、一般的炎症性疼痛、ヘルペス後神経痛、糖尿病性ニューロパシー、炎症性神経障害性疼痛(外傷)、三叉神経痛及び中枢性疼痛を含む疼痛が含まれる。
Xは、3~8員ヘテロシクリル、(C6~C10)アリール又は5~10員ヘテロアリールであり、ここで、Xは、1、2、3、4又は5個のR3基により場合により置換されており、
mは、1、2又は3であり、
Wは、N又はCR5であり、
Aは、H、D、(C1~C6)アルキル、(C1~C6)ハロアルキル、(C1~C6)ヒドロキシアルキル、(C1~C6)アミノアルキル、(C3~C8)シクロアルキル又は3~8員ヘテロシクリルであり、ここで、各(C1~C6)アルキル、(C1~C6)ハロアルキル、(C1~C6)ヒドロキシアルキル、(C1~C6)アミノアルキル、(C3~C8)シクロアルキル及び3~8員ヘテロシクリルは、D、オキソ、F、Cl、Br、OH、NH2、CN、NO2、(C1~C6)アルキル及び(C1~C6)アルコキシから独立して選択される1、2、3、又は4個の置換基で場合により置換されており、
Bは、(C3~C8)シクロアルキル、3~8員ヘテロシクリル、(C6~C10)アリール又は5~10員ヘテロアリールであり、ここで、(C3~C8)シクロアルキル、3~8員ヘテロシクリル、(C6~C10)アリール及び5~10員ヘテロアリールのそれぞれは、D、オキソ(=O)、F、Cl、Br、CN、Ra、ORa、NRaRb、(C1~C6)アルキル、-(C1~C4)アルキレン-ORa及び-(C1~C4)アルキレン-NRaRbから独立して選択される1、2、3、又は4個の置換基で場合により置換されており、
各R3、R4及びR5は、独立して、H、D、F、Cl、Br、CN、NO2、オキソ(=O)、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRb、-OC(=O)NRaRb、-OC(=O)ORa、-N(Rc)C(=O)NRaRb、-N(Rc)C(=O)ORa、-N(Rc)C(=O)Ra、-S(=O)2NRaRb、-S(=O)2Ra、-N(Rc)S(=O)2Ra、-N(Rc)-(C1~C4)アルキレン-S(=O)2Ra、-(C1~C4)アルキレン-C(=O)NRaRb、-(C1~C4)アルキレン-N(Rc)C(=O)NRaRb、-(C1~C4)アルキレン-N(Rc)C(=O)ORa、-(C1~C4)アルキレン-OC(=O)NRaRb、-(C1~C4)アルキレン-S(=O)2NRaRb、-(C1~C4)アルキレン-N(Rc)S(=O)2Ra、ORa、NRaRb、-(C1~C4)アルキレン-ORa、-(C1~C4)アルキレン-NRaRb、(C1~C6)アルキル、(C2~C6)アルケニル、(C2~C6)アルキニル、(C3~C8)シクロアルキル、-(C1~C4)アルキレン-(C3~C8)シクロアルキル、3~8員ヘテロシクリル、-(C1~C4)アルキレン-(3~8員ヘテロシクリル)、(C6~C10)アリール、-(C1~C4)アルキレン-(C6~C10)アリール、5~10員ヘテロアリール、又は-(C1~C4)アルキレン-(5~10員ヘテロアリール)であり、ここで、(C1~C6)アルキル、(C2~C6)アルケニル、(C2~C6)アルキニル、(C3~C8)シクロアルキル、-(C1~C4)アルキレン-(C3~C8)シクロアルキル、3~8員ヘテロシクリル、-(C1~C4)アルキレン-(3~8員ヘテロシクリル)、(C6~C10)アリール、-(C1~C4)アルキレン-(C6~C10)アリール、5~10員ヘテロアリール及び-(C1~C4)アルキレン-(5~10員ヘテロアリール)のそれぞれは、D、F、Cl、Br、CN、オキソ(=O)、Ra、ORa、NRaRb、(C1~C6)アルキル、-(C1~C4)アルキレン-ORa及び-(C1~C4)アルキレン-NRaRbから独立して選択される1、2、3、又は4個の置換基で場合により置換されており、
各Ra、Rb及びRcは、独立して、H、(C1~C6)アルキル、(C2~C6)アルケニル、(C2~C6)アルキニル、(C3~C6)シクロアルキル、-(C1~C4)アルキレン-(C3~C6)シクロアルキル、3~6員ヘテロシクリル、-(C1~C4)アルキレン-(3~6員ヘテロシクリル)、(C6~C10)アリール、-(C1~C4)アルキレン-(C6~C10)アリール、5~10員ヘテロアリール、若しくは-(C1~C4)アルキレン-(5~10員ヘテロアリール)であり、ここで、(C1~C6)アルキル、(C2~C6)アルケニル、(C2~C6)アルキニル、(C3~C6)シクロアルキル、-(C1~C4)アルキレン-(C3~C6)シクロアルキル、3~6員ヘテロシクリル、-(C1~C4)アルキレン-(3~6員ヘテロシクリル)、(C6~C10)アリール、-(C1~C4)アルキレン-(C6~C10)アリール、5~10員ヘテロアリール及び-(C1~C4)アルキレン-(5~10員ヘテロアリール)のそれぞれは、D、F、Cl、Br、CN、NO2、N3、OH、NH2、(C1~C6)アルキル、(C1~C6)ハロアルキル、(C1~C6)アルコキシ及び(C1~C6)アルキルアミノから独立して選択される1、2、3若しくは4個の置換基で場合により置換されており;又はRa及びRbは、それらが結合している窒素原子と一緒になって、場合により置換されている3~8員の複素環式環を形成する。
Table 1(化11)
一態様において、本明細書で特徴とされるのは、式(I)の化合物、又はTable 1(化11)に列挙されている化合物と、薬学的に許容される担体、アジュバント、又はビヒクルとを含む医薬組成物である。本明細書に開示される医薬組成物中における化合物の量は、生物学的試料において又は患者においてプロテインキナーゼを検知可能な程度に阻害するのに有効な量である。
a)血小板由来成長因子受容体(PDGFR)の活性を標的とする、減少させる又は阻害する化合物、例えば、PDGFRの活性を標的とする、減少させる又は阻害する化合物、特に、PDGF受容体を阻害する化合物、例えば、N-フェニル-2-ピリミジン-アミン誘導体、例えば、イマチニブ、SU101、SU6668及びGFB-111;
b)線維芽細胞成長因子受容体(FGFR)の活性を標的とする、減少させる又は阻害する化合物;
c)インスリン様成長因子受容体I(IGF-IR)の活性を標的とする、減少させる又は阻害する化合物、例えば、IGF-IRの活性を標的とする、減少させる又は阻害する化合物、特に、IGF-IR受容体を阻害する化合物、例えば、WO02/092599に開示されている化合物;
d)Trk受容体チロシンキナーゼファミリーの活性を標的とする、減少させる又は阻害する化合物;
e)Axl受容体チロシンキナーゼファミリーの活性を標的とする、減少させる又は阻害する化合物;
f)c-Met受容体の活性を標的とする、減少させる又は阻害する化合物;
g)Kit/SCFR受容体チロシンキナーゼの活性を標的とする、減少させる又は阻害する化合物;
h)C-kit受容体チロシンキナーゼ-(PDGFRファミリーの一部)の活性を標的とする、減少させる又は阻害する化合物、例えば、c-Kit受容体チロシンキナーゼファミリーの活性を標的とする、減少させる又は阻害する化合物、特に、c-Kit受容体を阻害する化合物、例えば、イマチニブ;
i)c-Ablファミリーのメンバー及びそれらの遺伝子融合産物、例えばBCR-Ablキナーゼの活性を標的とする、減少させる又は阻害する化合物、例えば、c-Ablファミリーメンバー及びそれらの遺伝子融合産物の活性を標的とする、減少させる又は阻害する化合物、例えば、N-フェニル-2-ピリミジン-アミン誘導体、例えば、イマチニブ、PD180970、AG957、NSC 680410又はParkeDavis社製PD173955;
j)プロテインキナーゼC(PKC)及びセリン/トレオニンキナーゼのRafファミリーのメンバー、MEK、SRC、JAK、FAK、PDK及びRas/MAPKファミリーメンバー、若しくはPl(3)キナーゼファミリー、若しくはPl(3)-キナーゼ関連キナーゼファミリーのメンバー、並びに/又はサイクリン依存性キナーゼファミリー(CDK)のメンバーの活性を標的とする、減少させる又は阻害する化合物であり、特に、米国特許第5,093,330号に開示されているスタウロスポリン誘導体、例えば、ミドスタウリンであり;更なる化合物の例としては、例えば、UCN-01;サフィンゴール;BAY 43-9006;ブリオスタチン1;ペリホシン;イルモホシン(llmofosine);RO 318220及びRO 320432;GO 6976;Isis 3521;LY333531/LY379196;WO00/09495に開示されているもの等のイソキノリン(isochinoline)化合物;FTI;PD184352;又はQAN697(P13K阻害剤)が挙げられる;
k)プロテインチロシンキナーゼ阻害剤の活性を標的とする、減少させる又は阻害する化合物、例えば、プロテインチロシンキナーゼ阻害剤の活性を標的とする、減少させる又は阻害する化合物には、イマチニブメシレート(GLEEVEC)又はチルホスチンが含まれる。チルホスチンは、好ましくは、低分子量(Mr<1500)化合物、又はその薬学的に許容される塩、特に、ベンジリデンマロニトリルクラス又はS-アリールベンゼンマロニトリル若しくは二基質キノリンクラスの化合物から選択される化合物、更に特に、チルホスチンA23/RG-50810、AG 99、チルホスチンAG 213、チルホスチンAG 1748、チルホスチンAG 490、チルホスチンB44、チルホスチンB44(+)エナンチオマー、チルホスチンAG 555、AG 494、チルホスチンAG 556、AG957及びアダホスチン(4-{[(2,5-ジヒドロキシフェニル)メチル]アミノ}-安息香酸アダマンチルエステル、NSC 680410、アダホスチンからなる群から選択される任意の化合物である;並びに、
I)受容体チロシンキナーゼの上皮成長因子ファミリー(ホモ又はヘテロ二量体としてのEGFR、ErbB2、ErbB3、ErbB4)の活性を標的とする、減少させる又は阻害する化合物、例えば、上皮成長因子受容体ファミリーの活性を標的とする、減少させる又は阻害する化合物は、特に、EGF受容体チロシンキナーゼファミリーのメンバー、例えば、EGF受容体、ErbB2、ErbB3及びErbB4を阻害する、又はEGF若しくはEGF関連リガンドに結合する、化合物、タンパク質又は抗体であり、特に、WO97/02266、例えば、実施例39の化合物、又はEP0564409;WO99/03854;EP0520722;EP0566226;EP0787722;EP0837063;米国特許第5,747,498号;WO98/10767;WO97/30034;WO97/49688;WO97/38983及び特に、WO96/30347、例えば、CP 358774として公知の化合物;WO96/33980、例えば、化合物ZD 1839;及びWO95/03283、例えば、化合物ZM105180に一般的且つ具体的に開示されている、化合物、タンパク質又はモノクローナル抗体であり、例えば、トラスツズマブ(HERCEPTIN)、セツキシマブ、イレッサ、タルセバ、OSI-774、CI-1033、EKB-569、GW-2016、E1.1、E2.4、E2.5、E6.2、E6.4、E2.1 1、E6.3又はE7.6.3;並びにWO03/013541に開示されている7H-ピロロ-[2,3-d]ピリミジン誘導体である。更なる抗血管新生化合物には、それらの活性について別の機序を有し、例えば、プロテインキナーゼ又は脂質キナーゼ阻害と無関係の化合物、例えば、サリドマイド(THALOMID)及びTNP-470が含まれる。プロテインホスファターゼ又は脂質ホスファターゼの活性を標的とする、減少させる又は阻害する化合物は、例えば、ホスファターゼ1、ホスファターゼ2A、PTEN又はCDC25の阻害剤、例えば、オカダ酸又はその誘導体である。
本明細書に開示される化合物は、キナーゼ活性、特にPI3-キナーゼ活性の阻害剤である。PI3-キナーゼ阻害剤である化合物は、根底にある病理が不適当なPI3-キナーゼ活性に(少なくとも部分的に)起因する障害、例えば喘息及び慢性閉塞性肺疾患(COPD)の処置において有用であり得る。「不適当なPI3-キナーゼ活性」は、特定の患者において予想される正常なPI3-キナーゼ活性から逸脱した任意のPI3-キナーゼ活性を指す。不適当なPI3-キナーゼは、例えば、活性の異常な増加、又はPI3-キナーゼ活性のタイミング及び/若しくは制御の異常の形態を取り得る。次いで、そのような不適当な活性は、例えば、不適当な又は制御されない活性化をもたらすプロテインキナーゼの過剰発現又は変異から生じ得る。したがって、別の態様において、本発明は、そのような障害を処置する方法を対象とする。
本発明を例証するために、以下の実施例が含まれる。しかしながら、これらの実施例は、本発明を制限するものではなく、本発明を実施する方法を示唆することを意図しているに過ぎないことを理解されたい。
ATP アデノシン三リン酸
AcOH、HAc、HOAc、CH3COOH 酢酸
AcOK、CH3COOK 酢酸カリウム
BSA N,O-ビス(トリメチルシリル)アセトアミド
BOC、Boc ブチルオキシカルボニル
N-BuOH ブチルアルコール
N-BuLi n-ブチルリチウム
Cs2CO3 炭酸セシウム
CH2Cl2、DCM 塩化メチレン
CHCl3 クロロホルム
CDCl3 重水素化クロロホルム
CH3CN アセトニトリル
CH3Cl 塩化メチル
Cu 銅
CuI ヨウ化第一銅
D2 重水素ガス
DIEA、DIPEA、iPr2Net N,N-ジイソプロピルエチルアミン
DMF ジメチルホルムアミド
DMAC ジメチルアセトアミド
DMAP 4-ジメチルアミノピリジン
DMSO ジメチルスルホキシド
DTT DL-ジチオトレイトール
Et3N、TEA トリエチルアミン
EtOAc、EA、酢酸エチル
Et2O ジエチルエーテル
EtOH エタノール
FBS ウシ胎児血清
Fe 鉄
g グラム
h 時間
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
HBr 臭化水素酸
HCl 塩酸
H2 水素
H2O 水
H2O2 過酸化水素
H3PO4 オルトリン酸
H2SO4 硫酸
HNO3 硝酸
HCOOK ギ酸カリウム
HCOONH4 ギ酸アンモニウム
HMDS ヘキサメチルジシラザン
HPLC 高速液体クロマトグラフィー又は高圧液体クロマトグラフィー
I2 ヨウ素
LiHMDS リチウムビス(トリメチルシリル)-アミド
LDA リチウムジイソプロピルアミド
MBP ミエリン塩基性タンパク質
MCPBA メタクロロ過安息香酸
MeCN、CH3CN アセトニトリル
MgSO4 硫酸マグネシウム
MeOH、CH3OH メタノール
MeI ヨウ化メチル
mL、ml ミリリットル
min 分
N2 窒素
NMP N-メチルピロリジノン
NaHCO3 重炭酸ナトリウム
NaBH4 水素化ホウ素ナトリウム
NaBH3CN シアノ水素化ホウ素ナトリウム
NaOtBu ナトリウムtert-ブトキシド
NaOMe、CH3ONa、NaOCH3 ナトリウムメトキシド
NaOH 水酸化ナトリウム
NaClO2 亜塩素酸ナトリウム
NaClO 次亜塩素酸ナトリウム
NaCl 塩化ナトリウム
NaH2PO4 重リン酸ナトリウム
NaH 水素化ナトリウム
NaI ヨウ化ナトリウム
Na2SO4 硫酸ナトリウム
Na2S2O3 チオ硫酸ナトリウム
NBS N-ブロモスクシンイミド
NIS N-ヨードスクシンイミド
NCS N-クロロスクシンイミド
NEt3 トリエチルアミン
NH3 アンモニア
NH4Cl 塩化アンモニウム
NH2OH・HCl ヒドロキシルアミン塩酸塩
(NH4)2Ce(NO3)6 硝酸セリウムアンモニウム
Pd/C パラジウム炭素
Pd2(dba)3 ビス(ジベンジリデンアセトン)パラジウム
Pd(OAc)2 酢酸パラジウム
Pd(OH)2 水酸化パラジウム
Pd(PPh3)4 パラジウムテトラキストリフェニルホスフィン
Pd(PPh3)2Cl2 ビス(トリフェニルホスフィン)パラジウム(II)クロリド
Pd(dppf)Cl2 1,1-ビス(ジフェニルホスフィノ)フェロセンパラジウムクロリド
PdCl2(PCy3)2 ビス(トリシクロヘキシルホスフィン)ジクロロパラジウム
P(t-Bu)3 トリ(tert-ブチル)ホスフィン
PE 石油エーテル(60~90℃)
PBS リン酸緩衝生理食塩水
Ph フェニル
POCl3 オキシ塩化リン
PhI(OAc)2 ヨードベンゼンジアセテート
K2CO3 炭酸カリウム
KOH 水酸化カリウム
RT rt r.t. 室温
Rt 保持時間
SOCl2 塩化チオニル
SO2Cl2 塩化スルフリル
t-BuOK カリウムtert-ブタノレート
TBS トリス緩衝生理食塩水
THF テトラヒドロフラン
TFA トリフルオロ酢酸
TEAC ビス(テトラ-エチルアンモニウム)カーボネート
Tris トリヒドロキシメチルアミノメタン
TsCl 4-トルエンスルホニルクロリド
μL マイクロリットル
X-Phos 5-ブロモ-4-クロロ-3-インドリルホスフェートp-トルイジン塩
本明細書に開示される化合物は、上記に例証した合成経路に従って調製することができる。化合物(1a)を、塩基の存在下で、化合物(2a)と反応させて、化合物(H)を得る。
本明細書に開示される中間体(2a)は、上記に例証した合成経路に従って調製することができる。最初に、化合物(2b)を、Pd触媒の存在下で化合物(3a)とカップリングさせて、化合物(2c)を得る。次いで、保護基を化合物(2c)から除去して、化合物(2a)を生成する。
(S)-2-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-5-(3-ヒドロキシ-3-メチルブタ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
DMF(10mL)中の(S)-tert-ブチル(1-(5-クロロ-4-オキソ-3-フェニル-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(1.01g、2.53mmol)(WO2015042077における実施例64の工程1~4の合成方法を参照)、ヨウ化第一銅(51mg、0.26mmol)、酢酸パラジウム(61mg、0.27mmol)、X-phos(243mg、0.51mmol)及びDIPEA(1.7mL、9.7mmol)の懸濁液に、2-メチルブタ-3-イン-2-オール(1mL、10.3mmol)をN2雰囲気下で添加した。反応混合物を100℃に6.5時間加熱し、室温に冷却し、EtOAc(100mL)で希釈し、次いで水(100mL×4)及び飽和ブライン(100mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=1/2)により精製して、表題化合物を薄黄色固体(610mg、54%)として得た。
MS(ESI、陽イオン)m/z:448.5[M+H]+。
EtOAc(10mL)中の(S)-tert-ブチル(1-(5-(3-ヒドロキシ-3-メチルブタ-1-イン-1-イル)-4-オキソ-3-フェニル-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(610mg、1.36mmol)の溶液に、EtOAc中塩化水素(ガス)(3M、10mL、30mmol)を添加した。反応物を室温で2時間撹拌し、次いでH2O(100mL)及びEtOAc(20mL)で希釈した。有機層を分離し、水性相をNaHCO3粉末でpH=8.5に塩基性化し、DCM(50mL×2)で抽出した。合わせた有機相を飽和ブライン(50mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(MeOH/DCM(v/v)=1/20)により精製して、表題化合物を薄黄色固体(246mg、52%)として得た。
MS (ESI, 陽イオン) m/z: 348.4 [M + H]+;
1HNMR (400 MHz, DMSO-d6) δ (ppm): 7.75 (dd, J = 7.6, 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.60-7.45 (m, 6H), 5.35 (s, 1H), 3.40- 3.34 (m, 1H), 1.91 (br.s, 2H), 1.41 (s, 6H), 1.14 (d, J = 6.4 Hz, 3H).
プロパン-2-オール(1mL)中の(S)-2-(1-アミノエチル)-5-(3-ヒドロキシ-3-メチルブタ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン(30.0mg、0.08mmol)、6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-アミン(25.2mg、0.12mmol)(WO2015042077における実施例3の工程1~4の合成方法を参照)及びDIPEA(16.2mg、0.12mmol)の混合物を、85℃に5時間加熱した。混合物を室温まで冷却し、次いで水(1mL)を滴下添加し、10分間撹拌し、濾過した。濾過ケーキを真空中で乾燥させて、表題化合物を薄黄色固体(25.8mg、57%)として得た。
MS (ESI, 陽イオン) m/z: 523.3 [M + H]+;
1HNMR (400 MHz, DMSO-d6) δ (ppm): 9.20 (d, J = 6.4 Hz, 1H), 7.98 (s, 1H), 7.80 (dd, J = 8.0, 8.0 Hz, 1H), 7.67-7.53 (m, 9H), 5.38 (s, 1H), 4.93-4.86 (m, 1H), 2.5 (s, 3H), 1.42 (s, 6H), 1.34 (d, J = 6.8 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)エチル)-5-(3-ヒドロキシ-3-メチルブタ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 523.3 [M + H]+;
1HNMR (400 MHz, CDCl3) δ (ppm): 8.50 (d, J = 7.2Hz, 1H), 8.01 (s, 1H), 7.63-7.52 (m, 6H), 7.44-7.42 (m, 1H), 7.35-7.33 (m, 1H), 6.39 (br.s, 2H), 5.13-5.07 (m, 1H), 3.06 (br.s, 1H), 2.67 (s, 3H), 1.58 (s, 6H), 1.43 (d, J = 6.4 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(5-メチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-4-イル)アミノ)エチル)-5-(3-ヒドロキシ-3-メチルブタ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 523.3 [M + H]+;
1HNMR (400 MHz, CDCl3) δ (ppm): 8.76 (d, J = 6.8 Hz, 1H), 7.98 (s, 1H), 7.63-7.45 (m, 7H), 7.32 (d, J = 7.6 Hz, 1H), 5.11-5.05 (m 1H), 3.05 (br.s, 1H), 2.72 (s, 3H), 1.58 (s, 6H), 1.44 (d, J = 6.8 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(2-メチル-2H-テトラゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-5-(3-ヒドロキシ-3-メチルブタ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 523.6 [M + H]+;
1H NMR (600 MHz, CDCl3) δ (ppm): 8.86 (d, J = 7.2 Hz, 1H), 8.00 (s, 1H), 7.62-7.50 (m, 6H), 7.48-7.46 (m, 1H), 7.35 (d, J = 7.8 Hz, 1H), 5.55 (br.s, 2H), 5.13-5.09 (m, 1H), 4.49 (s, 3H), 3.13 (br.s, 1H), 1.57(s, 6H), 1.47 (d, J = 6.6 Hz, 3H).
13C NMR (151 MHz, CDCl3) δ (ppm): 162.6, 161.2, 160.6, 159.1, 158.5, 157.8, 148.6, 136.4, 133.3, 132.9, 129.9, 129.6, 129.6, 129.1, 128.9, 127.7, 123.0, 121.2, 100.4, 83.2, 81.8, 65.6, 48.8, 39.8, 31.2, 31.2, 20.3.
2-((S)-1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-5-(3-ヒドロキシブタ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
DMAC(17mL)中の(S)-tert-ブチル(1-(5-クロロ-4-オキソ-3-フェニル-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(3.0g、7.5mmol)の溶液に、炭酸カリウム(1.6g、11mmol)、X-Phos(0.36g、0.74mmol)及び10%Pd/C(0.8g)を添加した。反応物を窒素で脱気した。110℃で終夜撹拌した後、反応混合物をCH2Cl2(100mL)で希釈し、濾過した。濾液をH2O(30mL×6)及び飽和ブライン(30mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=1/6)により精製して、表題化合物を黄色固体(2.6g、80%)として得た。
MS (ESI, 陽イオン) m/z: 434.3 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.68 (d, J = 4.4 Hz, 2H), 7.58 (m, 4H), 7.40 (d, J = 7.0 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 5.64 (d, J = 8.3 Hz, 1H), 4.77 (q, J = 6.3 Hz, 1H), 4.56 - 4.43 (m, 1H), 2.77 (s, 1H), 1.53 (d, J = 6.6 Hz, 3H), 1.43 (s, 9H), 1.27 (d, J = 6.7 Hz, 3H).
ジオキサン(10mL)中のtert-ブチル((1S)-1-(5-(3-クロロブタ-1-イン-1-イル)-4-オキソ-3-フェニル-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(1.0g、2.3mmol)の溶液に、濃HCl(1mL)を添加した。30℃で2時間撹拌した後、反応混合物を真空中で濃縮した。残留物をCH2Cl2(30mL)で希釈し、5M NaOHでpH=10に中和した。有機層を分離し、水性相をCH2Cl2(30mL×3)で抽出した。合わせた有機層をブライン(50mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮して、表題化合物を黄色固体(0.84g、110%)として得た。
MS (ESI, 陽イオン) m/z: 334.1 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.68 (d, J = 4.3 Hz, 2H), 7.62 - 7.49 (m, 4H), 7.30 (s, 2H), 4.78 (q, J = 6.6 Hz, 1H), 3.72 (s, 1H), 3.68 (q, J = 6.5 Hz, 1H), 2.00 (s, 2H), 1.54 (d, J = 6.6 Hz, 3H), 1.28 (d, J = 6.5 Hz, 3H).
n-ブタノール(1mL)中の2-((S)-1-アミノエチル)-5-(3-ヒドロキシブタ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン(61mg、0.18mmol)の溶液に、6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-アミン(39mg、0.18mmol)及びDIPEA(0.1mL、0.6mmol)を添加した。110℃で6時間撹拌した後、反応混合物を真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(MeOH/DCM(v/v)=1/20)により精製して、表題化合物を黄色固体(69mg、74%)として得た。
MS (ESI, 陽イオン) m/z: 509.1 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.85 (d, J = 7.0 Hz, 1H), 8.05 (s, 1H), 7.76 - 7.64 (m, 2H), 7.64 - 7.52 (m, 3H), 7.45 (d, J = 7.0 Hz, 1H), 7.38 (dd, J = 7.4, 1.8 Hz, 1H), 5.20 - 5.08 (m, 1H), 4.79 (dd, J = 14.0, 7.3 Hz, 1H), 2.55 (s,3H), 2.51 (s, 1H), 1.54 (d, J = 6.6 Hz, 3H), 1.47 (d, J = 6.7 Hz, 3H).
2-((S)-1-((6-アミノ-5-(5-メチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-4-イル)アミノ)エチル)-5-(3-ヒドロキシブタ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 509.5 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.79 (d, J = 6.6 Hz, 1H), 8.00 (s, 1H), 7.71 - 7.64 (m, 2H), 7.62 - 7.52 (m, 3H), 7.49 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 6.6 Hz, 1H), 5.17 - 5.06 (m, 1H), 4.79 (dd, J = 13.0, 6.5 Hz, 1H), 2.74 (s, 3H), 2.44 (s, 1H), 1.54 (d, J = 6.6 Hz, 3H), 1.48 (d, J = 6.7 Hz, 3H).
2-((S)-1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)エチル)-5-(3-ヒドロキシブタ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 509.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.52 (d, J = 7.1 Hz, 1H), 8.04 (s, 1H), 7.67 (d, J = 3.8 Hz, 2H), 7.64 - 7.52 (m, 3H), 7.46 (d, J = 7.3 Hz, 1H), 7.36 (d, J = 7.0 Hz, 1H), 6.40 (s, 2H), 5.20 - 5.10 (m, 1H), 4.79 (dd, J = 13.1, 6.3 Hz, 1H), 2.74 (s, 3H), 2.46 (s, 1H), 1.54 (d, J = 6.6 Hz, 3H), 1.47 (d, J = 6.6 Hz, 3H).
2-((S)-1-((6-アミノ-5-(2-メチル-2H-テトラゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-5-(3-ヒドロキシブタ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 509.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.90 (d, J = 6.8 Hz, 1H), 8.04 (s, 1H), 7.69 - 7.63 (m, 2H), 7.56 (m, 3H), 7.50 (d, J = 6.7 Hz, 1H), 7.36 (d, J = 7.3 Hz, 1H), 5.21 - 5.10 (m, 1H), 4.79 (dd, J = 13.1, 6.5 Hz, 1H), 4.52 (s, 3H), 2.54 (s, 1H), 1.54 (d, J = 6.6 Hz, 3H), 1.50 (d, J = 6.7 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-3-フェニル-5-(プロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
DMAC(50mL)中の(S)-tert-ブチル(1-(5-クロロ-4-オキソ-3-フェニル-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(1.5g、3.8mmol)の溶液に、プロパ-1-イン(50mL、ヘプタン中3質量%)、10%Pd/C(0.4g)、X-Phos(0.18g、0.38mmol)及び炭酸カリウム(0.78g、5.6mmol)を添加した。混合物を密封管に入れ、100℃で10時間加熱し、次いで室温まで冷却した。反応混合物を濾過し、EtOAc(100mL)で洗浄した。濾液を水(100mL×3)で洗浄した。有機相を真空中で濃縮して、粗生成物を黄色固体として得た。粗生成物をEtOAc中HClの混合物(30mL、4.0M)に室温で再溶解し、4時間撹拌した。混合物を水(30mL)に添加し、有機層を分離した。水性層を、氷水冷却にて固体NaOHを添加することによりpH=10に調整し、濾過し、濾過ケーキを真空中で乾燥させて、表題化合物を黄色固体(0.74g、65%)として得た。
MS (ESI, 陽イオン) m/z: 304.4[M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.69 - 7.60 (m, 2H), 7.60 - 7.45 (m, 4H), 7.30 (dd, J = 6.5, 3.3 Hz, 2H), 3.74 - 3.61 (m, 1H), 2.12 (s, 2H), 1.81 (s, 3H), 1.28 (d, J = 6.6 Hz, 3H).
プロパン-2-オール(2mL)中の(S)-2-(1-アミノエチル)-3-フェニル-5-(プロパ-1-イン-1-イル)キナゾリン-4(3H)-オン(82mg、0.27mmol)及び6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-アミン(68mg、0.32mmol)の混合物に、DIPEA(0.1mL、0.6mmol)を添加した。反応混合物を加熱還流し、4時間撹拌し、次いで室温まで冷却した。混合物に水(3mL)を添加し、30分間撹拌し、濾過した。濾過ケーキを真空中で乾燥させて、表題化合物を黄色固体(83mg、65%)として得た。
MS (ESI, 陽イオン) m/z: 479.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.90 (d, J = 6.7 Hz, 1H), 8.05 (d, J = 5.1 Hz, 1H), 7.73 - 7.33 (m, 8H), 5.16 (dd, J = 13.4, 6.6 Hz, 1H), 2.54 (s, 3H), 2.13 (s, 3H), 1.65 (s, 2H), 1.48 (dd, J = 10.4, 5.7 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)エチル)-3-フェニル-5-(プロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 479.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.55 (t, J = 9.2 Hz, 1H), 8.04 (d, J = 4.4 Hz, 1H), 7.70 - 7.32 (m, 8H), 5.24 - 5.07 (m, 1H), 2.75 (s, 3H), 2.13 (s, 3H), 1.65 (s, 2H), 1.47 (d, J = 6.6 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(5-メチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-4-イル)アミノ)エチル)-3-フェニル-5-(プロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 479.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.81 (dd, J = 25.2, 7.0 Hz, 1H), 8.01 (d, J = 5.9 Hz, 1H), 7.68 - 7.43 (m, 7H), 7.36 (d, J = 6.3 Hz, 1H), 5.13 (p, J = 6.8 Hz, 1H), 2.74 (s, 3H), 2.13 (s, 3H), 1.69 (s, 2H), 1.48 (d, J = 6.7 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(2-メチル-2H-テトラゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-3-フェニル-5-(プロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 479.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.93 (dd, J = 14.8, 7.2 Hz, 1H), 8.04 (d, J = 5.7 Hz, 1H), 7.65-7.45 (m, 7H), 7.37 (d, J = 6.3 Hz, 1H), 5.22 - 5.11 (m, 1H), 4.52 (s, 3H), 2.13 (s, 3H), 1.50 (d, J = 6.7 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(1-メチル-1H-1,2,4-トリアゾール-3-イル)ピリミジン-4-イル)アミノ)エチル)-3-フェニル-5-(プロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 478.2 [M + H]+;
1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.64 (d, J = 6.6 Hz, 1H), 8.77 (s, 1H), 7.91 (s, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.67 - 7.46 (m, 7H), 4.96 - 4.77 (m, 1H), 4.03 (s, 3H), 2.04 (s, 3H), 1.38 (d, J = 6.6 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)プロピル)-3-フェニル-5-(プロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
DMAC(4mL)中の(S)-tert-ブチル(1-(5-クロロ-4-オキソ-3-フェニル-3,4-ジヒドロキナゾリン-2-イル)プロピル)カルバメート(0.81g、2.0mmol)(WO2015042077における実施例1の工程1~3の合成方法を参照)の懸濁液に、炭酸カリウム(0.41g、2.9mmol)、X-Phos(95mg、0.2mmol)、10%Pd/C(0.21g)及びヘプタン中プロパ-1-インの溶液(13g、9.7mmol、3%)を添加した。反応物を窒素で脱気した。110℃で終夜撹拌した後、反応混合物をCH2Cl2(20mL)で希釈し、濾過した。濾液をH2O(8mL×5)及び飽和NaCl(8mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=1/8)により精製して、表題化合物を黄色油状物(0.43g、53%)として得た。
MS (ESI, 陽イオン) m/z: 418.1 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.64 - 7.51 (m, 6H), 7.40 - 7.32 (m, 1H), 7.32 - 7.27 (m, 1H), 5.49 (d, J = 8.2 Hz, 1H), 4.43 - 4.31 (m, 1H), 2.10 (s, 3H), 1.77 - 1.68 (m, 1H), 1.55 - 1.48 (m, 1H), 1.42 (s, 9H), 0.74 (t, J = 7.4 Hz, 3H).
ジオキサン(5mL)中の(S)-tert-ブチル(1-(3-シクロプロピル-4-オキソ-5-(プロパ-1-イン-1-イル)-3,4-ジヒドロキナゾリン-2-イル)プロピル)カルバメート(0.38g、0.91mmol)の懸濁液に、濃HCl(0.5mL)を添加した。35℃で3時間撹拌した後、反応混合物を真空中で濃縮した。残留物をCH2Cl2(20mL)で希釈し、5M NaOHでpH=10に中和した。水相をCH2Cl2(20mL×3)で抽出した。合わせた有機層を飽和ブライン(30mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮して、表題化合物を黄色油状物(0.29g、100%)として得た。
n-ブタノール(2mL)中の(S)-2-(1-アミノプロピル)-3-フェニル-5-(プロパ-1-イン-1-イル)キナゾリン-4(3H)-オン(0.11g、35mmol)の懸濁液に、6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-アミン(73mg、0.34mmol)及びDIPEA(0.2mL、1.1mmol)を添加した。110℃で終夜撹拌した後、反応混合物を室温まで冷却し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(MeOH/CH2Cl2(v/v)=1/400)により精製して、表題化合物を黄色固体(39mg、23%)として得た。
MS (ESI, 陽イオン) m/z: 493.1 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.76 (d, J = 7.2 Hz, 1H), 8.03 (s, 1H), 7.64 (d, J = 4.4 Hz, 2H), 7.60 - 7.53 (m, 4H), 7.45 (d, J = 6.9 Hz, 1H), 7.38 - 7.36 (m, 1H), 5.15 - 5.10 (m, 1H), 2.54 (s, 3H), 2.13 (s, 3H), 1.98 - 1.74 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)プロピル)-3-フェニル-5-(プロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 493.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.44 (d, J = 7.1 Hz, 1H), 8.02 (s, 1H), 7.65 - 7.57 (m, 6H), 7.45 (d, J = 7.1 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.35 (s, 2H), 5.14 - 5.09 (m, 1H), 2.74 (s, 3H), 2.13 (s, 3H), 1.97 - 1.76 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H).
(S)-3-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-2-フェニル-8-(プロパ-1-イン-1-イル)イソキノリン-1(2H)-オン
DMAC(10mL)中の(S)-3-(1-アミノエチル)-8-クロロ-2-フェニルイソキノリン-1(2H)-オン(1.5g、5.0mmol)(WO2015042078における実施例8の工程1~2の合成方法を参照)の混合物に、Cs2CO3(2.5g、7.7mmol)、PdCl2(PCy3)2(0.38g、0.51mmol)を添加した。混合物をN2でパージし、次いでプロピン(21mL、15mmol、n-ヘプタン中3~6%)を添加し、混合物を密封し、110℃で5.5時間加熱した。次いで、混合物を室温まで冷却し、EtOAc(150mL)及び水(30mL)を添加した。有機層を分離し、飽和ブライン(50mL×5)で洗浄し、Na2SO4で乾燥させ、濾過し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(PE/EtOAc/TEA(v/v/v)=1/10/0.5)により精製して、表題化合物を黄色固体(0.81g、53%)として得た。
MS (ESI, 陽イオン)m/z: 303.2 [M + H]+;
1H NMR (600 MHz, CDCl3) δ (ppm): 7.60 - 7.58 (m, 4 H), 7.48 (dd, J = 15.3, 7.9 Hz, 2 H), 7.42 (d, J = 7.7 Hz, 1 H), 7.34 (d, J = 7.4 Hz, 1 H), 6.76 (s, 1 H), 3.76 - 3.70 (m, 1 H), 2.13 (s, 3 H), 1.30 (d, J = 6.5 Hz, 3 H).
13C NMR (151 MHz, CDCl3) δ (ppm): 162.5, 138.0, 134.1, 131.6, 129.8, 129.7, 129.4, 129.0, 128.9, 125.6, 125.1, 124.7, 102.3, 92.8, 79.9, 46.9, 23.0, 5.4.
n-BuOH(1.5mL)中の(S)-3-(1-アミノエチル)-2-フェニル-8-(プロパ-1-イン-1-イル)イソキノリン-1(2H)-オン(33mg、0.11mmol)及び6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-アミン(25.5mg、0.12mmol)の懸濁液に、DIPEA(0.05mL、0.3mmol)を添加した。混合物を100℃に加熱し、3.5時間撹拌した。次いで、混合物を室温まで冷却し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(DCM/MeOH/TEA(v/v/v)=100/1/0.5)により精製して、表題化合物をオフホワイトの固体(22mg、43%)として得た。
MS (ESI, 陽イオン)m/z: 478.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.28 (d, J = 6.3 Hz, 1 H), 8.00 (s, 1 H), 7.58-7.48 (m, 3 H), 7.47 - 7.32 (m, 5 H), 6.54 (s, 1H), 5.04 - 4.95 (m, 1H), 2.49 (s, 3 H), 2.13 (s, 3 H), 1.47 (d, J = 6.8 Hz, 3 H).
(S)-3-(1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)エチル)-2-フェニル-8-(プロパ-1-イン-1-イル)イソキノリン-1(2H)-オン
MS (ESI, 陽イオン) m/z: 478.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.60 (d, J = 6.6 Hz, 1H), 8.01 (s, 1 H), 7.59 - 7.45 (m, 4 H), 7.44 - 7.39 (m, 2 H), 7.35 (d, J = 7.7 Hz, 2 H), 6.54 (s, 1 H), 6.05 (s, 2 H), 4.99 - 4.95 (m, 1 H), 2.69 (s, 3 H), 2.12 (s, 3 H), 1.47 (d, J = 6.8 Hz, 3 H).
(S)-3-(1-((6-アミノ-5-(5-メチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-4-イル)アミノ)エチル)-2-フェニル-8-(プロパ-1-イン-1-イル)イソキノリン-1(2H)-オン
MS (ESI, 陽イオン) m/z: 478.3 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.22 (d, J = 6.4 Hz, 1 H), 7.99 (s, 1 H), 7.56 - 7.55 (d, J = 6.7 Hz, 1 H), 7.53 - 7.43 (m, 3 H), 7.41 - 7.32 (m, 4 H), 6.55 (s, 1 H), 5.01 - 4.93 (m, 1 H), 2.71 (s, 3 H), 2.12 (s, 3 H), 1.46 (d, J = 6.7 Hz, 3 H).
(S)-3-(1-((6-アミノ-5-(1-メチル-1H-1,2,4-トリアゾール-3-イル)ピリミジン-4-イル)アミノ)エチル)-2-フェニル-8-(プロパ-1-イン-1-イル)イソキノリン-1(2H)-オン
MS (ESI, 陽イオン) m/z: 477.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 9.08 (d, J = 6.6 Hz, 1 H), 8.08 (s, 1 H), 7.91 (s, 1 H), 7.53 (d, J = 7.0 Hz, 1 H), 7.50 - 7.43 (m, 2 H), 7.41 (d, J = 7.2 Hz, 1 H), 7.38 - 7.29 (m, 4 H), 6.56 (s, 1 H), 4.99 - 4.88 (m, 1 H), 3.99 (s, 3 H), 2.10 (s, 3 H), 1.44 (d, J = 6.7 Hz, 3 H).
(S)-3-(1-((6-アミノ-5-(2-メチル-2H-テトラゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-2-フェニル-8-(プロパ-1-イン-1-イル)イソキノリン-1(2H)-オン
MS (ESI, 陽イオン) m/z: 478.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.47 (d, J = 6.5 Hz, 1 H), 7.98 (s, 1 H), 7.53 (t, J = 6.8 Hz, 1 H), 7.47 (d, J = 8.0 Hz, 2 H), 7.45 - 7.40 (m, 1 H), 7.40 - 7.30 (m, 4 H), 6.54 (s, 1 H), 5.03 - 4.94 (m, 1 H), 4.46 (s, 3 H), 2.10 (s, 3 H), 1.46 (d, J = 6.7 Hz, 3 H).
(S)-2-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-3-シクロプロピル-5-(3-ヒドロキシプロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
DMAC(18mL)中の(S)-tert-ブチル(1-(5-クロロ-3-シクロプロピル-4-オキソ-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(2.83g、7.78mmol)(WO2015042077における実施例33の工程1~3の合成方法を参照)及び炭酸セシウム(3.76g、11.5mmol)の混合物に、二酢酸パラジウム(86.8mg、0.39mmol)、X-phos(367.0mg、0.77mmol)をN2雰囲気下で添加し、次いでヘプタン中のプロパ-1-イン(40.0mL、21mmol)を添加した。反応物を密封管内にて110℃で5時間撹拌し、次いで室温まで冷却し、EtOAc(200mL)で希釈し、セライトパッドに通して濾過した。濾液を水(200mL×5)で洗浄し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=1/3)により精製して、表題化合物を薄黄色固体(970mg、34%)として得た。
MS(ESI、陽イオン)m/z:368[M+H]+;
EtOAc(10mL)中の(S)-tert-ブチル(1-(3-シクロプロピル-4-オキソ-5-(プロパ-1-イン-1-イル)-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(970.0mg、2.64mmol)の溶液に、濃塩化水素(36%、2.5mL)を添加した。得られた溶液を室温で0.5時間撹拌し、次いでH2O(30mL)及びEtOAc(10mL)で希釈した。有機層を分離し、水性相をNaHCO3粉末でpH=8.5に塩基性化し、次いでCH2Cl2(30mL×3)で抽出した。合わせた有機相を飽和ブライン(20mL)で洗浄し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(MeOH/CH2Cl2(v/v)=1/10)により精製して、表題化合物を黄色固体(110mg、16%)として得た。
MS (ESI, 陽イオン) m/z: 268.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.57-7.48 (m, 3H), 4.75 (q, J = 6.8 Hz, 1H), 2.93-2.87 (m, 1H), 2.20 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H), 1.39- 1.28 (m, 2H), 0.99-0.86 (m, 2H).
(S)-2-(1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)エチル)-3-シクロプロピル-5-(3-ヒドロキシプロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 443.2 [M + H]+;
1H NMR (600 MHz, CDCl3) δ (ppm): 8.61 (d, J = 7.2 Hz, 1H), 8.15 (s, 1H), 7.56 - 7.55 (m, 1H), 7.50 - 7.49 (m, 2H), 6.32 - 6.27 (m, 1H), 3.05 - 3.02 (m, 1H), 2.72 (s, 3H), 2.19 (s, 3H), 1.61 (d, J = 6.6 Hz, 3H), 1.44 - 1.40 (m, 2H), 1.08 - 1.05 (m, 1H), 1.00 - 0.96 (m, 1H).
13C NMR (150 MHz, CDCl3) δ (ppm): 162.9, 162.2, 160.8, 160.7, 160.3, 158.9, 158.1, 147.6, 133.3, 133.0, 126.4, 123.9, 121.0, 92.9, 81.3, 79.1, 47.7, 26.7, 21.1, 11.3, 10.7, 10.3, 5.3.
(S)-3-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-2-シクロプロピル-8-(プロパ-1-イン-1-イル)イソキノリン-1(2H)-オン
DMSO(10mL)中の(S)-3-(1-アミノエチル)-8-クロロ-2-シクロプロピルイソキノリン-1(2H)-オン(610mg、2.32mmol)(WO2015042078における実施例4の工程1~4の合成方法を参照)、炭酸セシウム(915mg、2.80mmol)、ジクロロビス(トリシクロヘキシルホスフィン)-パラジウム(II)(172mg、0.23mmol)の懸濁液に、ヘプタン中プロピンの溶液(24mL、13mmol、3質量%)をN2雰囲気下で添加した。得られた溶液を密封管(50mL)に入れ、120℃で4時間撹拌した。次いで、混合物を室温まで冷却し、EtOAc(20mL)で希釈し、セライトのパッドで濾過し、EtOAc(10mL×2)で洗浄した。濾液をH2O(15mL×3)及び飽和NaCl(20mL)で洗浄し、Na2SO4で乾燥させ、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(DCM/MeOH(v/v)=30/1)により精製して、表題化合物を黄色固体(560mg、90%)として得た。
MS (ESI, 陽イオン) m/z: 267.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.44 (d, J = 7.4 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.50 (s, 1H), 4.73 (q, J = 6.5 Hz, 1H), 2.97 - 2.77 (m, 1H), 2.15 (s, 3H), 1.37 (d, J = 6.5 Hz, 3H), 1.28 - 1.19 (m, 2H), 0.88 - 0.76 (m, 2H).
n-ブタノール(4mL)中の(S)-3-(1-アミノエチル)-2-シクロプロピル-8-(プロパ-1-イン-1-イル)イソキノリン-1(2H)-オン(120mg、0.45mmol)、6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)-ピリミジン-4-アミン(114.5mg、0.54mmol)及びDIPEA(76mg、58.8mmol)の懸濁液を、120℃で2時間加熱した。次いで、混合物を室温まで冷却し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(MeOH/DCM(v/v)=1/100)により精製して、表題化合物を淡黄色固体(10mg、5%)として得た。
MS (ESI, 陽イオン) m/z: 442.3 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm) 8.44 (d, J = 6.7 Hz, 1H), 8.13 (s, 1H), 7.48 (d, J = 6.7 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.37 (s, 1H), 6.14 (p, J = 6.8 Hz, 1H), 2.97 (ddd, J = 11.2, 6.9, 4.2 Hz, 1H), 2.48 (s, 3H), 2.20 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.28 - 1.19 (m, 2H), 0.96 - 0.83 (m, 2H).
13C NMR (100 MHz, CDCl3) δ (ppm): 173.3, 165.6, 163.7, 161.4, 159.8, 159.4, 148.2, 137.4, 133.5, 130.9, 125.1, 124.6, 102.2, 92.3, 81.9, 80.0, 46.7, 29.7, 27.1, 21.6, 11.5, 10.6, 5.3.
(S)-3-(1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)エチル)-2-シクロプロピル-8-(プロパ-1-イン-1-イル)イソキノリン-1(2H)-オン
MS (ESI, 陽イオン) m/z: 442.3 [M+H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.74 (d, J = 6.7 Hz, 1H), 8.11 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 6.40 (s, 1H), 6.22 - 6.13 (m, 1H), 3.04 - 2.96 (m, 1H), 2.69 (s, 3H), 2.21 (s, 3H), 1.64 (d, J = 6.7 Hz, 3H), 1.46 - 1.41 (m, 2H), 0.86 - 0.81 (m, 2H).
13C NMR (100 MHz, CDCl3) δ (ppm): 163.7, 162.8, 160.8, 159.8, 158.9, 158.4, 148.3, 137.5, 133.4, 130.9, 125.1, 124.5, 102.3, 92.2, 81.1, 80.1, 46.7, 29.7, 27.1, 21.7, 11.0, 10.6, 5.3.
(S)-3-(1-((6-アミノ-5-(5-メチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-4-イル)アミノ)エチル)-2-シクロプロピル-8-(プロパ-1-イン-1-イル)イソキノリン-1(2H)-オン
MS (ESI, 陽イオン) m/z: 442.2 [M+H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.38 (d, J = 6.8 Hz, 1H), 8.12 (s, 1H), 7.50 (d, J = 7.0 Hz, 1H), 7.41 (dd, J = 13.8, 6.2 Hz, 1H), 7.25 (d, J = 7.4 Hz, 1H), 6.41 (s, 1H), 6.21 - 6.09 (m, 1H), 3.08 - 2.88 (m, 1H), 2.72 (s, 3H), 2.21 (d, J = 9.8 Hz, 3H), 1.62 (t, J = 8.1 Hz, 3H), 1.28 - 1.19 (m, 2H), 0.96 - 0.83 (m, 2H).
13C NMR (100 MHz, CDCl3) δ (ppm): 174.5, 165.9, 163.9, 161.3, 159.5, 158.3, 148.6, 137.5, 133.5, 131.0, 125.3, 125.0, 124.6, 102.3, 92.3, 82.4, 80.2, 46.7, 27.1, 22.7, 21.6, 14.1, 12.4, 5.4.
(S)-2-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)プロピル)-3-シクロプロピル-5-(プロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
DMAC(8mL)中の(S)-tert-ブチル(1-(5-クロロ-3-シクロプロピル-4-オキソ-3,4-ジヒドロキナゾリン-2-イル)プロピル)カルバメート(1.5g、4.0mmol)(WO2015042077における実施例2の工程1~4の合成方法を参照)の懸濁液に、炭酸カリウム(0.83g、5.9mmol)、X-Phos(0.19g、0.4mmol)、10%Pd/C(0.42g)及びヘプタン中3%プロパ-1-イン(27g、20.2mmol)を添加した。反応物を窒素で脱気した。110℃で終夜撹拌した後、反応混合物をCH2Cl2(30mL)で希釈し、濾過した。濾液をH2O(15mL×6)及びブライン(15mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=1/6)により精製して、表題化合物を黄色固体(1.15g、76%)として得た。
MS(ESI、陽イオン)m/z:382.1[M+H]+;
ジオキサン(20mL)中の(S)-tert-ブチル(1-(3-シクロプロピル-4-オキソ-5-(プロパ-1-イン-1-イル)-3,4-ジヒドロキナゾリン-2-イル)プロピル)カルバメート(1.15g、3mmol)の懸濁液に、濃HCl(2mL)を添加した。35℃で3時間撹拌した後、反応混合物を真空中で濃縮した。残留物をCH2Cl2(50mL)で希釈し、5M NaOHでpH=10に中和した。水相をCH2Cl2(50mL×3)で抽出した。合わせた有機層をブライン(100mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮して、表題化合物を黄色固体(0.8g、94%)として得た。
MS(ESI、陽イオン)m/z:282.3[M+H]+。
n-ブタノール(2mL)中の(S)-2-(1-アミノプロピル)-3-シクロプロピル-5-(プロパ-1-イン-1-イル)キナゾリン-4(3H)-オン(133mg、0.47mmol)の懸濁液に、6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-アミン(100mg、0.47mmol)及びDIPEA(0.17mL、0.97mmol)を添加した。110℃で終夜撹拌した後、反応混合物を室温まで冷却し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(MeOH/CH2Cl2(v/v)=1/400)により精製して、表題化合物を黄色固体(85mg、39%)として得た。
MS (ESI, 陽イオン) m/z: 457.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 9.00 (d, J = 7.8 Hz, 1H), 8.15 (s, 1H), 7.60 - 7.46 (m, 3H), 6.37 - 6.27 (m, 1H), 3.09 - 3.00 (m, 1H), 2.52 (s, 3H), 2.20 (s, 3H), 2.15 - 2.02 (m, 1H), 2.03 - 1.90 (m, 1H), 1.16 - 1.08 (m, 1H), 1.03 - 0.92 (m, 4H), 0.91 - 0.81 (m, 2H).
(S)-2-(1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)プロピル)-3-シクロプロピル-5-(プロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 457.1 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.51 (d, J = 7.8 Hz, 1H), 8.16 (s, 1H), 7.59 - 7.49 (m, 3H), 6.59 (s, 2H), 6.35 (dd, J = 13.1, 7.4 Hz, 1H), 3.10 - 3.05 (m, 1H), 2.74 (s, 3H), 2.22 (s, 3H), 2.13 - 1.95 (m, 2H), 1.32 - 1.25 (m, 1H), 1.17 - 1.13 (m, 1H), 1.02 (t, J = 7.4 Hz, 3H), 0.98 - 0.96 (m, 1H), 0.92 - 0.86 (m, 1H).
(S)-2-(1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)プロピル)-3-シクロプロピル-5-(3-ヒドロキシプロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
DMAC(8mL)中の(S)-tert-ブチル(1-(5-クロロ-3-シクロプロピル-4-オキソ-3,4-ジヒドロキナゾリン-2-イル)プロピル)カルバメート(1.5g、4.0mmol)の溶液に、炭酸カリウム(0.83g、5.9mmol)、X-Phos(0.19g、0.39mmol)、10%Pd/C(0.42g)及びプロパ-2-イン-1-オール(1.2mL、20mmol)を窒素雰囲気下で添加した。110℃で終夜撹拌した後、反応混合物をCH2Cl2(30mL)で希釈し、濾過した。濾液をH2O(15mL×6)及びブライン(15mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=1/4)により精製して、表題化合物を黄色油状物(1.66g、100%)として得た。
MS(ESI、陽イオン)m/z:398.2[M+H]+。
1,4-ジオキサン(20mL)中の(S)-tert-ブチル(1-(3-シクロプロピル-5-(3-ヒドロキシプロパ-1-イン-1-イル)-4-オキソ-3,4-ジヒドロキナゾリン-2-イル)プロピル)カルバメート(1.66g、4.2mmol)の懸濁液に、濃HCl(2mL)を添加した。30℃で2時間撹拌した後、反応混合物を真空中で濃縮した。残留物をCH2Cl2(50mL)で希釈し、5M NaOHでpH=10に中和した。水相をCH2Cl2(50mL×3)で抽出した。合わせた有機層をブライン(100mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮して、表題化合物を黄色油状物(0.94g、76%)として得た。
MS(ESI、陽イオン)m/z:298.1[M+H]+。
n-ブタノール(3mL)中の(S)-2-(1-アミノプロピル)-3-シクロプロピル-5-(3-ヒドロキシプロパ-1-イン-1-イル)キナゾリン-4(3H)-オン(200mg、0.67mmol)の懸濁液に、6-クロロ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-アミン(114mg、0.54mmol)及びDIPEA(0.24mL、1.4mmol)を添加した。110℃で終夜撹拌した後、反応混合物を室温まで冷却し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(MeOH/CH2Cl2(v/v)=1/400)により精製して、表題化合物を黄色固体として得た。(58mg、18%)。
MS (ESI, 陽イオン) m/z: 473.1 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.58 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.63 - 7.54 (m, 3H), 6.54 (s, 2H), 6.35 (dd, J = 12.9, 7.4 Hz, 1H), 4.62 (s, 2H), 3.75 (q, J = 7.0 Hz, 1H), 3.12 - 3.06 (m, 1H), 2.74 (s, 3H), 2.14 - 1.96 (m, 2H), 1.28 - 1.27 (m, 1H), 1.19 - 1.16 (m, 1H), 1.04 (t, J = 7.4 Hz, 3H), 0.98 - 0.94 (m, 1H), 0.92 - 0.88 (m, 1H).
(S)-2-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)プロピル)-3-シクロプロピル-5-(3-ヒドロキシプロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 473.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.97 (d, J = 7.5 Hz, 1H), 8.17 (s, 1H), 7.62 - 7.61 (m, 2H), 7.56 (dd, J = 8.7, 4.5 Hz, 1H), 6.34 (dd, J = 12.7, 7.4 Hz, 1H), 5.84 (s, 2H), 4.63 (s, 2H), 3.11 - 3.06 (m, 1H), 2.54 (s, 3H), 2.17 - 1.94 (m, 2H), 1.31 - 1.28 (m, 1H), 1.19 - 1.16 (m, 1H), 1.03 (t, J = 7.4 Hz, 3H), 0.98 - 0.93 (m, 1H), 0.88 - 0.85 (m, 1H).
(S)-2-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-3-シクロプロピル-5-(3-ヒドロキシプロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
DMAC(23mL)中の(S)-tert-ブチル(1-(5-クロロ-3-シクロプロピル-4-オキソ-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(2.45gg、6.73mmol)の溶液に、10%Pd/C(0.73g)、X-phos(0.65g、1.36mmol)及び炭酸カリウム(1.91g、13.74mmol)をN2雰囲気下で添加した。次いで、混合物にプロパ-2-イン-1-オール(2.4mL、41.0mmol)を添加し、反応物を110℃で20時間撹拌した。混合物を室温まで冷却し、EtOAc(100mL)で希釈し、セライトパッドに通して濾過した。濾液を水(200mL×4)、及び飽和ブライン(200mL)で洗浄し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=3/2)により精製して、表題化合物を黄色固体(250mg、10%)として得た。
MS(ESI、陽イオン)m/z:384.3[M+H]+;
EtOAc(5mL)中の(S)-tert-ブチル(1-(3-シクロプロピル-5-(3-ヒドロキシプロパ-1-イン-1-イル)-4-オキソ-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(0.25g、0.65mmol)の溶液に、濃塩化水素(36%、0.55mL)を添加した。得られた溶液を室温で1時間撹拌し、次いでH2O(20mL)及びEtOAc(20mL)で希釈した。有機層を分離し、水性相をNaHCO3粉末でpH=8.5に塩基性化し、CH2Cl2(30mL×3)で抽出した。合わせた有機相を飽和NaCl(20mL)で洗浄し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(MeOH/CH2Cl2(v/v)=3/100)により精製して、表題化合物を黄色固体(98mg、53%)として得た。
MS (ESI, 陽イオン) m/z: 284.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.60 - 7.49 (m, 3H), 4.77 (q, J = 6.4 Hz, 1H), 4.58 (s, 2H), 2.88 - 2.85 (m, 1H), 1.45 - 1.44 (d, J = 6.4 Hz, 3H), 1.33 - 1.28 (m, 2H), 0.93 - 0.82 (m, 2H).
n-ブタノール(1mL)中の(S)-2-(1-アミノエチル)-3-シクロプロピル-5-(3-ヒドロキシプロパ-1-イン-1-イル)キナゾリン-4(3H)-オン(34.0mg、0.12mmol)、6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-アミン(30.3mg、0.143mmol)及びDIPEA(23.0mg、0.17mmol)の混合物を、120℃に2時間加熱した。混合物を室温まで冷却し、真空中で濃縮した。残留物を分取TLC(MeOH/CH2Cl2(v/v)=1/25)により精製して、表題化合物を薄黄色固体(20.7mg、38%)として得た。
MS (ESI, 陽イオン) m/z: 459.2 [M + H]+;
1H NMR (600 MHz, CDCl3) δ (ppm): 9.098 (d, J = 6.6 Hz, 1H), 8.15 (s, 1H), 7.60 - 7.58 (m, 2H), 7.53 (d, J = 6.0 Hz, 1H), 6.29 - 6.25 (m, 1H), 5.85 (bs, 1H), 4.60 (s, 2H), 3.05 (m, 1H), 2.52 (s, 3H), 1.64 (d, J = 6.6 Hz, 3H), 1.42 (m, 2H), 1.10 - 1.09 (m, 1H), 0.97 - 0.96 (m, 1H).
13C NMR (150 MHz, CDCl3) δ (ppm): 173.3, 165.6, 162.1, 161.5, 160.1, 159.6, 158.8, 147.6, 133.1, 133.0, 127.5, 122.2, 120.8, 93.9, 84.8, 82.0, 51.8, 47.7, 26.6, 20.8, 11.6, 10.6, 10.2.
(S)-2-(1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)エチル)-3-シクロプロピル-5-(3-ヒドロキシプロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 459.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.63 (d, J = 7.2 Hz, 1H), 8.16 (s, 1H), 7.57 - 7.52 (m, 3H), 6.34-6.28 (m, 1H), 4.60 (s, 2H), 3.09-3.03 (m, 1H), 2.73 (s, 3H), 2.51 (br.s, 1H), 1.63 (d, J = 6.8 Hz, 3H), 1.44 - 1.41 (m, 2H), 1.12 - 1.08 (m, 1H), 0.99 - 0.94 (m, 1H).
(S)-2-(1-((6-アミノ-5-(1-メチル-1H-1,2,4-トリアゾール-3-イル)ピリミジン-4-イル)アミノ)エチル)-3-シクロプロピル-5-(3-ヒドロキシプロパ-1-イン-1-イル)キナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 458.3 [M + H]+;
1H NMR (600 MHz, CDCl3) δ (ppm): 9.45 (d, J = 7.2 Hz, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.56 - 7.54 (m, 2H), 7.51 - 7.49 (m, 1H), 6.34 - 6.29 (m, 1H), 4.59 (s, 2H), 4.03 (s, 3H), 3.11 - 3.07 (m,1H), 1.65 (d, J = 6.6 Hz, 3H), 1.41 - 1.38 (m, 2H), 1.19 - 1.15 (m, 1H), 0.94 - 0.91 (m, 1H).
13C NMR (150 MHz, CDCl3) δ (ppm): 162.4, 161.4, 160.5, 160.3, 158.8, 156.6, 148.1, 141.9, 132.9, 132.8, 127.5, 122.3, 121.1, 93.8, 86.2, 85.2, 52.0, 47.7, 36.5, 26.9, 20.9, 10.5, 10.4.
(S)-3-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)-ピリミジン-4-イル)アミノ)エチル)-2-シクロプロピル-8-(3-ヒドロキシプロパ-1-イン-1-イル)-イソキノリン-1(2H)-オン
DMSO(20mL)中の(S)-tert-ブチル(1-(8-クロロ-2-シクロプロピル-1-オキソ-1,2-ジヒドロイソキノリン-3-イル)エチル)カルバメート(500mg、1.90mmol)、炭酸セシウム(748mg、2.30mmol)及びジクロロビス(トリシクロヘキシルホスフィン)-パラジウム(II)(143mg、0.19mmol)の懸濁液に、プロパ-2-イン-1-オール(0.4mL、7mmol)を、N2雰囲気下で添加した。得られた混合物を50mLの密封管内にて120℃で2時間撹拌し、次いで室温に冷却し、EtOAc(40mL)で希釈し、セライトのパッドに通して濾過し、EtOAc(10mL×3)で洗浄した。濾液をH2O(20mL×3)及び飽和ブライン(20mL)で洗浄し、Na2SO4で乾燥させ、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(MeOH/DCM(v/v)=1/30)により精製して、表題化合物を黄色固体(81mg、15%)として得た。
MS (ESI, 陽イオン) m/z: 283.2[M+H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.46 (t, J = 6.4 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 6.59 (s, 1H), 4.85 - 4.79 (m, 1H), 4.58 (s, 1H), 3.07 - 2.99 (m, 1H), 1.46 (d, J = 6.5 Hz, 2H), 1.35 - 1.26 (m, 2H), 0.86 - 0.78 (m, 2H).
i-PrOH(4mL)中の(S)-3-(1-アミノエチル)-2-シクロプロピル-1-オキソ-1,2-ジヒドロイソキノリン-8-カルボニトリル(43mg、0.14mmol)、6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)-ピリミジン-4-アミン(37.0mg、0.17mmol)、DIPEA(30.0mg、0.21mmol)の懸濁液を、100℃で2時間加熱した。混合物を室温まで冷却し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(MeOH/DCM(v/v)=1/100)により精製して、表題化合物を淡黄色固体(20mg、29%)として得た。
MS (ESI, 陽イオン) m/z: 458.2 [M+H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.45 (d, J = 6.6 Hz, 1H), 8.12 (s, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 6.41 (s, 1H), 6.18 - 6.06 (m, 1H), 4.60 (s, 2H), 3.06 - 2.93 (m, 1H), 2.48 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H), 1.35 - 1.30 (m, 2H), 0.96 - 0.87 (m, 2H).
13C NMR (100 MHz, CDCl3) δ (ppm): 173.3, 165.7, 163.7, 161.4, 159. 8, 159.4, 148.6, 137.5, 133.1, 131.1, 126.0, 125.0, 123.1, 102.3, 93.7, 86.2, 81.9, 52.0, 46.7, 29.7, 27.2, 21.6, 11.5, 10.6.
(S)-2-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-5-(3-ヒドロキシプロパ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
DMAC(8mL)中のtert-ブチル(1-(5-クロロ-4-オキソ-3-フェニル-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(0.99g、2.5mmol)、10%Pd/C(0.27g)、X-phos(0.21g、0.44mmol)、炭酸カリウム(0.52g、32.54mmol)の混合物に、プロパ-2-イン-1-オール(0.3mL、5mmol)をN2雰囲気下で添加した。反応物を115℃で9時間撹拌し、次いで室温まで冷却し、EtOAc(100mL)で希釈し、セライトパッドに通して濾過した。濾液を水(100mL×4)、及び飽和ブライン(100mL)で洗浄し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=3/2)により精製して、表題化合物を薄黄色固体(554mg、53%)として得た。
MS (ESI, 陽イオン) m/z: 420.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.67 (d, J = 4.4 Hz, 2H), 7.60 - 7.49 (m, 4H), 7.38 (d, J = 6.4 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 5.61 (d, J = 7.2 Hz, 1H), 4.50 (d, J = 4.0 Hz, 2H), 4.50 - 4.49 (m, 1H), 2.11 (br.s, 1H), 1.41 (s, 9H), 1.25 (d, J = 6.4 Hz, 3H).
EtOAc(4mL)及びCH2Cl2(4mL)中の(S)-tert-ブチル(1-(5-(3-ヒドロキシプロパ-1-イン-1-イル)-4-オキソ-3-フェニル-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(0.55g、1.31mmol)の溶液に、塩化水素(36%、1mL)を添加した。得られた溶液を室温で1時間撹拌し、次いで真空中で濃縮した。残留物をH2O(20mL)及びEtOAc(20mL)で希釈した。有機層を分離し、水性層をNaHCO3粉末でpH=8.5に塩基性化し、次いでCH2Cl2(20mL×3)で抽出した。合わせた有機相を飽和ブライン(20mL)で洗浄し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(MeOH/CH2Cl2(v/v)=3/200)により精製して、表題化合物を薄黄色固体(237mg、56%)として得た。
MS (ESI, 陽イオン) m/z: 320.4 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.66 - 7.65 (m, 2H), 7.57 - 7.49 (m, 4H), 7.27 - 7.24 (m, 2H), 4.48 (s, 2H), 3.65 (q, J = 6.4 Hz, 1H), 1.91 (br, s, 3H), 1.25 (d, J = 6.4 Hz, 3H).
n-ブタノール(1mL)中の(S)-2-(1-アミノエチル)-5-(3-ヒドロキシプロパ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン(42.5mg、0.13mmol)、6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-アミン(31.2mg、0.15mmol)及びDIPEA(34.6mg、0.27mmol)の混合物を、120℃に2時間加熱した。次いで、混合物を室温まで冷却し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(MeOH/CH2Cl2(v/v)=1/50)により精製して、表題化合物を薄黄色固体(26.8mg、47%)として得た。
MS (ESI, 陽イオン) m/z: 495.2 [M + H]+;
1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.21 (d, J = 6.4 Hz, 1H), 7.98 (s, 1H), 7.82 (dd, J = 8.0, 7.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.59 - 7.54 (m, 8H), 5.27 (t, J = 6.0 Hz, 1H), 4.96 - 4.89 (m, 1H), 4.29 (d, J = 6.0 Hz, 2H), 2.50 (s, 3H), 1.36 (d, J = 6.4 Hz, 3H).
13C NMR (100 MHz, DMSO-d6) δ (ppm): 172.8, 165.2, 161.1 , 159.7, 159.3, 158.3, 158.0, 147.7, 136.2, 133.9, 132.7, 129.5, 129.3, 129.2, 128.8, 127.1, 122.3, 120.4, 95.5, 82.7, 80.2, 49.7, 48.3, 20.1, 11.1.
(S)-2-(1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)エチル)-5-(3-ヒドロキシプロパ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 495.3 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.51 (d, J = 6.8 Hz, 1H), 8.00 (s, 1H), 7.65 - 7.64 (m, 2H), 7.59 - 7.51 (m, 4H), 7.44 - 7.43 (m, 1H), 7.34 - 7.32 (m, 1H), 6.39 (br.s, 2H), 5.15 - 5.08 (m, 1H), 4.49 (s, 2H), 4.49 (s, 15H), 2.71 (s, 3H), 2.71 (br.s, 1H),1.45 (d, J = 6.8 Hz, 3H).
13C NMR (150 MHz, CDCl3) δ (ppm): 162.9, 161.4, 160.9, 160.4, 158.7, 158.6, 158.1, 148.4, 136.1, 133.6, 133.3, 130.1, 129.8, 129.8, 128.9, 127.9, 122.9, 121.0, 94.1, 84.8, 81.3, 51.9, 48.7, 20.5, 11.3.
(S)-2-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)プロピル)-5-(3-ヒドロキシプロパ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
DMAC(3mL)中の(S)-tert-ブチル(1-(5-クロロ-4-オキソ-3-フェニル-3,4-ジヒドロキナゾリン-2-イル)プロピル)カルバメート(0.60g、1.4mmol)の懸濁液に、炭酸カリウム(0.3g、2mmol)、X-Phos(71mg、0.15mmol)、10%Pd/C(0.15g)及びプロパ-2-イン-1-オール(0.42mL、7.2mmol)を添加した。反応物を窒素で脱気した。110℃で終夜撹拌した後、反応混合物をCH2Cl2(20mL)で希釈し、次いで濾過した。濾液をH2O(6mL×6)及び飽和ブライン(6mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=1/6)により精製して、表題化合物を黄色固体(0.32g、51%)として得た。
MS(ESI、陽イオン)m/z:434.2[M+H]+。
ジオキサン(5mL)中の(S)-tert-ブチル(1-(5-(3-ヒドロキシプロパ-1-イン-1-イル)-4-オキソ-3-フェニル-3,4-ジヒドロキナゾリン-2-イル)プロピル)カルバメート(0.32g、0.75mmol)の懸濁液に、濃HCl(0.5mL)を添加した。35℃で2時間撹拌した後、反応混合物を真空中で濃縮した。残留物をCH2Cl2(20mL)で希釈し、5M NaOHでpH=10に中和した。水相をCH2Cl2(20ml×3)で抽出した。合わせた有機層を飽和ブライン(50mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮して、表題化合物を黄色固体(0.31g、100%)として得た。
MS(ESI、陽イオン)m/z:334.1[M+H]+。
n-ブタノール(2.5mL)中の(S)-2-(1-アミノプロピル)-5-(3-ヒドロキシプロパ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン(0.16g、0.46mmol)の懸濁液に、6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-l)ピリミジン-4-アミン(0.11g、0.51mmol)及びDIPEA(0.2mL、1.1mmol)を添加した。110℃で終夜撹拌した後、反応混合物を室温まで冷却し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(MeOH/CH2Cl2(v/v)=1/200)により精製して、表題化合物を黄色固体(33mg、14%)として得た。
MS (ESI, 陽イオン) m/z: 509.1 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.72 (d, J = 7.2 Hz, 1H), 8.03 (s, 1H), 7.70 - 7.65 (m, 2H), 7.61 - 7.54 (m, 4H), 7.47 (d, J = 6.2 Hz, 1H), 7.37 (d, J = 9.4 Hz, 1H), 5.73 (s, 2H), 5.14 - 5.09 (m, 1H), 4.53 (s, 2H), 2.54 (s, 3H), 2.19 (s, 1H), 1.98 - 1.77 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)プロピル)-5-(3-ヒドロキシプロパ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 509.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 8.45 (d, J = 7.6 Hz, 1H), 8.02 (s, 1H), 7.67 - 7.65 (m, 2H), 7.62 - 7.54 (m, 4H), 7.47 (d, J = 7.1 Hz, 1H), 7.35 (dd, J = 7.2, 2.0 Hz, 1H), 6.33 (s, 2H), 5.13 - 5.08 (m, 1H), 4.52 (s, 2H), 2.73 (s, 3H), 2.19 (s, 1H), 1.97 - 1.77 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(5-メチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-4-イル)アミノ)エチル)-5-(3-ヒドロキシプロパ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
MS(ESI, 陽イオン) m/z: 495.2 [M + H]+.
1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.95 (d, J = 6.6 Hz, 1H), 7.96 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.63 - 7.53 (m, 6H), 7.50 (s, 2 H), 5.28 - 5.26 (m, 1H), 4.95 - 4.85 (m, 1 H), 4.30 (d, J = 5.9 Hz, 2 H), 2.77 (s, 3 H), 1.37 (d, J = 6.6 Hz, 3 H).
(S)-2-(1-((6-アミノ-5-(2-メチル-2H-テトラゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-5-(3-ヒドロキシプロパ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 495.2 [M + H]+;
1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.98 (d, J = 6.7 Hz, 1H), 7.97 (s, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.63 - 7.53 (m, 6H), 7.48 (s, 2 H), 5.28 (t, J = 5.9 Hz, 1 H), 4.98 - 4.88 (m, 1H), 4.55 (s, 3H), 4.30 (d, J = 5.9 Hz, 2H), 1.39 (d, J = 6.6 Hz, 3H).
(S)-3-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-8-(3-ヒドロキシプロパ-1-イン-1-イル)-2-フェニルイソキノリン-1(2H)-オン
-30℃で、乾燥THF(81mL)中の2-クロロ-6-メチル-N-フェニル-ベンズアミド(10.0g、40.70mmol)の懸濁液に、n-BuLi(50mL、120mmol、ヘキサン中2.4mol/L)を30分間かけて滴下添加した。添加後、混合物を-30℃で1.5時間撹拌して、赤褐色溶液(i)を得、これを次の工程で直接使用した。
メタノール(112mL)中のtert-ブチル(S)-(4-(3-クロロ-2-(フェニルカルバモイル)フェニル)-3-オキソブタン-2-イル)カルバメート(17.0g、40.8mmol)の懸濁液に、濃HCl溶液(112mL、36%)を添加した。混合物を加熱還流し、終夜撹拌した。次いで、混合物を室温まで冷却し、真空中で濃縮した。残留物をPE/EtOAc(200mL/100mL)及び水(200mL)で希釈した。水性層をPE/EA(100mL/50mL)で洗浄し、次いでNa2CO3粉末でPH=10に調整し、DCM(200mL×3)で抽出した。合わせた有機層を飽和NaCl(300mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮して、表題化合物を黄色固体(9.2g、76%)として得た。
MS (ESI, 陽イオン)m/z: 282.1 [M - NH3 + H]+;
1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.67 - 7.60 (m, 2 H), 7.59 - 7.52 (m, 2 H), 7.52 - 7.43 (m, 2 H), 7.38 - 7.31 (m, 2 H), 6.92 (s, 1 H), 3.53 - 3.33 (m, 1 H), 1.08 (d, J = 6.5 Hz, 3 H).
DMAC(10mL)中の(S)-3-(1-アミノエチル)-8-クロロ-2-フェニルイソキノリン-1(2H)-オン(1.5g、5.0mmol)の懸濁液に、Cs2CO3(2.5g、7.7mmol)、PdCl2(PCy3)2(375mg、0.51mmol)を添加した。混合物をN2でパージし、次いでプロパ-2-イン-1-オール(0.85g、15.0mmol)を添加した。混合物を密封し、110℃に加熱し、5.5時間撹拌した。混合物を室温まで冷却し、EtOAc(150mL)及び水(30mL)を添加した。有機層を分離し、飽和NaCl(50mL×5)で洗浄し、Na2SO4で乾燥させ、濾過し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(PE/EtOAc/TEA(v/v/v)=1/10/0.5)により精製して、表題化合物を黄色固体(805mg、53%)として得た。
MS (ESI, 陽イオン) m/z: 319.2 [M + H]+;
1H NMR (600 MHz, CDCl3) δ (ppm): 7.60 - 7.48 (m, 4 H), 7.50 - 7.46 (dd, J = 15.3, 7.9 Hz, 2 H), 7.42 - 7.41 (d, J = 7.7 Hz, 1 H), 7.34 - 7.33 (d, J = 7.4 Hz, 1 H), 6.76 (s, 1 H), 3.77 - 3.69 (m, 1 H), 2.13 (s, 3 H), 1.30 (d, J = 6.5 Hz, 3 H).
13C NMR (151 MHz, CDCl3) δ (ppm): 162.5, 138.0, 134.1, 131.6, 129.8, 129.7, 129.4, 129.0, 128.9, 125.6, 125.1, 124.7, 102.3, 92.8, 79.9, 46.9, 23.0, 5.4.
n-BuOH(1.5mL)中の(S)-3-(1-アミノエチル)-8-(3-ヒドロキシプロパ-1-イン-1-イル)-2-フェニルイソキノリン-1(2H)-オン(40mg、0.13mmol)及び6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-アミン(30mg、0.14mmol)の懸濁液に、DIPEA(0.05mL)を添加した。混合物を80℃で6時間撹拌し、次いで室温まで冷却し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(DCM/MeOH/TEA(v/v/v)=100/1/0.5)により精製して、表題化合物をオフホワイトの固体(12mg、23%)として得た。
MS (ESI, 陽イオン) m/z: 494.3 [M + H]+;
1H NMR (600 MHz, DMSO-d6) δ (ppm): 8.38 (d, J = 6.4 Hz, 1 H), 7.98 (s, 1 H), 7.66 - 7.60 (m, 2 H), 7.56 - 7.50 (m, 2 H), 7.43 - 7.41(m, 4 H), 6.73 (s, 1 H), 4.78- 4.72 (m, 1 H), 4.28 (d, J = 5.9 Hz, 2 H), 2.44 (s, 3 H), 1.41(d, J = 6.8 Hz, 3 H).
13C NMR (151 MHz, DMSO-d6) δ (ppm): 173.4, 165.7, 161.5, 161.3, 159.7, 159.0, 147.8, 138.6, 138.3, 133.5, 132.4, 130.0, 129.7, 129.6, 129.3, 128.8, 127.0 124.3, 123.4, 101.6, 95.6, 84.4, 81.0, 50.3, 47.6, 20.9, 11.6.
(S)-3-(1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)エチル)-8-(3-ヒドロキシプロパ-1-イン-1-イル)-2-フェニルイソキノリン-1(2H)-オン
MS (ESI, 陽イオン)m/z: 494.3 [M + H]+;
1H NMR (600 MHz, CD3OD) δ (ppm): 8.70 (d, J = 5.7 Hz, 1 H), 7.92 (s, 1 H), 7.58 - 7.50 (m, 3H), 7.48 - 7.36 (m, 5 H), 6.67 (s, 1 H), 5.02 - 4.91 (m, 1 H), 4.40 (s, 2 H), 2.67 (s, 3 H), 1.46 (d, J = 5.5 Hz, 3 H).
13C NMR (151 MHz, CD3OD/CDCl3) δ (ppm): 162.8, 162.7, 161.5, 159.6, 158.4, 158.1, 146.6, 138.3, 137.5, 133.6, 131.9, 129.3, 129.3, 129.2, 128.8, 128.8, 126.5, 124.3, 123.5, 103.3, 93.9, 84.8, 50.9, 47.3, 29.6, 20.7, 10.7.
(S)-2-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-6-フルオロ-5-(3-ヒドロキシプロパ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
フラスコに、2-ブロモ-3-フルオロ-6-ニトロ-安息香酸(2.0g、7.6mmol)及びSOCl2(10mL)を添加した。混合物を80℃で5.0時間撹拌し、次いで室温まで冷却し、真空中で濃縮して、黄色液体を得た。液体をDCM(15mL)に溶解し、次いでDCM(10mL)中のTEA(2.5mL、18.0mmol)及びアニリン(0.85mL、9.3mmol)の撹拌溶液中に0℃で添加した。添加後、混合物を0℃で2時間撹拌し続けた。次いで、混合物を真空中で濃縮し、残留物を水(50mL)及びDCM(100mL)に溶解した。水相をDCM(50mL)で抽出した。合わせた有機相を1.0M HCl(100mL)及び飽和NaHCO3水溶液(100mL×2)で洗浄し、無水Na2SO4で乾燥させ、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(PE/EtOAc(v/v)=5/1)により精製して、表題化合物を黄色固体(2.27g、88%)として得た。
MS (ESI, 陽イオン) m/z: 340.1 [M+H]+;
1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.76 (s, 1 H), 8.41 (dd, J = 9.2, 4.5 Hz, 1 H), 7.79 (dd, J = 9.0, 8.0 Hz, 1 H), 7.63 (d, J = 7.8 Hz, 2 H), 7.39 (t, J = 7.9 Hz, 2 H), 7.16 (t, J = 7.4 Hz, 1 H).
エタノール(20mL)中の2-ブロモ-3-フルオロ-6-ニトロ-N-フェニルベンズアミド(2.2g、6.7mmol)の混合物に、Fe粉(1.9g、76.3mmol)、及び水(4.0mL)中のHCOONH4(1.7g、27.0mmol)の溶液を添加した。混合物を90℃で終夜加熱した。混合物を50℃に冷却し、セライトに通して濾過し、濾液を真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=1/5)により精製して、表題化合物を薄桃色固体(1.13g、55%)として得た。
MS(ESI、陽イオン)m/z:310.1[M+H]+;
0℃で、DCM(10mL)中の6-アミノ-2-ブロモ-3-フルオロ-N-フェニルベンズアミド(1.13g、3.66mmol)及び(2S)-2-(tert-ブトキシカルボニルアミノ)プロパン酸(843mg、4.39mmol)の懸濁液に、DIPEA(1.3mL、7.4mmol)及びHATU(1.7g、4.38mmol)を添加し、次いで混合物を45℃で終夜撹拌した。混合物を水(30mL)及びDCM(50mL)で希釈し、水性層をDCM(30mL)で抽出した。合わせた有機層を無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=1/5)により精製して、表題化合物を黄色固体(1.5g、85%)として得た。
MS(ESI、陽イオン)m/z:502.0[M+Na]+。
CH3CN(5mL)中の(S)-tert-ブチル(1-((3-ブロモ-4-フルオロ-2-(フェニルカルバモイル)フェニル)アミノ)-1-オキソプロパン-2-イル)カルバメート(860mg、1.79mmol)の懸濁液に、DIPEA(0.70mL、4.0mmol)、DMAP(219mg、1.79mmol)及びBSA(1.5mL、6.0mmol)を添加した。混合物を密封管に入れ、130℃に26時間加熱した。次いで、混合物を室温まで冷却し、EtOAc(100mL)で希釈し、飽和ブライン(50mL×2)及び1.0M HCl水溶液(50mL)で洗浄した。有機相を無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=1/5)により精製して、表題化合物を黄色固体(630mg、76%)として得た。
MS (ESI, 陽イオン) m/z: 461.8 [M+H]+;
1H NMR (600 MHz, CDCl3) δ (ppm): 7.71 (dd, J = 8.9, 4.9 Hz, 1 H), 7.63 (t, J = 7.1 Hz, 1 H), 7.60 - 7.52 (m, 3 H), 7.42 (d, J = 6.8 Hz, 1 H), 7.30 (d, J = 7.3 Hz, 1 H), 5.55 (d, J = 6.7 Hz, 1 H), 4.53 (m, 1 H), 1.44 (s, 9 H), 1.28 (d, J = 6.7 Hz, 3 H).
DMAC(5.0mL)中の(S)-tert-ブチル(1-(5-ブロモ-6-フルオロ-4-オキソ-3-フェニル-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(530mg、1.14mmol)及びCs2CO3(561mg、1.72mmol)の懸濁液に、PdCl2(PCy3)2(85.0mg、0.12mmol)及びプロパ-2-イン-1-オール(0.2mL、3.0mmol)を添加した。混合物をN2でパージし、密封し、次いで100℃で3.0時間撹拌した。混合物を室温に冷却し、EtOAc(50mL)及び水(10mL)で希釈した。水相をEtOAc(20mL)で抽出した。合わせた有機相を飽和ブライン(10mL×3)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=1/2)により精製して、表題化合物を黄色油状物(93.0mg、19%)として得た。
MS(ESI、陽イオン)m/z:438.1[M+H]+;
EtOAc(1.0mL)中の(S)-tert-ブチル(1-(6-フルオロ-5-(3-ヒドロキシプロパ-1-イン-1-イル)-4-オキソ-3-フェニル-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(93.0mg、0.21mmol)の懸濁液に、EtOAc中HClの溶液(2.0mL、6.0mmol、3.0M)を添加した。混合物を室温で1.0時間撹拌し、次いで反応混合物に水(20mL)及びEtOAc(10mL)を添加した。有機層を分離し、水性層をEtOAc(10mL)で洗浄し、Na2CO3粉末でpH=10に供し、次いでEtOAc(20mL×2)で抽出した。合わせた有機層を無水Na2SO4で乾燥させ、濾過し、真空中で濃縮して、表題化合物を黄色油状物(53mg、74%)として得、これを更に精製することなく次の工程で直接使用した。
MS(ESI、陽イオン)m/z:338.1[M+H]+。
n-BuOH(1.5mL)中の(S)-2-(1-アミノエチル)-6-フルオロ-5-(3-ヒドロキシプロパ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン(53.0mg、0.16mmol)及び6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-アミン(37.0mg、0.18mmol)の懸濁液に、DIPEA(0.06mL、0.4mmol)を添加した。混合物を90℃に加熱し、3.0時間撹拌し、次いで真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(MeOH/DCM(v/v)=1/40)により精製して、表題化合物を淡黄色固体(22mg、27%)として得た。
MS (ESI, 陽イオン) m/z: 513.2 [M + H]+;
1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.19 (d, J = 6.5 Hz, 1 H), 7.99 (s, 1 H), 7.87 (t, J = 9.0 Hz, 1 H), 7.75 (dd, J = 8.9, 5.1 Hz, 1 H), 7.68 - 7.47 (m, 7 H), 4.99 - 4.86 (m, 1 H), 4.34 (d, J = 5.6 Hz, 2 H), 2.51 (s, 3 H), 1.37 (d, J = 6.5 Hz, 3 H).
(S)-2-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-3-シクロプロピル-5-エチニルキナゾリン-4(3H)-オン
DMAC(10mL)中の(S)-tert-ブチル(1-(5-クロロ-3-シクロプロピル-4-オキソ-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(1.04g、2.86mmol)の混合物に、エチニルトリメチルシラン(4.0mL、28.3mmol)、10%Pd/C(0.30g)、X-phos(0.14g、0.29mmol)及び炭酸カリウム(0.60g、4.0mmol)を添加した。混合物を窒素で数回脱気し、70℃に6.5時間加熱した。次いで、混合物を室温まで冷却し、EtOAc(50mL)及び水(10mL)で希釈した。有機層を分離し、水(20mL)及び飽和ブライン(20mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=1/5)により精製して、表題化合物を薄黄色固体(0.77g、76%)として得た。
MS (ESI, 陽イオン) m/z: 354.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.68 - 7.53 (m, 3H), 5.72 - 5.54 (m, 2H), 3.54 (s, 1H), 3.00 - 2.89 (m, 1H), 1.48 - 1.44 (m, 12H), 1.42 - 1.37 (m, 2H), 1.12 - 1.03 (m, 1H), 1.00 - 0.90 (m, 1H).
(S)-tert-ブチル(1-(3-シクロプロピル-5-エチニル-4-オキソ-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメートの固体(0.77g、2.18mmol)に、EtOAc中塩化水素の溶液(10mL、40mmol、4.0mol/L)を添加した。反応物を室温で終夜撹拌し、次いでH2O(20mL)を添加し、混合物を更に10分間撹拌した。有機層を分離し、水性相をNaOH粉末でpH=10に塩基性化し、CH2Cl2(15mL×3)で抽出した。合わせた有機層を無水Na2SO4で乾燥させ、濾過し、真空中で濃縮して、表題化合物を褐色固体(0.49g、89%)として得た。
MS (ESI, 陽イオン) m/z: 254.3 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.66 - 7.51 (m, 3H), 4.83 - 4.67 (m, 1H), 3.53 (s, 1H), 2.97 - 2.83 (m, 1H), 1.43 (d, J = 6.6 Hz, 3H), 1.38 - 1.26 (m, 2H), 1.01 - 0.84 (m, 2H).
プロパン-2-オール(3mL)中の(S)-2-(1-アミノエチル)-3-シクロプロピル-5-エチニルキナゾリン-4(3H)-オン(50mg、0.20mmol)、6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-アミン(43mg、0.20mmol)及びDIPEA(0.10mL、0.60mmol)の混合物を、85℃に12時間加熱した。混合物を室温まで冷却し、次いで水(5mL)を滴下添加し、30分間撹拌し、濾過した。濾過ケーキを水(1.0mL)で洗浄し、真空中で乾燥させて、表題化合物をオフホワイトの固体(59mg、70%)として得た。
MS (ESI, 陽イオン) m/z: 429.2 [M + H]+;
1H NMR (600 MHz, DMSO-d6) δ (ppm): 9.35 (d, J = 6.7 Hz, 1H), 8.13 (s, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 7.8 Hz, 2H), 6.17 - 6.06 (m, 1H), 4.46 (s, 1H), 3.16 - 3.08 (m, 1H), 2.50 (s, 3H), 1.59 (d, J = 6.5 Hz, 3H), 1.30 - 1.24 (m, 2H), 1.07 - 1.02 (m, 1H), 0.89 - 0.83 (m, 1H).
(S)-2-(1-((6-アミノ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-5-エチニル-3-フェニルキナゾリン-4(3H)-オン
DMAC(20mL)中の(S)-tert-ブチル(1-(5-クロロ-4-オキソ-3-フェニル-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメート(2.00g、5.00mmol)の混合物に、エチニルトリメチルシラン(7.0mL、50mmol)、10%Pd/C(0.53g)、X-phos(0.24g、0.50mmol)及び炭酸カリウム(1.00g、7.24mmol)を添加した。混合物を窒素で数回脱気し、80℃に12時間加熱した。次いで、混合物を室温まで冷却し、EtOAc(150mL)で希釈し、濾過した。濾液を水(50mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。残留物をシリカゲルカラムクロマトグラフィー(EtOAc/PE(v/v)=1/15)により精製して、表題化合物を薄黄色固体(1.76g、76%)として得た。
MS (ESI, 陽イオン) m/z: 390.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.73 - 7.64 (m, 3H), 7.61 - 7.46 (m, 3H), 7.42 - 7.33 (m, 1H), 7.32 - 7.27 (m, 1H), 5.63 (d, J = 6.8 Hz, 1H), 4.61 - 4.45 (m, 1H), 3.46 (s, 1H), 1.39 (s, 9H), 1.26 (d, J = 6.7 Hz, 3H).
(S)-tert-ブチル(1-(5-エチニル-4-オキソ-3-フェニル-3,4-ジヒドロキナゾリン-2-イル)エチル)カルバメートの固体(0.74g、1.90mmol)に、EtOAc中塩化水素の溶液(30mL、120mmol、4.0mol/L)を添加した。反応物を室温で2時間撹拌し、次いでH2O(30mL)を添加し、混合物を更に10分間撹拌した。有機層を分離し、水性相をNaOH粉末でpH=10に塩基性化し、濾過し、真空中で乾燥させて、表題化合物を褐色固体(0.49g、89%)として得た。
MS (ESI, 陽イオン) m/z: 290.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.75 - 7.64 (m, 3H), 7.58 - 7.47 (m, 3H), 7.32 - 7.26 (m, 2H), 3.69 (q, J = 6.6 Hz, 1H), 3.46 (s, 1H), 1.28 (d, J = 6.6 Hz, 3H).
プロパン-2-オール(5mL)中の(S)-2-(1-アミノエチル)-5-エチニル-3-フェニルキナゾリン-4(3H)-オン(50mg、0.17mmol)、6-クロロ-5-(3-メチル-1,2,4-オキサジアゾール-5-イル)ピリミジン-4-アミン(38mg、0.18mmol)及びDIPEA(0.10mL、0.60mmol)の混合物を、90℃に4時間加熱した。混合物を室温まで冷却し、次いで水(5mL)を滴下添加し、混合物を更に30分間撹拌し、濾過した。濾過ケーキを真空中で乾燥させて、表題化合物を白色固体(57mg、71%)として得た。
MS (ESI, 陽イオン) m/z: 465.3 [M + H]+;
1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.23 (d, J = 6.6 Hz, 1H), 7.99 (s, 1H), 7.88 - 7.81 (m, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.63 - 7.53 (m, 5H), 4.99 - 4.88 (m, 1H), 4.41 (s, 1H), 2.50 (s, 3H), 1.36 (d, J = 6.5 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)エチル)-5-エチニル-3-フェニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 465.3 [M + H]+;
1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.77 (d, J = 6.7 Hz, 1H), 7.96 (s, 1H), 7.84 - 7.77 (m, 1H), 7.72 - 7.47 (m, 7H), 7.26 (s, 2H), 4.93 - 4.82 (m, 1H), 4.40 (s, 1H), 2.60 (s, 3H), 1.37 (d, J = 6.6 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(1-メチル-1H-1,2,4-トリアゾール-3-イル)ピリミジン-4-イル)アミノ)エチル)-5-(3-ヒドロキシプロパ-1-イン-1-イル)-3-フェニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 494.2 [M + H]+;
1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.58 (d, J = 6.6 Hz, 1H), 8.76 (s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.63 - 7.51 (m, 5H), 7.09 (s, 1H), 5.28 (t, J = 5.8 Hz, 1H), 4.90 - 4.83 (m, 1H), 4.308 (d, J = 4.2 Hz, 2H), 4.03 (s, 3H), 1.39 (d, J = 6.6 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(5-メチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-4-イル)アミノ)エチル)-5-エチニル-3-フェニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 465.2 [M + H]+;
1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.95 (d, J = 6.7 Hz, 1H), 7.96 (s, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.67 (dd, J = 13.8, 7.7 Hz, 2H), 7.59 (d, J = 8.7 Hz, 5H), 7.50 (s, 2H), 4.94 - 4.86 (m, 1H), 4.40 (s, 1H), 2.77 (s, 3H), 1.37 (d, J = 6.6 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(2-メチル-2H-テトラゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-5-エチニル-3-フェニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 465.1 [M + H]+;
1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.98 (d, J = 6.8 Hz, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.59 (d, J = 9.9 Hz, 5H), 7.48 (s, 2H), 4.99 - 4.87 (m, 1H), 4.55 (s, 3H), 4.40 (s, 1H), 1.39 (d, J = 6.6 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(1-メチル-1H-1,2,4-トリアゾール-3-イル)ピリミジン-4-イル)アミノ)エチル)-5-エチニル-3-フェニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 464.3 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 9.41 (s, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.76 - 7.60 (m, 3H), 7.60 - 7.43 (m, 4H), 7.34 (d, J = 7.5 Hz, 1H), 5.21 - 5.09 (m, 1H), 4.05 (s, 3H), 3.47 (s, 1H), 1.52 (d, J = 6.7 Hz, 3H).
(S)-2-(1-((6-アミノ-5-(5-メチル-1,3,4-オキサジアゾール-2-イル)ピリミジン-4-イル)アミノ)エチル)-3-シクロプロピル-5-エチニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 429.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 9.04 (d, J = 7.2 Hz, 1H), 8.15 (s, 1H), 7.66 - 7.49 (m, 3H), 6.44 - 6.23 (m, 1H), 3.56 (s, 1H), 3.11 - 2.99 (m, 1H), 2.74 (s, 3H), 1.66 (d, J = 6.6 Hz, 3H), 1.46 - 1.34 (m, 2H), 1.23 - 1.11 (m, 1H), 1.07 - 0.93 (m, 1H).
(S)-2-(1-((6-アミノ-5-(5-メチル-1,2,4-オキサジアゾール-3-イル)ピリミジン-4-イル)アミノ)エチル)-3-シクロプロピル-5-エチニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 429.2 [M + H]+;
1H NMR (400 MHz, CDCl3) δ (ppm): 9.01 (d, J = 7.2 Hz, 1H), 8.12 (s, 1H), 7.65 - 7.58 (m, 3H), 6.37 - 6.25 (m, 1H), 3.54 (s, 1H), 3.12 - 3.04 (m, 1H), 2.72 (s, 3H), 1.64 (d, J = 6.6 Hz, 3H), 1.46 - 1.39 (m, 2H), 1.24 - 1.15 (m, 1H), 1.01 - 0.94 (m, 1H).
(S)-2-(1-((6-アミノ-5-(2-メチル-2H-テトラゾール-5-イル)ピリミジン-4-イル)アミノ)エチル)-3-シクロプロピル-5-エチニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 429.3 [M + H]+;
1H NMR (600 MHz, CDCl3) δ (ppm): 9.14 (d, J = 7.3 Hz, 1H), 8.15 (s, 1H), 7.65 - 7.56 (m, 3H), 6.39 - 6.31 (m, 1H), 4.50 (s, 3H), 3.54 (s, 1H), 3.13 - 3.05 (m, 1H), 1.66 (d, J = 6.7 Hz, 3H), 1.47 - 1.38 (m, 2H), 1.20 - 1.13 (m, 1H), 1.01 - 0.93 (m, 1H).
(S)-2-(1-((6-アミノ-5-(1-メチル-1H-1,2,4-トリアゾール-3-イル)ピリミジン-4-イル)アミノ)エチル)-3-シクロプロピル-5-エチニルキナゾリン-4(3H)-オン
MS (ESI, 陽イオン) m/z: 428.2 [M + H]+;
1H NMR (600 MHz, CDCl3) δ (ppm): 9.61 (d, J = 7.4 Hz, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.67 - 7.52 (m, 3H), 6.38 - 6.31 (m, 1H), 4.04 (s, 3H), 3.56 (s, 1H), 3.27 (s, 2H), 3.15 - 3.08 (m, 1H)., 1.67 (d, J = 6.7 Hz, 3H), 1.48 - 1.37 (m, 2H), 1.24 - 1.13 (m, 1H), 1.03 - 0.92 (m, 1H).
分析に使用されるLC/MS/MSシステムは、Agilent社1200シリーズ真空デガッサー、バイナリポンプ、ウェルプレートオートサンプラー、サーモスタット付きカラムコンパートメント、エレクトロスプレーイオン化(ESI)源を有するAgilent社G6430三連四重極質量分析計で構成される。定量分析は、MRMモードを使用して行った。MRMトランジションについてのパラメーターをTable A(表1)に示す。
ヒト及びラットの肝ミクロソームにおける化合物安定性
ヒト又はラットの肝ミクロソームのインキュベーションを、ポリプロピレン管内で、二連で行った。典型的なインキュベーション混合物は、総容量200μLのリン酸カリウム緩衝液(PBS、100mM、pH7.4)中、ヒト又はラットの肝ミクロソーム(タンパク質0.5mg/mL)、目的の化合物(5μM)及びNADPH(1.0mM)で構成した。化合物をDMSOに溶解し、DMSOの最終濃度が0.05%となるようにPBSで希釈した。3分間のプレインキュベーション後にタンパク質の添加により酵素反応を開始させ、大気開放した水浴中において37℃でインキュベートした。等量の氷冷アセトニトリルを添加することにより、反応を様々な時点(0、5、10、15、30、60分)で停止させた。試料を、LC/MS/MSアッセイまで-80℃で貯蔵した。
ヒト又はラットの肝ミクロソームインキュベーションにおける化合物の濃度を、各反応について関連ゼロ時点対照に対する百分率としてプロットした。インビボCLintを外挿した(参考文献:Naritomi, Y.; Terashita, S.; Kimura, S.; Suzuki, A.; Kagayama, A.; and Sugiyama, Y.; Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metab. Dispos.、2001、29:1316~1324頁)。
マウス、ラット、イヌ及びサルにおける本明細書に開示される化合物の静脈内及び経口投与後の薬物動態の評価
本明細書に開示される化合物を、マウス、ラット、イヌ又はサルにおける薬物動態研究において評価する。化合物は、水溶液、水溶液中2%HPMC+1%TWEEN(登録商標)80、生理食塩水中5%DMSO+5%ソルトール、4%MC懸濁液又はカプセル剤として投与される。静脈内投与について、動物には一般的に、1又は2mg/kgの用量で投与される。経口(p.o.)投与について、マウス及びラットには一般的に、5又は10mg/kgの用量が投与され、イヌ及びサルには一般的に、10mg/kgの用量が投与される。血液試料(0.3mL)を、0.25、0.5、1.0、2.0、3.0、4.0、6.0、8.0、12及び24時間の時点で、又は0.083、0.25、0.5、1.0、2.0、4.0、6.0、8.0及び24時間の時点で採取し、3,000又は4000rpmで2~10分間遠心分離する。血漿溶液を収集し、上記の通りにLC/MS/MSにより分析するまで-20℃又は-70℃で貯蔵する。
キナーゼ活性アッセイ
PI3キナーゼ及びmTORキナーゼの阻害剤としての本明細書に開示される化合物の有効性は、以下の通り評価することができる。
キナーゼアッセイは、固定化ミエリン塩基性タンパク質(MBP)へのγ-33P ATPの取り込みの測定により実施することができる。高結合白色384ウェルプレート(Greiner社)を、60μL/ウェルのトリス緩衝生理食塩水(TBS;50mMトリス pH8.0、138mM NaCl、2.7mM KCl)中20μg/mL MBPの4℃で24時間のインキュベーションにより、MBP(Sigma社#M-1891)でコーティングする。プレートを100μLのTBSで3回洗浄する。キナーゼ反応は、キナーゼ緩衝液(5mM Hepes pH7.6、15mM NaCl、0.01%ウシガンマグロブリン(Sigma社#I-5506)、10mM MgCl2、1mM DTT、0.02%TritonX-100)中、総容量34μLで行う。化合物希釈をDMSO中で実施し、1%の最終DMSO濃度までアッセイウェルに添加する。各データポイントを二連で測定し、それぞれ個々の化合物決定について少なくとも2回の二連のアッセイを実施する。酵素を、例えば10nM又は20nMの最終濃度まで添加する。未標識ATP及びγ-33P ATPの混合物を添加して、反応を開始させる(典型的には、1ウェル当たり2×106cpmのγ-33P ATP(3000Ci/mmole)及び10μM未標識ATP)。反応を、振盪しながら室温で1時間行う。プレートをTBSで7回洗浄し、続いて50μL/ウェルのシンチレーション液(Wallac社)を添加する。プレートを、Wallac社Triluxカウンターを使用して読み取る。これは、そのようなアッセイの1つの形式に過ぎず、当業者に公知の通り、様々な他の形式が可能である。
PI3K(p110α/p85α)(h)[非放射性アッセイ]
PI3K(p110α/p85α)(h)を、10μMホスファチジルイノシトール4,5-ビスリン酸及びMgATP(必要に応じた濃度)を含有するアッセイ緩衝液中でインキュベートする。ATP溶液の添加により反応を開始させる。室温で30分間のインキュベーション後、EDTA及びビオチン化ホスファチジルイノシトール-3,4,5-トリスリン酸を含有する停止溶液の添加により反応を停止させる。最後に、ユウロピウム標識抗GSTモノクローナル抗体、GSTタグ付きGRP1 PHドメイン及びストレプトアビジンアロフィコシアニンを含有する、検出緩衝液を加える。次いで、プレートを時間分解蛍光モードで読み取り、均一時間分解蛍光(HTRF)シグナルを式HTRF=10000×(Em665nm/Em620nm)に従って決定する。
PI3K(p110β/p85α)(h)を、10μMホスファチジルイノシトール-4,5-ビスリン酸及びMgATP(必要に応じた濃度)を含有するアッセイ緩衝液中でインキュベートする。MgATP混合物の添加により反応を開始させる。室温で30分間のインキュベーション後、EDTA及びビオチン化ホスファチジルイノシトール-3,4,5-トリスリン酸を含有する停止溶液の添加により反応を停止させる。最後に、ユウロピウム標識抗GSTモノクローナル抗体、GSTタグ付きGRP1 PHドメイン及びストレプトアビジン-アロフィコシアニンを含有する検出緩衝液を加える。次いで、プレートを時間分解蛍光モードで読み取り、均一時間分解蛍光(HTRF)シグナルを式HTRF=10000×(Em665nm/Em620nm)に従って決定する。
PI3K(p110δ/p85α)(h)を、10μMホスファチジルイノシトール-4,5-ビスリン酸及びMgATP(必要に応じた濃度)を含有するアッセイ緩衝液中でインキュベートする。MgATP混合物の添加により反応を開始させる。室温で30分間のインキュベーション後、EDTA及びビオチン化ホスファチジルイノシトール-3,4,5-トリスリン酸を含有する停止溶液の添加により反応を停止させる。最後に、ユウロピウム標識抗GSTモノクローナル抗体、GSTタグ付きGRP1 PHドメイン及びストレプトアビジン-アロフィコシアニンを含有する、検出緩衝液を加える。次いで、プレートを時間分解蛍光モードで読み取り、均一時間分解蛍光(HTRF)シグナルを式HTRF=10000×(Em665nm/Em620nm)に従って決定する。
PI3K(p120γ)(h)を、10μMホスファチジルイノシトール-4,5-ビスリン酸及びMgATP(必要に応じた濃度)を含有するアッセイ緩衝液中でインキュベートする。MgATP混合物の添加により反応を開始させる。室温で30分間のインキュベーション後、EDTA及びビオチン化ホスファチジルイノシトール-3,4,5-トリスリン酸を含有する停止溶液の添加により反応を停止させる。最後に、ユウロピウム標識抗GSTモノクローナル抗体、GSTタグ付きGRP1 PHドメイン及びストレプトアビジン-アロフィコシアニンを含有する、検出緩衝液を加える。次いで、プレートを時間分解蛍光モードで読み取り、均一時間分解蛍光(HTRF)シグナルを式HTRF=10000×(Em665nm/Em620nm)に従って決定する。
mTOR(h)を、50mM HEPES pH7.5、1mM EDTA、0.01%TWEEN(登録商標)20、2mg/mLの基質、3mM塩化マンガン及び[γ-33P-ATP](比活性およそ500cpm/pmol、必要に応じた濃度)とともにインキュベートする。MnATP混合物の添加により反応を開始させる。室温で40分間のインキュベーション後、3%リン酸溶液の添加により反応を停止させる。次いで、10μLの反応物をP30フィルターマット上にスポットし、75mMリン酸中で3回5分間洗浄し、メタノール中で1回洗浄した後、乾燥及びシンチレーション計数を行う。
p-AKT HTRFアッセイ
PI3K-α及びPI3K-βに対する化合物の阻害活性を、それぞれSKOV3及び786-O細胞において評価する一方、PI3K-δアイソフォームに対する阻害アッセイを、抗免疫グロブリンM(抗IgM)抗体と架橋したヒトBリンパ腫細胞の受容体細胞系のRAJI細胞において行った。PI3K-γに対する化合物の阻害能を、試験前にC5aのGPCRアゴニストを介して蓄積すべきであるマウスマクロファージ様細胞系RAW264.7において評価した。
細胞増殖アッセイ
1.対数増殖期中に細胞を採取し、Count-starを使用して細胞数を計数する。
2.細胞濃度をそれぞれの培養培地により1.0×105細胞/mLに調整する。
3.細胞懸濁液90μLを1×104細胞/ウェルの最終細胞密度で96ウェルプレートに添加する(細胞濃度はデータベース又は密度最適化アッセイに従って調整されることになる)。
4.翌日、10×溶液を調製する(トップ作業濃度:9つの用量レベルを達成する3.16倍系列希釈で培地中10μMの試験物)。
5.試験物及び参照対照両方の薬物溶液10μLをプレートの各ウェル(各薬物濃度について二連)中に分配する。(培養培地中のDMSO最終濃度:0.1%)
6.試験プレートを加湿インキュベーター中にて5%CO2、37℃で72時間インキュベートし、次いでCTGアッセイによって測定する。
7.プレート及びその内容物を室温でおよそ30分間平衡化する。
8.CellTiter-Glo 50μLを各ウェルに添加する。
9.データを、GraphPad Prism 5.0を使用してグラフ表示する。
hERGアッセイ
電圧クランププロトコール:コンピュータソフトウェアを使用して電圧クランププロトコールをセットした。ホールセルモデルにおいて、細胞を-80mVに保持し、最初に-50mVに80ミリ秒間脱分極させ、次いで+20mVに4800ミリ秒間脱分極させて、hERGチャンネルを活性化した。その後、細胞を-50mVに5000ミリ秒間再分極させて、特徴的なテール電流を誘発した。最後に、細胞を-80mVに再度保持した。テール電流のピーク値を分析のためにサンプリングした。
Claims (11)
- 式(I):
[式中、
各R1及びR2は、独立して、H、D、F、CN、NO2、若しくは(C1~C6)アルキルであり、ここで、前記(C1~C6)アルキルのそれぞれは、D、F、Cl、Br、オキソ(=O)、及びCNから独立して選択される1、2、3若しくは4個の置換基で場合により置換されており、
Xは、
mは、1、2又は3であり、
Wは、Nであり、
Aは、H、D、(C1~C6)アルキル、又は(C1~C6)ヒドロキシアルキルであり、ここで、各(C1~C6)アルキル及び(C1~C6)ヒドロキシアルキルは、D、オキソ、F、Cl、Br、OH、NH2、CN、NO2、(C1~C6)アルキル及び(C1~C6)アルコキシから独立して選択される1、2、3、又は4個の置換基で場合により置換されており、
Bは、シクロプロピル又はフェニルであり、ここで、前記シクロプロピル及びフェニルのそれぞれは、D、オキソ(=O)、F、Cl、Br、CN、メチル、エチル、n-プロピル、イソプロピル、及びtert-ブチルから独立して選択される1、2、3、又は4個の置換基で場合により置換されており、
各R3及びR4は、独立して、H、D、F、Cl、Br、CN、NO2 、(C1~C6)アルキル、(C2~C6)アルケニル、又は(C2~C6)アルキニルであり、ここで、前記(C1~C6)アルキル、(C2~C6)アルケニル、及び(C2~C6)アルキニルのそれぞれは、D、F、Cl、Br、CN、オキソ(=O)、及び(C1~C6)アルキルから独立して選択される1、2、3、又は4個の置換基で場合により置換されている]。 - 式(II):
- Aが、H、D、(C1~C4)アルキル、又は(C1~C4)ヒドロキシアルキルであり、ここで、各(C1~C4)アルキル及び(C1~C4)ヒドロキシアルキルが、D、オキソ、F、Cl、Br、OH、NH2、CN、NO2、(C1~C4)アルキル及び(C1~C4)アルコキシから独立して選択される1、2、3、又は4個の置換基で場合により置換されている;又は
Aが、H、D、メチル、エチル、n-プロピル、イソプロピル、tert-ブチル、ヒドロキシメチル、2-ヒドロキシエチル、1-ヒドロキシエチル、又は2-ヒドロキシプロパ-2-イルであり、ここで、各メチル、エチル、n-プロピル、イソプロピル、tert-ブチル、ヒドロキシメチル、2-ヒドロキシエチル、1-ヒドロキシエチル、及び2-ヒドロキシプロパ-2-イルが、D、オキソ、F、Cl、Br、OH、NH2、CN、NO2、メチル、エチル、n-プロピル、イソプロピル、tert-ブチル、メトキシル及びエトキシルから独立して選択される1、2、3、又は4個の置換基で場合により置換されている、請求項1又は2に記載の化合物。 - 各R1及びR2が、独立して、H、D、F、CN、NO2、又は(C1~C4)アルキルであり、ここで、前記(C1~C4)アルキルのそれぞれが、D、F、Cl、Br、オキソ(=O)、及びCNから独立して選択される1、2、3若しくは4個の置換基で場合により置換されており;又は
各R1及びR2が、独立して、H、D、F、CN、メチル、エチル、n-プロピル、又はイソプロピルであり、ここで、メチル、エチル、n-プロピル、及びイソプロピルのそれぞれが、D、F、Cl、Br、オキソ(=O)、及びCNから独立して選択される1、2、3若しくは4個の置換基で場合により置換されている、請求項1から3のいずれか一項に記載の化合物。 - 各R3及びR4が、独立して、H、D、F、Cl、Br、CN、NO2 、(C1~C4)アルキル、(C2~C4)アルケニル、又は(C2~C4)アルキニルであり、ここで、前記(C1~C4)アルキル、(C2~C4)アルケニル、及び(C2~C4)アルキニルのそれぞれが、D、F、Cl、Br、CN、オキソ(=O)、及び(C1~C4)アルキルから独立して選択される1、2、3、又は4個の置換基で場合により置換されている;又は
各R3及びR4が、独立して、H、D、F、Cl、Br、CN、NO2 、メチル、エチル、n-プロピル、イソプロピル、ビニル、プロペニル、アリル、エチニル、プロピニル、又はプロパルギルであり、ここで、エチル、n-プロピル、イソプロピル、ビニル、プロペニル、アリル、エチニル、プロピニル、及びプロパルギルのそれぞれが、D、F、Cl、Br、CN、オキソ(=O)、メチル、エチル、n-プロピル及びイソプロピルから独立して選択される1、2、3、又は4個の置換基で場合により置換されている、請求項1から4のいずれか一項に記載の化合物。 - 以下の構造:
- 請求項1から6のいずれか一項に記載の化合物と、1つ又は複数の薬学的に許容される担体、賦形剤、希釈剤、アジュバント、ビヒクル又はそれらの組合せとを含む医薬組成物。
- 1つ又は複数の治療剤を更に含む、請求項7に記載の医薬組成物。
- 患者における不適当なPI3-キナーゼ活性により媒介される障害の重症度を、予防する、管理する、処置する又は低下させる際に使用するための、請求項1から6のいずれか一項に記載の化合物又は請求項7若しくは8に記載の医薬組成物。
- 前記障害が、喘息、慢性閉塞性肺疾患(COPD)、ウイルス性呼吸器感染症、呼吸器疾患のウイルス増悪、アスペルギルス症、リーシュマニア症、アレルギー性鼻炎、アトピー性皮膚炎、関節リウマチ、多発性硬化症、炎症性腸疾患、血栓症、アテローム性動脈硬化症、血液学的悪性腫瘍、神経変性疾患、膵炎、多臓器不全、腎臓疾患、血小板凝集、がん、精子運動性、移植拒絶、移植片拒絶、肺損傷、関節リウマチ若しくは変形性関節症に関連する疼痛、背痛、一般的炎症性疼痛、ヘルペス後神経痛、糖尿病性ニューロパシー、炎症性神経障害性疼痛(外傷)、三叉神経痛、又は中枢性疼痛である、請求項9に記載の化合物又は医薬組成物。
- 喘息、慢性閉塞性肺疾患(COPD)、ウイルス性呼吸器感染症、呼吸器疾患のウイルス増悪、アスペルギルス症、リーシュマニア症、アレルギー性鼻炎、アトピー性皮膚炎、関節リウマチ、多発性硬化症、炎症性腸疾患、血栓症、アテローム性動脈硬化症、血液学的悪性腫瘍、神経変性疾患、膵炎、多臓器不全、腎臓疾患、血小板凝集、がん、精子運動性、移植拒絶、移植片拒絶、肺損傷、関節リウマチ若しくは変形性関節症に関連する疼痛、背痛、一般的炎症性疼痛、ヘルペス後神経痛、糖尿病性ニューロパシー、炎症性神経障害性疼痛(外傷)、三叉神経痛又は中枢性疼痛から選択される障害又は疾患の処置のための医薬の製造において使用するための、請求項1から6のいずれか一項に記載の化合物、又は請求項7若しくは8に記載の医薬組成物。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014525438A (ja) | 2011-08-29 | 2014-09-29 | インフィニティー ファーマシューティカルズ, インコーポレイテッド | 複素環式化合物及びその使用 |
WO2015168079A1 (en) | 2014-04-29 | 2015-11-05 | Infinity Pharmaceuticals, Inc. | Pyrimidine or pyridine derivatives useful as pi3k inhibitors |
JP2016530338A (ja) | 2013-09-22 | 2016-09-29 | キャリター・サイエンシーズ・リミテッド・ライアビリティ・カンパニーCalitor Sciences, Llc | 置換されているアミノピリミジン化合物および使用方法 |
JP2016534146A5 (ja) | 2014-09-17 | 2017-07-27 |
Family Cites Families (125)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1524747A (en) | 1976-05-11 | 1978-09-13 | Ici Ltd | Polypeptide |
LU88769I2 (fr) | 1982-07-23 | 1996-11-05 | Zeneca Ltd | Bicalutamide et ses sels et esters pharmaceutiquement acceptables (Casodex (R)) |
GB8327256D0 (en) | 1983-10-12 | 1983-11-16 | Ici Plc | Steroid derivatives |
US5093330A (en) | 1987-06-15 | 1992-03-03 | Ciba-Geigy Corporation | Staurosporine derivatives substituted at methylamino nitrogen |
US5010099A (en) | 1989-08-11 | 1991-04-23 | Harbor Branch Oceanographic Institution, Inc. | Discodermolide compounds, compositions containing same and method of preparation and use |
NZ243082A (en) | 1991-06-28 | 1995-02-24 | Ici Plc | 4-anilino-quinazoline derivatives; pharmaceutical compositions, preparatory processes, and use thereof |
GB9127376D0 (en) | 1991-12-24 | 1992-02-19 | Wellcome Found | Amidino derivatives |
GB9300059D0 (en) | 1992-01-20 | 1993-03-03 | Zeneca Ltd | Quinazoline derivatives |
CZ283425B6 (cs) | 1992-04-02 | 1998-04-15 | Smithkline Beecham Corporation | Fenylové deriváty a farmaceutické prostředky s jejich obsahem |
TW225528B (ja) | 1992-04-03 | 1994-06-21 | Ciba Geigy Ag | |
GB9314893D0 (en) | 1993-07-19 | 1993-09-01 | Zeneca Ltd | Quinazoline derivatives |
CA2192668A1 (en) | 1994-06-15 | 1995-12-21 | Harold Francis Hodson | Amidino sulfone derivatives for use as inos inhibitors claims |
CA2216796C (en) | 1995-03-30 | 2003-09-02 | Pfizer Inc. | Quinazoline derivatives |
PT820279E (pt) | 1995-04-14 | 2002-11-29 | Smithkline Beecham Corp | Inalador de doses calibradas para albuterol |
GB9508538D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
US5747498A (en) | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
US5843901A (en) | 1995-06-07 | 1998-12-01 | Advanced Research & Technology Institute | LHRH antagonist peptides |
CA2224435C (en) | 1995-07-06 | 2008-08-05 | Novartis Ag | Pyrrolopyrimidines and processes for the preparation thereof |
US5760041A (en) | 1996-02-05 | 1998-06-02 | American Cyanamid Company | 4-aminoquinazoline EGFR Inhibitors |
GB9603095D0 (en) | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
CA2249446C (en) | 1996-04-12 | 2008-06-17 | Warner-Lambert Company | Irreversible inhibitors of tyrosine kinases |
DE69734513T2 (de) | 1996-06-24 | 2006-07-27 | Pfizer Inc. | Phenylamino-substituierte tricyclische derivate zur behandlung hyperproliferativer krankheiten |
WO1998008849A1 (de) | 1996-08-30 | 1998-03-05 | Novartis Aktiengesellschaft | Verfahren zur herstellung von epothilonen und zwischenprodukte innerhalb des verfahrens |
CA2264908C (en) | 1996-09-06 | 2006-04-25 | Obducat Ab | Method for anisotropic etching of structures in conducting materials |
AU4342997A (en) | 1996-09-13 | 1998-04-02 | Sugen, Inc. | Use of quinazoline derivatives for the manufacture of a medicament in the reatment of hyperproliferative skin disorders |
EP0837063A1 (en) | 1996-10-17 | 1998-04-22 | Pfizer Inc. | 4-Aminoquinazoline derivatives |
WO1998022461A1 (de) | 1996-11-18 | 1998-05-28 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Epothilone c, d, e und f, deren herstellung und deren verwendung als cytostatische mittel bzw. als pflanzenschutzmittel |
US6441186B1 (en) | 1996-12-13 | 2002-08-27 | The Scripps Research Institute | Epothilone analogs |
MY117948A (en) | 1997-01-13 | 2004-08-30 | Glaxo Group Ltd | Nitride oxide synthase inhibitors. |
DE19723722A1 (de) | 1997-05-30 | 1998-12-10 | Schering Ag | Nichtsteroidale Gestagene |
TW533865U (en) | 1997-06-10 | 2003-05-21 | Glaxo Group Ltd | Dispenser for dispensing medicament and actuation indicating device |
CO4940418A1 (es) | 1997-07-18 | 2000-07-24 | Novartis Ag | Modificacion de cristal de un derivado de n-fenil-2- pirimidinamina, procesos para su fabricacion y su uso |
GB9721069D0 (en) | 1997-10-03 | 1997-12-03 | Pharmacia & Upjohn Spa | Polymeric derivatives of camptothecin |
US6506766B1 (en) | 1998-02-13 | 2003-01-14 | Abbott Laboratories | Glucocortiocoid-selective antinflammatory agents |
US6194181B1 (en) | 1998-02-19 | 2001-02-27 | Novartis Ag | Fermentative preparation process for and crystal forms of cytostatics |
IL138113A0 (en) | 1998-02-25 | 2001-10-31 | Sloan Kettering Inst Cancer | Synthesis of epothilones, intermediates thereto and analogues thereof |
GB9811599D0 (en) | 1998-05-30 | 1998-07-29 | Glaxo Group Ltd | Nitric oxide synthase inhibitors |
PT1107964E (pt) | 1998-08-11 | 2010-06-11 | Novartis Ag | Derivados de isoquinolina com actividade inibidora da angiogénese |
CA2350189A1 (en) | 1998-11-20 | 2000-06-02 | Kosan Biosciences, Inc. | Recombinant methods and materials for producing epothilone and epothilone derivatives |
US6315112B1 (en) | 1998-12-18 | 2001-11-13 | Smithkline Beecham Corporation | Method and package for storing a pressurized container containing a drug |
US6390291B1 (en) | 1998-12-18 | 2002-05-21 | Smithkline Beecham Corporation | Method and package for storing a pressurized container containing a drug |
US6119853A (en) | 1998-12-18 | 2000-09-19 | Glaxo Wellcome Inc. | Method and package for storing a pressurized container containing a drug |
US6352152B1 (en) | 1998-12-18 | 2002-03-05 | Smithkline Beecham Corporation | Method and package for storing a pressurized container containing a drug |
ES2165768B1 (es) | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | Nuevos derivados de quinuclidina y composiciones farmaceuticas que los contienen. |
US6667300B2 (en) | 2000-04-25 | 2003-12-23 | Icos Corporation | Inhibitors of human phosphatidylinositol 3-kinase delta |
PE20020354A1 (es) | 2000-09-01 | 2002-06-12 | Novartis Ag | Compuestos de hidroxamato como inhibidores de histona-desacetilasa (hda) |
PL362711A1 (en) | 2000-09-29 | 2004-11-02 | Glaxo Group Limited | Morpholin-acetamide derivatives for the treatment of inflammatory diseases |
NZ525656A (en) | 2000-11-07 | 2004-12-24 | Novartis Ag | Indolylmaleimide derivatives as protein kinase C inhibitors |
GB0031179D0 (en) | 2000-12-21 | 2001-01-31 | Glaxo Group Ltd | Nitric oxide synthase inhibitors |
US6484903B2 (en) | 2001-01-09 | 2002-11-26 | Riverwood International Corporation | Carton with an improved dispensing feature in combination with a unique handle |
TWI238824B (en) | 2001-05-14 | 2005-09-01 | Novartis Ag | 4-amino-5-phenyl-7-cyclobutyl-pyrrolo[2,3-d]pyrimidine derivatives |
GB0119249D0 (en) | 2001-08-07 | 2001-10-03 | Novartis Ag | Organic compounds |
DE60309829T2 (de) | 2002-01-14 | 2007-09-13 | Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield | Glucocorticoidmimetika, verfahren zu ihrer herstellung, diese enthaltende pharmazeutische formulierungen und ihre verwendungen |
CA2473886C (en) | 2002-01-22 | 2012-08-21 | The Regents Of The University Of California | Non-steroidal ligands for the glucocorticoid receptor, compositions and uses thereof |
AU2003230700A1 (en) | 2002-03-26 | 2003-10-13 | Boehringer Ingelheim Pharmaceuticals, Inc. | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof |
CN1633296A (zh) | 2002-03-26 | 2005-06-29 | 贝林格尔·英格海姆药物公司 | 糖皮质素模拟物、其制备方法、药物组合物及其用途 |
DE10215316C1 (de) | 2002-04-02 | 2003-12-18 | Schering Ag | Chinolin- und Isochinolin-Derivate, ein pharmazeutisches Mittel und ihre Verwendung als Entzündungshemmer |
TWI324064B (en) | 2002-04-03 | 2010-05-01 | Novartis Ag | Indolylmaleimide derivatives |
EP1496892B1 (en) | 2002-04-11 | 2011-01-26 | Merck Sharp & Dohme Corp. | 1h-benzo(f)indazol-5-yl derivatives as selective glucocorticoid receptor modulators |
US7186864B2 (en) | 2002-05-29 | 2007-03-06 | Boehringer Ingelheim Pharmaceuticals, Inc. | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof |
US7074806B2 (en) | 2002-06-06 | 2006-07-11 | Boehringer Ingelheim Pharmaceuticals, Inc. | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof |
ES2518940T3 (es) | 2002-07-08 | 2014-11-06 | Pfizer Products Inc. | Moduladores del receptor de glucocorticoides |
WO2004009017A2 (en) | 2002-07-18 | 2004-01-29 | Bristol-Myers Squibb Company | Modulators of the glucocorticoid receptor and method |
WO2004018429A2 (en) | 2002-08-21 | 2004-03-04 | Boehringer Ingelheim Pharmaceuticals, Inc. | Substituted hihydroquinolines as glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof |
JP4520309B2 (ja) | 2002-09-20 | 2010-08-04 | メルク・シャープ・エンド・ドーム・コーポレイション | 選択的糖質コルチコイド受容体調節剤としてのオクタヒドロ−2−H−ナフト[1,2−f]インドール−4−カルボキサミド誘導体 |
GB0224084D0 (en) | 2002-10-16 | 2002-11-27 | Glaxo Group Ltd | Novel compounds |
KR20050084224A (ko) | 2002-12-09 | 2005-08-26 | 더 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 | 야누스 티로신 키나제 3을 선택적으로 저해하는 방법 |
PL1699512T3 (pl) | 2003-11-03 | 2012-11-30 | Glaxo Group Ltd | Urządzenie do dozowania płynów |
EP1704145B1 (en) | 2004-01-12 | 2012-06-13 | YM BioSciences Australia Pty Ltd | Selective kinase inhibitors |
EP3943494A1 (en) | 2004-05-13 | 2022-01-26 | Icos Corporation | Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta |
WO2006000398A1 (en) | 2004-06-28 | 2006-01-05 | Glaxo Group Limited | 2,3-benzoxazin derivatives as non-steroidal glucocorticoid receptor modulators |
WO2006000401A1 (en) | 2004-06-28 | 2006-01-05 | Glaxo Group Limited | Substituted oxazines as glucocorticoid receptor modulators |
GB0418045D0 (en) | 2004-08-12 | 2004-09-15 | Glaxo Group Ltd | Compounds |
KR100867071B1 (ko) | 2004-10-19 | 2008-11-04 | 에프. 호프만-라 로슈 아게 | 퀴놀린 유도체 |
CA2909277A1 (en) | 2006-04-04 | 2007-10-11 | Kevan M. Shokat | Kinase antagonists |
US8193182B2 (en) | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
CN101965336B (zh) | 2008-01-04 | 2015-06-17 | 英特利凯恩有限责任公司 | 某些化学实体、组合物和方法 |
GB0918249D0 (en) | 2009-10-19 | 2009-12-02 | Respivert Ltd | Compounds |
CA2799579A1 (en) | 2010-05-21 | 2011-11-24 | Intellikine, Inc. | Chemical compounds, compositions and methods for kinase modulation |
MY168757A (en) | 2011-05-04 | 2018-12-04 | Rhizen Pharmaceuticals S A | Novel compounds as modulators of protein kinases |
EP2734530A1 (en) | 2011-07-19 | 2014-05-28 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
AU2012284088B2 (en) | 2011-07-19 | 2015-10-08 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
US8940742B2 (en) | 2012-04-10 | 2015-01-27 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
SG11201501173SA (en) | 2012-08-08 | 2015-05-28 | Kbp Biosciences Co Ltd | PI3Kδ INHIBITOR |
US9388189B2 (en) | 2012-10-16 | 2016-07-12 | Almirall, S.A. | Pyrrolotriazinone derivatives as PI3K inhibitors |
PT2935246T (pt) | 2012-12-21 | 2018-10-10 | Gilead Calistoga Llc | Inibidores de fosfatidilinositol 3-quinase de quinazolinona ou isoquinolinona |
ES2677919T3 (es) | 2012-12-21 | 2018-08-07 | Gilead Calistoga Llc | Aminoalquil-quinazolonas sustituidas con pirimidina como inhibidores de la fosfatidilinositol 3-quinasa |
WO2014128612A1 (en) | 2013-02-20 | 2014-08-28 | Novartis Ag | Quinazolin-4-one derivatives |
US9216985B2 (en) | 2013-03-28 | 2015-12-22 | Scifluor Life Sciences, Inc. | 3-aryl-2-((arylamino)methyl)quinazolin-4-(3H)-ones |
CN105308034B (zh) | 2013-06-14 | 2017-10-31 | 吉利德科学公司 | 磷脂酰肌醇3‑激酶抑制剂 |
EP3016955B1 (en) | 2013-07-02 | 2018-03-07 | Rhizen Pharmaceuticals S.A. | Pi3k protein kinase inhibitors, particularly delta and/or gamma inhibitors |
UY35675A (es) | 2013-07-24 | 2015-02-27 | Novartis Ag | Derivados sustituidos de quinazolin-4-ona |
CN104447727B (zh) | 2013-09-02 | 2018-04-27 | 广东东阳光药业有限公司 | 取代的氨基嘧啶类化合物及其使用方法和用途 |
US9751888B2 (en) | 2013-10-04 | 2017-09-05 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
CN105793255B (zh) | 2013-10-04 | 2018-11-16 | 无限药品股份有限公司 | 杂环化合物及其用途 |
WO2015091532A1 (en) | 2013-12-19 | 2015-06-25 | Almirall, S.A. | Pyrrolopyrimidine derivatives as pi3k inhibitors |
US9775844B2 (en) | 2014-03-19 | 2017-10-03 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
CN105130966B (zh) | 2014-05-07 | 2019-05-24 | 广东东阳光药业有限公司 | 炔基化合物及其使用方法和用途 |
WO2015175579A1 (en) | 2014-05-15 | 2015-11-19 | Calitor Sciences, Llc | Alkynyl compounds and methods of use |
EA201692266A1 (ru) | 2014-06-13 | 2017-06-30 | Джилид Сайэнс, Инк. | Ингибиторы фосфатидилинозитол-3-киназы |
BR112016028819A2 (pt) | 2014-06-13 | 2017-08-22 | Gilead Sciences Inc | composição farmacêutica, métodos para tratar uma doença ou condição em um ser humano e para inibir a atividade de um polipeptídeo de fosfatidilinositol 3-quinase e reações imunológicas excessivas ou destrutivas ou o crescimento ou a proliferação de células cancerosas, kit, composto, sal farmaceuticamente aceitável, isômero ou mistura dos mesmos, e, uso de um composto, sal farmaceuticamente aceitável ou mistura dos mesmos. |
KR20170012557A (ko) | 2014-06-13 | 2017-02-02 | 길리애드 사이언시즈, 인코포레이티드 | 포스파티딜이노시톨 3-키나제 억제제 |
MX2016016517A (es) | 2014-06-13 | 2017-05-01 | Gilead Sciences Inc | Inhibidores de fosfatidilinositol 3-cinasa. |
MX2016016530A (es) | 2014-06-13 | 2017-03-27 | Gilead Sciences Inc | Inhibidores de fosfatidilinositol 3-quinasa. |
KR20170015521A (ko) | 2014-06-24 | 2017-02-08 | 길리애드 사이언시즈, 인코포레이티드 | 포스파티딜이노시톨 3-키나제 억제제 |
BR112017000132A2 (pt) | 2014-07-04 | 2018-01-09 | Lupin Ltd | composto, composição farmacêutica e método de tratamento ou prevenção de uma doença responsiva à inibição da atividade de pi3k |
WO2016054491A1 (en) | 2014-10-03 | 2016-04-07 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
CN105924434A (zh) | 2015-02-28 | 2016-09-07 | 广东东阳光药业有限公司 | 取代的氨基嘧啶类化合物及其使用方法和用途 |
CN105924433B (zh) | 2015-02-28 | 2020-12-22 | 广东东阳光药业有限公司 | 取代的氨基嘧啶类化合物及其使用方法和用途 |
CN105936635B (zh) | 2015-03-06 | 2019-06-21 | 南京圣和药业股份有限公司 | 作为磷脂酰肌醇3-激酶δ抑制剂的化合物及其应用 |
CN106008479B (zh) | 2015-03-06 | 2020-01-10 | 南京圣和药业股份有限公司 | 作为磷脂酰肌醇3-激酶δ抑制剂的取代嘧啶类化合物及其应用 |
WO2016149160A1 (en) * | 2015-03-15 | 2016-09-22 | Sunshine Lake Pharma Co., Ltd. | Substituted aminopyrimidine compounds and methods of use |
KR101845931B1 (ko) | 2015-06-18 | 2018-04-05 | 한국화학연구원 | 헤테로아릴 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 pi3 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물 |
CN106366085A (zh) | 2015-07-25 | 2017-02-01 | 复旦大学 | 异喹啉酮类化合物或其盐及其制备方法和用途 |
WO2017103825A1 (en) | 2015-12-18 | 2017-06-22 | Lupin Limited | Quinolizinone derivatives as pi3k inhibitors |
CN106995438B (zh) | 2016-01-22 | 2019-09-20 | 中国科学院上海药物研究所 | 一类取代喹唑啉-4-酮类化合物及其制备方法和医药用途 |
US10759806B2 (en) | 2016-03-17 | 2020-09-01 | Infinity Pharmaceuticals, Inc. | Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as PI3K kinase inhibitors |
TW201806953A (zh) | 2016-04-26 | 2018-03-01 | 印度商托仁特生技有限公司 | 取代稠合嘧啶酮化合物 |
JP6909236B2 (ja) | 2016-04-29 | 2021-07-28 | ユーハン・コーポレイションYUHAN Corporation | キナゾリン誘導体またはその塩およびそれを含む医薬組成物 |
WO2017214269A1 (en) | 2016-06-08 | 2017-12-14 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
KR101932146B1 (ko) | 2016-07-14 | 2018-12-24 | 주식회사 바이오웨이 | Pi3k를 억제하는 신규한 퀴나졸리논 유도체 및 이를 포함하는 약학적 조성물 |
GB201615282D0 (en) | 2016-09-08 | 2016-10-26 | Univ Bath | Tankyrase inhibitors |
CA3047730A1 (en) | 2016-12-20 | 2018-06-28 | Oligomerix, Inc. | Quinazolinones that inhibit the formation of tau oligomers and their method of use |
CN107286113A (zh) | 2017-06-16 | 2017-10-24 | 中国药科大学 | 一种异喹啉酮衍生物及其制备方法和用途 |
CN107417628A (zh) | 2017-06-28 | 2017-12-01 | 中国人民解放军军事医学科学院毒物药物研究所 | 二芳基喹唑啉酮类化合物、其制备方法及其医药用途以及包含该类化合物的药物组合物 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014525438A (ja) | 2011-08-29 | 2014-09-29 | インフィニティー ファーマシューティカルズ, インコーポレイテッド | 複素環式化合物及びその使用 |
JP2016530338A (ja) | 2013-09-22 | 2016-09-29 | キャリター・サイエンシーズ・リミテッド・ライアビリティ・カンパニーCalitor Sciences, Llc | 置換されているアミノピリミジン化合物および使用方法 |
WO2015168079A1 (en) | 2014-04-29 | 2015-11-05 | Infinity Pharmaceuticals, Inc. | Pyrimidine or pyridine derivatives useful as pi3k inhibitors |
JP2016534146A5 (ja) | 2014-09-17 | 2017-07-27 |
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