JP2021521194A - KRas G12C阻害剤及びそれを使用する方法 - Google Patents
KRas G12C阻害剤及びそれを使用する方法 Download PDFInfo
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- JP2021521194A JP2021521194A JP2020555848A JP2020555848A JP2021521194A JP 2021521194 A JP2021521194 A JP 2021521194A JP 2020555848 A JP2020555848 A JP 2020555848A JP 2020555848 A JP2020555848 A JP 2020555848A JP 2021521194 A JP2021521194 A JP 2021521194A
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- 229960004295 valine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- 229950011257 veliparib Drugs 0.000 description 1
- JNAHVYVRKWKWKQ-CYBMUJFWSA-N veliparib Chemical compound N=1C2=CC=CC(C(N)=O)=C2NC=1[C@@]1(C)CCCN1 JNAHVYVRKWKWKQ-CYBMUJFWSA-N 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
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- 239000011647 vitamin D3 Substances 0.000 description 1
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- 238000005406 washing Methods 0.000 description 1
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- 238000001262 western blot Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 235000020138 yakult Nutrition 0.000 description 1
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- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 235000016804 zinc Nutrition 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
- 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
- 229950009819 zotarolimus Drugs 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D403/02—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 two hetero rings
- C07D403/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
Description
略語:本明細書では、以下の略語が使用され得る:
本明細書で開示される化合物は、本明細書で開示される化合物の1つ以上の原子が、同じ原子番号を有するが、通常、天然に見出される原子質量又は質量数と異なる原子質量又は質量数を有する原子によって置換された、全ての薬学的に許容される同位体標識化合物を含む。開示された化合物に組み込むことができる同位体の例には、水素、炭素、窒素、酸素、リン、フッ素、塩素、及びヨウ素の同位体、例えば、それぞれ2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I、及び125Iが含まれる。これらの放射性標識化合物は、例えば、作用部位若しくは作用様式、又は薬理学的に重要な作用部位に対する結合親和性を同定することによって、化合物の有効性の決定又は測定を助けるのに有用であろう。本開示の特定の同位体標識化合物、例えば、放射性同位体を組み込んだものは、薬剤及び/又は基質組織分布の研究に有用である。放射性同位体のトリチウム、すなわち3H、及び炭素14、すなわち14Cは、取り込みの容易さ及び検知の容易な手段の観点から、この目的ために特に有効である。
本明細書に開示される化合物は、いくつかの特定の方法を介して合成することができる。特定の合成経路及び下記の包括的スキームの概要を示す実施例は、溶媒、濃度、試薬、保護基、合成工程の順序、時間、温度などが十分に当業者の技術及び判断の範囲内で必要に応じて変更できることを容易に理解する、通常の能力を有する合成化学者に指針を提供することが意図されている。
実施形態1
本発明の一実施形態において、本発明は、
又はその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、若しくはそのアトロプ異性体の薬学的に許容される塩を含む。
本発明の別の実施形態では、本発明は、
又はその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、若しくはそのアトロプ異性体の薬学的に許容される塩を含む。
本発明の別の実施形態では、本発明は、
又はその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、若しくはそのアトロプ異性体の薬学的に許容される塩を含む。
本発明の別の実施形態では、本発明は、
又はその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、そのアトロプ異性体の薬学的に許容される塩を含む。
本発明の別の実施形態では、本発明は、
又はその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、そのアトロプ異性体の薬学的に許容される塩を含む。
本発明の別の実施形態では、本発明は、
又はその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、若しくはそのアトロプ異性体の薬学的に許容される塩を含む。
本発明の別の実施形態では、本発明は、
又はその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、若しくはそのアトロプ異性体の薬学的に許容される塩を含む。
本発明の別の実施形態では、本発明は、
又はその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、若しくはそのアトロプ異性体の薬学的に許容される塩を含む。
本発明の別の実施形態では、本発明は、
又はその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、若しくはそのアトロプ異性体の薬学的に許容される塩を含む。
本発明の別の実施形態では、本発明は、
又はその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、若しくはそのアトロプ異性体の薬学的に許容される塩を含む。
本発明の別の実施形態では、本発明は、
又はその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、若しくはそのアトロプ異性体の薬学的に許容される塩を含む。
本発明の別の実施形態では、本発明は、薬学的に許容される塩の形態における、実施形態1〜11のいずれか1つの化合物を含む。
本発明の別の実施形態では、本発明は、実施形態1〜12のいずれか1つの化合物及び薬学的に許容される賦形剤を含む医薬組成物を含む。
本発明の別の実施形態では、本発明は、細胞中でKRAS G12Cを阻害する方法であって、細胞を、実施形態1〜13のいずれか1つの化合物と接触させることを含む方法を含む。
本発明の別の実施形態では、本発明は、対象においてがんを治療する方法であって、対象に治療有効量の実施形態1〜13のいずれか1つの化合物又は製剤を投与することを含む方法を含む。
本発明の別の実施形態では、本発明は、がんが、肺がん、膵臓がん、又は結腸直腸がんである、実施形態15の方法を含む。
本発明の別の実施形態では、がんは、肺がんである。
本発明の別の実施形態では、がんは、膵臓がんである。
本発明の別の実施形態では、がんは、結腸直腸がんである。
本発明の別の実施形態では、本発明は、必要とする患者に治療有効量の追加の薬学的に活性な化合物を投与することを含む。
本発明の別の実施形態では、追加の薬学的に活性な化合物は、ニボルマブである。
本発明の別の実施形態では、追加の薬学的に活性な化合物は、ペムブロリズマブである。
本発明の別の実施形態では、追加の薬学的に活性な化合物は、AMG 404である。
本発明の別の実施形態では、追加の薬学的に活性な化合物は、抗PD−1アンタゴニストである。
本発明の別の実施形態では、追加の薬学的に活性な化合物は、AMG 176である。
本発明の別の実施形態では、追加の薬学的に活性な化合物は、ダラツムマブである。
本発明の別の実施形態では、本発明は、対象におけるがんを治療するための実施形態1〜26のいずれか1つによる化合物又は製剤の使用を含む。
本発明の別の実施形態では、本発明は、がんを治療するための医薬の作製における実施形態1〜27のいずれか1つによる化合物又は製剤を含む。
本発明の別の実施形態では、がんは、非小細胞肺がんである。
また、本明細書では、例えば、希釈剤又は担体などの薬学的に許容される賦形剤と共に、本明細書に開示される化合物を含む医薬組成物も提供する。本発明での使用に好適な化合物及び医薬組成物としては、化合物がその意図された目的を達成するのに有効な量で投与できるものが挙げられる。化合物の投与は、以下により詳細に記載される。
本開示は、RAS媒介性細胞シグナル伝達を阻害する方法であって、細胞を、有効量の本明細書に開示される1つ以上の化合物と接触させることを含む方法を提供する。RAS媒介性シグナル伝達の阻害は、当該技術分野で知られる広範囲の種々の方法によって評価し、実証することができる。非限定的な例として、(a)RASのGTPase活性の減少;(b)GTP結合親和性の減少又はGDP結合親和性の増加;(c)GTPのKoffの増加又はGDPのKoffの減少;(d)pMEK、pERK又はpAKTレベルの減少など、RAS経路下流のシグナル伝達分子のレベルの減少;及び/又は(e)Rafを含むが、これに限定されない下流のシグナル伝達分子へのRAS複合体の結合の減少を示すことが挙げられる。上記の1つ以上を決定するために、キット及び市販のアッセイを利用することができる。
本開示はまた、他の経路、若しくは同じ経路の他の成分を調節することが知られている薬剤、又は標的酵素の重複するセットさえも、本開示の化合物、又はその薬学的に許容される塩と組み合わせて使用される、併用療法の方法を提供する。一態様では、そのような治療は、相乗的又は相加的な治療効果を提供するために、本開示の1つ以上の化合物と、化学療法剤、治療抗体及び放射線治療との組み合わせを含むが、これらに限定されない。
実施例8−1:6−クロロ−7−(2−フルオロ−6−ヒドロキシフェニル)−1−(2−(2−プロパニル)フェニル)−4−(4−(2−プロペノイル)−1−ピペラジニル)−2(1H)−キナゾリノン
2,2,2−トリフルオロ酢酸(S)−1−(3−メチルピペラジン−1−イル)プロパ−2−エン−1−オン(実施例8−1、工程6b)
実施例9−1:6−クロロ−7−(2,3−ジクロロ−5−ヒドロキシフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)−2(1H)−キナゾリノン。
実施例54−1:6−クロロ−7−(2−フルオロ−6−ヒドロキシフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(メチルスルホニル)フェニル)ピリド[2,3−d]ピリミジン−2(1H)−オン
実施例55−1:6−クロロ−7−(2−フルオロ−6−ヒドロキシフェニル)−1−(3−メチル−5−(2−プロパニル)−1,2−オキサゾール−4−イル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例56−1:6−クロロ−7−(2−フルオロ−6−ヒドロキシ−フェニル)−4−[(2S)−2−メチル−4−プロパ−2−エノイル−ピペラジン−1−イル]−1−[2−(ペンタフルオロ−λ6−スルファニル)フェニル]ピリド[2,3−d]ピリミジン−2−オン。
実施例57−1:1−(2−エチル−4−メチル−3−ピリジニル)−6−フルオロ−7−(2−フルオロ−6−ヒドロキシフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例58−1:6−フルオロ−7−(2−フルオロ−6−ヒドロキシフェニル)−1−(2−(2−メチル−2−プロパニル)フェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン
実施例59−1:6−フルオロ−7−(2−フルオロ−6−ヒドロキシフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(1−(トリフルオロメチル)シクロプロピル)フェニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例60−1:6−クロロ−1−(3−シクロプロピル−2−ピリジニル)−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例61−1:6,7−ジクロロ−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
ピーク2(異性体2、698mg、98.0% ee)。1H NMR(400MHz,DMSO−d6)δppm 8.37(s,1H),7.47−7.52(m,1H),7.40−7.46(m,1H),7.30(td,J=7.5,1.5Hz,1H),7.12(dd,J=7.8,0.9Hz,1H),4.77(br s,1H),4.19(br d,J=13.5Hz,1H),3.90−4.05(m,1H),3.82(br d,J=13.5Hz,1H),3.62(br t,J=11.4Hz,1H),3.02−3.18(m,1H),2.41−2.50(m,2H),1.45(s,9H),1.34(d,J=6.6Hz,3H),1.08(d,J=6.8Hz,3H),1.02(d,J=6.6Hz,3H).m/z(ESI,+veイオン):532.3(m+H)+.
実施例62−1:6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)−2(1H)−キナゾリノン。
実施例63−1:6−フルオロ−7−(2−フルオロ−6−ヒドロキシフェニル)−1−(2−メチル−6−(2−プロパニル)フェニル)−4−((3S)−3−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例64−1:(M)−6−クロロ−7−(2−フルオロフェニル)−1−(2−メチル−6−(2−プロパニル)フェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例65−1:(M)−7−(6−アミノ−3−クロロ−2−ピリジニル)−6−フルオロ−1−(4−メチル−2−(2−プロパニル)−3−ピリジニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例66−1:6−クロロ−1−(2,6−ジエチルフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−7−(1−ピペリジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例67−1:6−クロロ−7−(3−フルオロ−4−ピリジニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例68−1:7−(2−クロロ−6−ヒドロキシフェニル)−6−フルオロ−1−(2−メチル−6−(2−プロパニル)フェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例69−1:6−クロロ−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−7−(1−ピペリジニル)−1−(2−(2−プロパニル)フェニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例70−1:7−(6−アミノ−3−クロロ−2−ピリジニル)−6−クロロ−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例71−1:7−(6−アミノ−3−クロロ−2−ピリジニル)−6−フルオロ−1−(2−メチル−6−(2−プロパニル)フェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例72−1:(M)−6−フルオロ−7−(5−フルオロ−2−ヒドロキシフェニル)−1−(4−メチル−2−(2−プロパニル)−3−ピリジニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例73−1:(M)−7−(2−アミノ−6−フルオロフェニル)−6−クロロ−1−(4−メチル−2−(2−プロパニル)−3−ピリジニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例74−1:7−(2−フルオロフェニル)−6−メチル−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例75−1:(M)−4−(cis−2,6−ジメチル−4−(2−プロペノイル)−1−ピペラジニル)−6−フルオロ−7−(2−フルオロ−6−ヒドロキシフェニル)−1−(4−メチル−2−(2−プロパニル)−3−ピリジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例76−1:(M)−6−クロロ−7−(2−フルオロフェニル)−1−(4−メチル−2−(2−プロパニル)−3−ピリジニル)−4−((1−(2−プロペノイル)−3−アゼチジニル)アミノ)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例:77−1:3−(2−フルオロフェニル)−2−メチル−5−(2−メチルフェニル)−8−(4−(2−プロペノイル)−1−ピペラジニル)−6H−ピリミド[1,6−b]ピリダジン−6−オン。
実施例:78−1:(M)−6−クロロ−7−(2−フルオロフェニル)−1−(4−メチル−2−(2−プロパニル)−3−ピリジニル)−4−((3R)−3−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例79−1:(M)−6−クロロ−7−(2−フルオロフェニル)−1−(4−メチル−2−(2−プロパニル)−3−ピリジニル)−4−((1−(2−プロペノイル)−3−アゼチジニル)オキシ)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例80−1:6−クロロ−1−(4−((ジメチルアミノ)メチル)−2−メチル−6−(2−プロパニル)フェニル)−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例81−1:3−(2−ブロモフェニル)−2−メチル−5−(2−メチルフェニル)−8−(4−(2−プロペノイル)−1−ピペラジニル)−6H−ピリミド[1,6−b]ピリダジン−6−オン。
実施例82−1:(M)−6−クロロ−7−(5−メチル−1H−インダゾール−4−イル)−1−(4−メチル−2−(2−プロパニル)−3−ピリジニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例83−1:(P)−6−クロロ−7−(2−フルオロフェニル)−1−(5−ヒドロキシ−4−メチル−2−(2−プロパニル)−3−ピリジニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン及び実施例84−1:(P)−6−クロロ−7−(2−フルオロフェニル)−1−(4−(ヒドロキシメチル)−2−(2−プロパニル)−3−ピリジニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
画分1:黄色固体としての(P)−(S)−4−(1−(5−アセトキシ−2−イソプロピル−4−メチルピリジン−3−イル)−6−クロロ−7−(2−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリド[2,3−d]ピリミジン−4−イル)−3−メチルピペラジン−1−カルボン酸tert−ブチル(中間体83C、0.051g、0.077mmol、収率15.3%)。1H NMR(400MHz,DMSO−d6)δppm 8.33(s,1H),7.48−7.55(m,1H),7.18−7.34(m,4H),4.96(br s,1H),4.26(br d,J=13.5Hz,1H),3.93−4.06(m,1H),3.85(br d,J=12.9Hz,1H),3.69−3.81(m,1H),3.03−3.26(m,2H),2.69−2.77(m,1H),2.34(s,3H),1.46(s,12H),1.35(br d,J=6.4Hz,3H),1.08(d,J=6.6Hz,3H),0.92(d,J=6.6Hz,3H).19F NMR(376MHz,DMSO−d6)δppm −113.61(s,1F).m/z(ESI,+veイオン):665.0(m+H).
画分2:黄色固体としての(P)−(S)−4−(1−(4−(アセトキシメチル)−2−イソプロピルピリジン−3−イル)−6−クロロ−7−(2−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリド[2,3−d]ピリミジン−4−イル)−3−メチルピペラジン−1−カルボン酸tert−ブチル(中間体83D、0.042g、0.062mmol、収率12%)。1H NMR(400MHz,DMSO−d6)δppm 8.56(d,J=4.8Hz,1H),8.43(s,1H),7.46−7.56(m,1H),7.20−7.35(m,4H),4.89(br s,1H),4.77−4.86(m,2H),4.29(br d,J=13.1Hz,1H),3.95−4.05(m,1H),3.86(br d,J=13.5Hz,1H),3.64−3.76(m,1H),3.04−3.28(m,2H),2.72(dt,J=13.5,6.7Hz,1H),1.86(s,3H),1.46(s,9H),1.38(br d,J=6.2Hz,3H),1.07(br d,J=6.6Hz,3H),0.95(br d,J=6.6Hz,3H).19F NMR(376MHz,DMSO−d6)δppm−113.85(br s,1F).m/z(ESI,+veイオン):665.0(m+H).
実施例85−1:1−(4−(3−クロロ−2−(2−フルオロフェニル)−7−(ヒドロキシメチル)−8−(2−イソプロピルフェニル)−1,6−ナフチリジン−5−イル)ピペラジン−1−イル)プロパ−2−エン−1−オン。
実施例86−1:1−((3S)−4−(3−クロロ−7−((ジメチルアミノ)メチル)−2−(2−フルオロフェニル)−8−(2−イソプロピルフェニル)−1,6−ナフチリジン−5−イル)−3−メチルピペラジン−1−イル)プロパ−2−エン−1−オン。
実施例87−1:6−クロロ−4−((2S,6S)−2,6−ジメチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(4,6−ジ(2−プロパニル)−5−ピリミジニル)−7−(2−フルオロフェニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
実施例88
6−クロロ−7−(2−フルオロフェニル)−1−(2−(2−プロパニル)フェニル)−4−(4−(2−プロペノイル)−1−ピペラジニル)−2(1H)−キナゾリノン。
6−クロロ−1−(2,2−ジメチルプロピル)−7−(2−フルオロ−6−ヒドロキシフェニル)−4−(4−(2−プロペノイル)−1−ピペラジニル)−2(1H)−キナゾリノン。
6−クロロ−7−(2−フルオロ−6−ヒドロキシフェニル)−8−メチル−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)−2(1H)−キナゾリノン。
6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(1−(2−プロパニル)−1H−イミダゾール−2−イル)−2(1H)−キナゾリノン。
6−クロロ−4−(4−((2E)−4−(ジメチルアミノ)−2−ブテノイル)−1−ピペラジニル)−7−(2−フルオロ−6−ヒドロキシフェニル)−1−(2−(2−プロパニル)フェニル)−2(1H)−キナゾリノン。
6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(トリフルオロメチル)フェニル)−2(1H)−キナゾリノン。
6−クロロ−7−シクロプロピル−1−(2,6−ジエチルフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
6,7−ジシクロプロピル−1−(2,6−ジエチルフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
(2R)−1−(6−クロロ−1−(2,6−ジエチルフェニル)−7−(2−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリド[2,3−d]ピリミジン−4−イル)−4−(2−プロペノイル)−2−ピペラジンカルボン酸。
6−クロロ−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−7−(2−オキソ−1,2−ジヒドロ−3−ピリジニル)−1−(2−(2−プロパニル)フェニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
2−(6−クロロ−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−2−オキソ−1−(2−(2−プロパニル)フェニル)−1,2−ジヒドロピリド[2,3−d]ピリミジン−7−イル)−3−フルオロベンゾニトリル。
6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(5−(2−プロパニル)−4−ピリミジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
6−クロロ−7−(2−フルオロ−6−ヒドロキシフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−フェニルピリド[2,3−d]ピリミジン−2(1H)−オン。
6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−メチルプロピル)−3−ピリジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
7−(2−フルオロフェニル)−6−メチル−1−(2−メチル−6−(2−プロパニル)フェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
6−クロロ−1−(2,6−ジエチルフェニル)−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−2(1H)−キナゾリノン。
6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(3−(2−プロパニル)−2−ピリジニル)−2(1H)−キナゾリノン。
6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(4−(2−プロパニル)−1,3−チアゾール−5−イル)−2(1H)−キナゾリノン。
6−クロロ−7−(2−フルオロ−6−ヒドロキシフェニル)−1−(2−メチル−6−(2−プロパニル)フェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−2(1H)−キナゾリノン
1−(2,6−ジエチルフェニル)−7−(2−フルオロ−6−ヒドロキシフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン
6−エチル−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)−2(1H)−プテリジノン。
7−(2−フルオロフェニル)−6−メトキシ−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)−2(1H)−プテリジノン。
6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)ピリド[3,2−d]ピリミジン−2(1H)−オン。
6−クロロ−7−(2−フルオロフェニル)−1−(4−メチル−2−(2−プロパニル)−3−ピリジニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−2(1H)−プテリジノン
(M)−6,7−ジクロロ−1−(2−メチル−6−(2−プロパニル)フェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
7−(5−クロロ−2−ヒドロキシフェニル)−6−フルオロ−1−(2−メチル−6−(2−プロパニル)フェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。(P1からのMアトロプ異性体、x線なし)
7−(5−クロロ−2−ヒドロキシフェニル)−6−フルオロ−1−(2−メチル−6−(2−プロパニル)フェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。(ピーク2からのPアトロプ異性体、x線なし)。
(M)−6−クロロ−7−((2R)−2−メチル−1−ピペリジニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)ピリド[2,3−d]ピリミジン−2(1H)−オン及び(M)−6−クロロ−7−((2S)−2−メチル−1−ピペリジニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)ピリド[2,3−d]ピリミジン−2(1H)−オンの混合物。
ピーク1((M)−異性体:中間体115A、720mg、97.5% ee)。1H NMR(400MHz,DMSO−d6)δppm 8.41(s,1H),7.46−7.51(m,1H),7.39−7.45(m,1H),7.29(td,J=7.5,1.6Hz,1H),7.12(dd,J=7.7,1.0Hz,1H),4.88(br s,1H),4.06(br d,J=13.3Hz,1H),3.88−4.00(m,1H),3.83(br d,J=13.3Hz,1H),3.72(br t,J=10.9Hz,1H),2.92−3.14(m,1H),2.39−2.48(m,2H),1.45(s,9H),1.30(d,J=6.6Hz,3H),1.07(d,J=6.8Hz,3H),1.01(d,J=6.8Hz,3H).m/z(ESI,+veイオン)532.3(m+H)+.
ピーク2((P)−異性体、698mg、98% ee)。1H NMR(400MHz,DMSO−d6)δppm 8.37(s,1H),7.47−7.52(m,1H),7.40−7.46(m,1H),7.30(td,J=7.5,1.5Hz,1H),7.12(dd,J=7.8,0.9Hz,1H),4.77(br s,1H),4.19(br d,J=13.5Hz,1H),3.90−4.05(m,1H),3.82(br d,J=13.5Hz,1H),3.62(br t,J=11.4Hz,1H),3.02−3.18(m,1H),2.41−2.50(m,2H),1.45(s,9H),1.34(d,J=6.6Hz,3H),1.08(d,J=6.8Hz,3H),1.02(d,J=6.6Hz,3H).m/z(ESI,+veイオン):532.3(m+H)+.
1−((3S)−4−(6−クロロ−1−(2,6−ジエチルフェニル)−7−(2−フルオロフェニル)−2−スルファニリデン−1,2−ジヒドロ−4−キナゾリニル)−3−メチル−1−ピペラジニル)−2−プロペン−1−オン
1−(4−(2−アジドエトキシ)−2−(2−プロパニル)フェニル)−6−クロロ−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−7−(1−ピペリジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
工程1:水(3mL)及びDMSO(1mL)中の4−(6−クロロ−1−(2−イソプロピル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)フェニル)−2−オキソ−7−(ピペリジン−1−イル)−1,2−ジヒドロピリド[2,3−d]ピリミジン−4−イル)−3−メチルピペラジン−1−カルボン酸(S)−tert−ブチル(313mg、0.44mmol)、1,10−フェナントロリン(16mg、0.089mmol)、硫酸銅(II)(7.0mg、0.044mmol)、水酸化カリウム(75mg、1.33mmol)の反応混合物を、室温の大気下で2時間撹拌した。反応混合物を、飽和塩化アンモニウムでクエンチし、EtOAc(50mL)で抽出した。有機相を分離し、塩水で洗浄し、MgSO4で乾燥させ、真空中で濃縮した。粗生成物を、シリカゲルクロマトグラフィー(溶離液:0〜60% DCM−MeOH(4:1)/DCM)により精製して、4−(6−クロロ−1−(4−ヒドロキシ−2−イソプロピルフェニル)−2−オキソ−7−(ピペリジン−1−イル)−1,2−ジヒドロピリド[2,3−d]ピリミジン−4−イル)−3−メチルピペラジン−1−カルボン酸(S)−tert−ブチル(150mg、0.25mmol、収率56.8%)を得た。1H NMR(400MHz,CDCl3)δppm 7.67(1H,s),6.72−6.79(2H,m),6.62−6.72(1H,m),6.49−6.56(1H,m),4.63−4.92(1H,m),4.10−4.26(2H,m),3.87−4.07(1H,m),3.43−3.71(1H,m),3.27−3.39(4H,m),2.97−3.27(1H,m),2.52(1H,dt,J=13.4,6.7Hz),1.93(3H,br s),1.53−1.69(6H,m),1.34−1.48(1H,m),1.24(9H,s),1.20(3H,dd,J=6.8,1.9Hz),0.93−1.00(3H,m).m/z(ESI,+veイオン):597.4(m+H)+.
6−クロロ−1−(2,6−ジエチルフェニル)−7−(2−フルオロフェニル)−4−(1−(2−プロペノイル)−4−ピペリジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン
6−クロロ−7−(2−フルオロ−6−ヒドロキシフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン
1−(2,2−ジメチルプロピル)−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1,8−ナフチリジン−2(1H)−オン及び6−クロロ−1−(2,2−ジメチルプロピル)−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1,8−ナフチリジン−2(1H)−オン
6−クロロ−1−(2,2−ジメチルプロピル)−7−(2−フルオロフェニル)−4−(4−(2−プロペノイル)−1−ピペラジニル)−1,8−ナフチリジン−2(1H)−オン及び1−(2,2−ジメチルプロピル)−7−(2−フルオロフェニル)−4−(4−(2−プロペノイル)−1−ピペラジニル)−1,8−ナフチリジン−2(1H)−オン
TFA(0.5mL、6.49mmol)を、DCM(3mL)中の4−(7−(2−フルオロフェニル)−1−ネオペンチル−2−オキソ−1,2−ジヒドロ−1,8−ナフチリジン−4−イル)ピペラジン−1−カルボン酸tert−ブチル(48mg、0.097mmol)の溶液に室温で加えた。25分後、反応混合物を真空中で濃縮した。残渣をDCM(3mL)中で溶解させ、溶液を0℃まで冷却した。DIPEA(0.085mL、0.49mmol)及び塩化アクリロイル(7.9μL、0.097mmol)を順次加え、反応混合物を0℃で10分間撹拌した。反応混合物を飽和NaHCO3で処理し、DCMで抽出した。有機相をMgSO4で乾燥させ、真空中で濃縮した。粗生成物を、シリカゲルクロマトグラフィー(溶離液:0〜20% DCM−MeOH(4:1)/DCM)により精製して、1−(2,2−ジメチルプロピル)−7−(2−フルオロフェニル)−4−(4−(2−プロペノイル)−1−ピペラジニル)−1,8−ナフチリジン−2(1H)−オン(実施例123)を得た。1H NMR(400MHz,DMSO−d6)δppm 8.30(1H,d,J=8.3Hz),8.10−8.19(1H,m),7.71−7.79(1H,m),7.52−7.61(1H,m),7.32−7.48(2H,m),6.81−6.93(1H,m),6.11−6.22(1H,m),6.05−6.11(1H,m),5.68−5.81(1H,m),4.44(2H,br s),3.82(4H,br s),3.06−3.20(4H,m),0.88−0.95(9H,s).19F NMR(376MHz,DMSO−d6)δppm−115.48(1F,s).m/z(ESI,+veイオン):449.2(m+H)+.
6−クロロ−1−(2,2−ジメチルプロピル)−7−(2−フルオロフェニル)−4−(1−(2−プロペノイル)−1,2,3,6−テトラヒドロ−4−ピリジニル)−1,8−ナフチリジン−2(1H)−オン
TFA(0.5mL、6.49mmol)を、DCM(3mL)中の4−(6−クロロ−7−(2−フルオロフェニル)−1−ネオペンチル−2−オキソ−1,2−ジヒドロ−1,8−ナフチリジン−4−イル)−5,6−ジヒドロピリジン−1(2H)−カルボン酸tert−ブチル(117mg、0.222mmol)の溶液に室温で加えた。20分後、反応混合物を真空中で濃縮した。残渣をDCM(1mL)中で溶解させ、溶液を0℃まで冷却した。DIPEA(0.19mL、1.11mmol)及び塩化アクリロイル(0.018mL、0.22mmol)を順次加え、反応混合物を0℃で10分間撹拌した。反応混合物を、飽和NaHCO3で処理し、DCMで抽出した。有機層をMgSO4で乾燥させ、真空中で濃縮した。粗生成物を、シリカゲルクロマトグラフィー(溶離液:0〜30% DCM−MeOH(4:1)/DCM)により精製して、6−クロロ−1−(2,2−ジメチルプロピル)−7−(2−フルオロフェニル)−4−(1−(2−プロペノイル)−1,2,3,6−テトラヒドロ−4−ピリジニル)−1,8−ナフチリジン−2(1H)−オンを得た。1H NMR(400MHz,DMSO−d6)δppm 8.28(1H,s),7.59−7.66(1H,m),7.50−7.56(1H,m),7.36−7.46(2H,m),6.76−7.01(1H,m),6.68(1H,s),6.13−6.24(1H,m),5.99−6.11(1H,m),5.74(1H,br d,J=10.2Hz),4.19−4.44(6H,m),3.80−3.92(2H,m),0.90(9H,s).19F NMR(376MHz,DMSO−d6)δppm−114.23(1F,s).m/z(ESI,+veイオン):480.2(m+H)+.
6−クロロ−1−(2,2−ジメチルプロピル)−7−(2−フルオロフェニル)−4−(1−(2−プロペノイル)−4−ピペリジニル)−1,8−ナフチリジン−2(1H)−オン
6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)−1,8−ナフチリジン−2(1H)−オン及び7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)−1,8−ナフチリジン−2(1H)−オン
工程3−1:THF(3mL)中の5−クロロ−6−(2−フルオロフェニル)−2−((2−イソプロピルフェニル)アミノ)ニコチン酸(186mg、0.483mmol)及びCDI(86mg、0.531mmol)の混合物を50℃まで1時間加熱し、続いて室温でさらに1.5時間撹拌した。別々のフラスコにおいて、イソプロピルマグネシウムクロリド(THF中2.0M、1.1mL、2.2mmol)を、THF(3mL)中のマロン酸モノ−ベンジル(200mg、1mmol、Sigma−Aldrich Corporation、St.Louis、MO)の溶液に0℃で加えた。30分後、反応物を50℃まで1.5時間加熱した。両方の溶液を0℃まで冷却し、マロン酸マグネシウム溶液を、ニコチン酸溶液に滴下して加えた。氷浴を取り外し、混合物を室温まで一晩撹拌した。5N HClを、透明になるまで反応混合物に滴下して加えた。溶液をEtOAc(40mL)で抽出した。有機抽出物を塩水で洗浄し、MgSO4で乾燥させ、真空中で濃縮した。粗生成物を、シリカゲルクロマトグラフィー(溶離液:0〜20% EtOAc/ヘプタン)により精製して、山吹色の油として3−(5−クロロ−6−(2−フルオロフェニル)−2−((2−イソプロピルフェニル)アミノ)ピリジン−3−イル)−3−オキソプロパン酸ベンジル(152mg、0.3mmol、収率61%)を得た。19F NMR(376MHz,CDCl3)δppm−112.46(1F,s),−112.54(1F,s).m/z(ESI,+veイオン):517.1(m+H)+.
工程6−1:TFA(0.5mL、6.49mmol)を、DCM(3mL、室温)中の4−(6−クロロ−7−(2−フルオロフェニル)−1−(2−イソプロピルフェニル)−2−オキソ−1,2−ジヒドロ−1,8−ナフチリジン−4−イル)−3−メチルピペラジン−1−カルボン酸(S)−tert−ブチル及び4−(7−(2−フルオロフェニル)−1−(2−イソプロピルフェニル)−2−オキソ−1,2−ジヒドロ−1,8−ナフチリジン−4−イル)−3−メチルピペラジン−1−カルボン酸(S)−tert−ブチル(58mg、0.098mmol)の1:1の混合物に室温で加えた。20分後、反応混合物を真空中で濃縮した。得られた残渣をDCM(3mL)中で溶解させ、0℃まで冷却した。DIPEA(0.086mL、0.491mmol)及び塩化アクリロイル(8.0μl、0.098mmol)を順次加え、反応混合物を0℃で10分間撹拌した。反応混合物を、飽和NaHCO3で処理し、DCMで抽出した。有機相をMgSO4で乾燥させ、真空中で濃縮した。粗生成物を、シリカゲルクロマトグラフィー(溶離液:0〜30% DCM−MeOH(4:1)/DCM)により精製して、2種の生成物を得た。6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)−1,8−ナフチリジン−2(1H)−オン(実施例126)。1H NMR(400MHz,DMSO−d6)δppm 8.33(1H,d,J=5.0Hz),7.45−7.51(1H,m),7.40−7.45(1H,m),7.35(1H,t,J=7.6Hz),7.14−7.32(4H,m),7.05−7.14(1H,m),6.88(1H,br s),6.28(1H,d,J=14.5Hz),6.14−6.24(1H,m),5.73−5.78(1H,m),4.32(1H,br d,J=12.4Hz),3.97−4.16(1H,m),3.89(2H,br d,J=18.9Hz),3.60−3.75(1H,m),3.00(1H,br d,J=8.7Hz),2.37−2.44(1H,m),2.08(1H,s),0.99−1.09(6H,m),0.96(3H,t,J=7.3Hz).19F NMR(376MHz,DMSO−d6)δppm−114.06(1F,s),−114.17(1F,s),−114.20(1F,s).m/z(ESI,+veイオン):545.2(m+H)+.
7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(2−プロパニル)フェニル)−1,8−ナフチリジン−2(1H)−オン(実施例127)。1H NMR(400MHz,DMSO−d6)δppm 8.37(1H,dd,J=8.3,3.3Hz),7.75(1H,d,J=7.9Hz),7.50−7.53(1H,m),7.39−7.49(3H,m),7.26−7.35(2H,m),7.13−7.19(1H,m),7.07−7.13(1H,m),6.82−6.97(1H,m),6.14−6.24(2H,m),5.72−5.79(1H,m),4.29−4.41(1H,m),4.03−4.16(1H,m),3.82−4.01(3H,m),3.59(1H,br d,J=8.5Hz),3.01−3.09(1H,m),1.08(3H,t,J=7.4Hz),1.02(3H,br d,J=3.3Hz),0.95(2H,d,J=6.8Hz),0.91(2H,d,J=6.8Hz)19F NMR(376MHz,DMSO−d6)δppm−115.14(1F,s),−115.16(1F,s),−115.18(1F,s).m/z(ESI,+veイオン):511.2(m+H)+.
7−ブロモ−6−クロロ−4−(4−(2−プロペノイル)−1−ピペラジニル)−1−(2−(トリフルオロメチル)フェニル)−2(1H)−キナゾリノン。
(M)−6−クロロ−7−(2−フルオロ−6−ヒドロキシフェニル)−1−(4−メチル−2−(2−プロパニル)−3−ピリジニル)−4−((3R)−3−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン
1−(4−(3−クロロ−2−(2−フルオロフェニル)−8−(2−(2−プロパニル)フェニル)−1,6−ナフチリジン−5−イル)−1−ピペラジニル)−2−プロペン−1−オン。
5−(4−アクリロイルピペラジン−1−イル)−3−クロロ−2−(2−フルオロフェニル)−7−メチル−1,6−ナフチリジン−8−カルボン酸メチル
2−(6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−2−オキソピリド[2,3−d]ピリミジン−1(2H)−イル)−3−(2−プロパニル)安息香酸。
6−クロロ−1−(4−クロロ−6−(2−プロパニル)−5−ピリミジニル)−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
1−((3S)−4−(3−クロロ−2−(2−フルオロフェニル)−7−メトキシ−8−(2−メチルフェニル)−1,6−ナフチリジン−5−イル)−3−メチル−1−ピペラジニル)−2−プロペン−1−オン。
(M)−6−クロロ−7−(2−フルオロフェニル)−1−(4−メチル−2−(2−プロパニル)−3−ピリジニル)−4−((1R,5S)−6−(2−プロペノイル)−3,6−ジアザビシクロ[3.1.1]ヘプタン−3−イル)ピリド[2,3−d]ピリミジン−2(1H)−オン
1−(6−アミノ−4−メチル−2−(2−プロパニル)−3−ピリジニル)−6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
塩化オキサリル(DCM中2M、0.46mL、0.91mmol)を、1,2−ジクロロエタン(10mL)中の2,5,6−トリクロロニコチンアミド(中間体P、187mg、0.831mmol)の溶液に窒素雰囲気下で加えた。得られた混合物を、80℃に1時間加熱した。混合物を室温まで冷却し、MeCN(5mL)中の6−イソプロピル−N2,N2−ビス(4−メトキシベンジル)−4−メチルピリジン−2,5−ジアミン(中間体I−33、337mg、0.831mmol)の溶液を加えた。1時間後、混合物を、飽和NH4Cl(5mL)でクエンチし、飽和NaHCO3(25mL)で希釈した。混合物をEtOAc(2×100mL)で抽出した。合わせた有機抽出物をMgSO4で乾燥させ、減圧下で濃縮した。粗生成物を、シリカゲルクロマトグラフィー(溶離液:0〜100% EtOAc−EtOH(3:1)/ヘプタン)により精製して、黄色固体としてN−((6−(ビス(4−メトキシベンジル)アミノ)−2−イソプロピル−4−メチルピリジン−3−イル)カルバモイル)−2,5,6−トリクロロニコチンアミドを得た。m/z(ESI、+veイオン):656.0(M+H)+.生成物をさらに精製することなく次の工程に使用した。
KHMDS(THF中1M、1.662mL、1.662mmol)を、テトラヒドロフラン(15mL)中のN−((6−(ビス(4−メトキシベンジル)アミノ)−2−イソプロピル−4−メチルピリジン−3−イル)カルバモイル)−2,5,6−トリクロロニコチンアミド(546mg、0.831mmol)の溶液に窒素雰囲気下にて0℃で滴下して加えた。添加が完了した後、反応混合物を0℃で30分間撹拌した。反応混合物を、飽和NH4Cl(5mL)でクエンチし、飽和NaHCO3(16mL)で希釈し、EtOAc(2×100mL)で抽出した。合わせた有機抽出物を、MgSO4で乾燥させ、減圧下で濃縮した。粗生成物を、シリカゲルクロマトグラフィー(溶離液:0〜100% EtOAc−EtOH(3:1)/ヘプタン)により精製して、黄色固体として1−(6−(ビス(4−メトキシベンジル)アミノ)−2−イソプロピル−4−メチルピリジン−3−イル)−6,7−ジクロロピリド[2,3−d]ピリミジン−2,4(1H,3H)−ジオン(476mg、0.767mmol、収率92%)を得た。m/z(ESI、+veイオン):620.0(M+H)+.
1,1’−ジメチルトリエチルアミン(0.46mL、2.66mmol)及び酸化塩化リン(0.18mL、1.898mmol)を、アセトニトリル(8mL)中の1−(6−(ビス(4−メトキシベンジル)アミノ)−2−イソプロピル−4−メチルピリジン−3−イル)−6,7−ジクロロピリド[2,3−d]ピリミジン−2,4(1H,3H)−ジオン(471mg、0.759mmol)の溶液に加えた。得られた混合物を、窒素雰囲気下で70℃まで30分間加熱した。反応混合物を室温まで冷却し、MeCN(4mL)中の(3S)−1−(tert−ブトキシカルボニル)−3−メチルピペラジン(0.30mL、1.518mmol、Combi−Blocks、San Diego、CA)及び1,1’−ジメチルトリエチルアミン(0.46mL、2.66mmol)の混合物を加えた。30分後、反応混合物を水(20mL)で希釈し、EtOAc(2×50mL)で抽出した。合わせた有機抽出物をMgSO4で乾燥させ、減圧下で濃縮した。粗生成物を、シリカゲルクロマトグラフィー(溶離液:0〜80% EtOAc−EtOH(3:1)/ヘプタン)により精製して、黄色固体として(S)−4−(1−(6−(ビス(4−メトキシベンジル)アミノ)−2−イソプロピル−4−メチルピリジン−3−イル)−6,7−ジクロロ−2−オキソ−1,2−ジヒドロピリド[2,3−d]ピリミジン−4−イル)−3−メチルピペラジン−1−カルボン酸tert−ブチルを得た。m/z(ESI、+veイオン):(M−i−C4H8=746.0)
1,4−ジオキサン(7mL)中の(S)−4−(1−(6−(ビス(4−メトキシベンジル)アミノ)−2−イソプロピル−4−メチルピリジン−3−イル)−6,7−ジクロロ−2−オキソ−1,2−ジヒドロピリド[2,3−d]ピリミジン−4−イル)−3−メチルピペラジン−1−カルボン酸tert−ブチル(609mg、0.759mmol)、(2−フルオロフェニル)ボランジオール(212mg、1.517mmol、Combi−Blocks、San Diego、CA)、(1,1’−ビス(ジフェニルホスフィノ)フェロセン)ジクロロパラジウム(56mg、0.076mmol)、及び酢酸カリウム(371mg、3.79mmol)の混合物を、窒素雰囲気下で80℃まで1時間加熱した。反応混合物を飽和NaHCO3(10mL)で希釈し、EtOAc(2×50mL)で抽出した。合わせた有機抽出物を、MgSO4で乾燥させ、減圧下で濃縮した。粗生成物を、シリカゲルクロマトグラフィー(溶離液:0〜100% EtOAc−EtOH(3:1)/ヘプタン)により精製して、黄色固体として(S)−4−(1−(6−(ビス(4−メトキシベンジル)アミノ)−2−イソプロピル−4−メチルピリジン−3−イル)−6−クロロ−7−(2−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリド[2,3−d]ピリミジン−4−イル)−3−メチルピペラジン−1−カルボン酸tert−ブチル(654mg、0.758mmol、収率100%)を得た。m/z(ESI、+veイオン):862.2(M+H)+.
TFA(3.6mL、48.7mmol)中の(S)−4−(4−アクリロイル−2−メチルピペラジン−1−イル)−1−(6−(ビス(4−メトキシベンジル)アミノ)−2−イソプロピル−4−メチルピリジン−3−イル)−6−クロロ−7−(2−フルオロフェニル)ピリド[2,3−d]ピリミジン−2(1H)−オン(568mg、0.696mmol)の溶液を、マイクロ波中で100℃まで10分間加熱した。反応混合物を減圧下で濃縮し、残渣をDCM(20mL)中で溶解させた。飽和NaHCO3(50mL)を0℃でゆっくりと加えた。添加が完了した後、有機層を分離し、MgSO4で乾燥させ、真空中で濃縮した。粗生成物を、シリカゲルクロマトグラフィー(溶離液:0〜10% MeOH(2M NH3/ヘプタン)により精製して、黄色固体、TFA塩として1−(6−アミノ−4−メチル−2−(2−プロパニル)−3−ピリジニル)−6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン(165mg、0.143mmol、収率41.2%)を得た。1H NMR(DMSO−d6)δ:8.40(br s,1H),7.48−7.60(m,1H),7.22−7.36(m,3H),6.78−6.93(m,1H),6.15−6.25(m,2H),5.70−5.84(m,3H),4.79−5.03(m,1H),4.22−4.49(m,2H),3.96−4.19(m,1H),3.40−3.83(m,2H),3.01−3.29(m,2H),1.73(s,3H),1.29−1.35(m,3H),0.99(d,J=6.8Hz,3H),0.86−0.89(m,3H).19F NMR(DMSO−d6)δ:−114.09(s,1F),−114.13(s,1F).m/z(ESI,+veイオン):576.0(m+H)+
6−クロロ−7−(2−フルオロフェニル)−1−(4−メチル−6−オキソ−2−(2−プロパニル)−1,6−ジヒドロ−3−ピリジニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン
1−((3S)−4−(3−クロロ−8−(2,6−ジ(2−プロパニル)フェニル)−2−(2−フルオロフェニル)ピリド[2,3−d]ピリダジン−5−イル)−3−メチル−1−ピペラジニル)−2−プロペン−1−オン
1−(2−アミノ−4,6−ジ(2−プロパニル)−5−ピリミジニル)−6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
m/z(ESI、+veイオン):569.8/571.8(M+H)。
1H NMR(400MHz,DMSO−d6)δppm 0.86(d,J=6.63Hz,6H)1.02(d,J=6.63Hz,6H)2.68(五重項,J=6.69Hz,2H)6.58(s,2H)7.21(td,J=7.52,1.55Hz,1H)7.28−7.35(m,2H)7.48−7.56(m,1H)8.54(s,1H)12.15(s,1H).m/z(ESI,+veイオンイオン):469.0(m+H).
6−クロロ−1−(4−(ジメチルアミノ)−6−(2−プロパニル)−5−ピリミジニル)−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
4−(6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−2−オキソピリド[2,3−d]ピリミジン−1(2H)−イル)−3−メチル−5−(2−プロパニル)安息香酸。
2−(6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−2−オキソピリド[2,3−d]ピリミジン−1(2H)−イル)−3−(2−プロパニル)ベンズアミド。
実施例142−1(1番目に溶出する異性体):2−(6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−2−オキソピリド[2,3−d]ピリミジン−1(2H)−イル)−3−(2−プロパニル)ベンズアミド。1H NMR(400MHz,DMSO−d6)δ 8.29−8.37(m,1H),7.38−7.49(m,4H),7.34(dd,J=7.88,15.34Hz,1H),7.10−7.25(m,3H),6.95(br s,1H),6.71−6.86(m,1H),6.14(d,J=15.34Hz,1H),5.69(dd,J=2.07,10.37Hz,1H),4.79−4.94(m,1H),3.90−4.40(m,3H),3.28−3.78(m,2H),2.92−3.19(m,1H),2.62−2.74(m,1H),1.23(d,J=6.43Hz,3H),1.02(d,J=6.84Hz,3H),0.91(d,J=7.05Hz,3H).m/z(ESI,+veイオン)M+1=589.3.
実施例142−2(2番目に溶出する異性体):2−(6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−2−オキソピリド[2,3−d]ピリミジン−1(2H)−イル)−3−(2−プロパニル)ベンズアミド。1H NMR(400MHz,DMSO−d6)δ 8.38(d,J=6.22Hz,1H),7.45−7.58(m,4H),7.41(t,J=13.70Hz,1H),7.19−7.32(m,3H),7.03(s,1H),6.78−6.94(m,1H),6.21(dd,J=6.43,16.59Hz,1H),5.76(d,J=10.37Hz,1H),4.76−4.90(m,1H),4.26−4.49(m,1H),3.98−4.25(m,2H),3.38−3.76(m,2H),2.99−3.30(m,1H),2.64−2.79(m,1H),1.30(d,J=6.63Hz,3H),0.96−1.16(m,6H).19F NMR(376MHz,DMSO−d6)δ−113.26(s,1F).19F NMR(376MHz,DMSO−d6)δ−113.21(s,1F).m/z(ESI,+veイオン)M+1=589.3.
7−(2−フルオロフェニル)−6−メチル−1−(4−メチル−2−(2−プロパニル)−3−ピリジニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−2(1H)−プテリジノン。
3−クロロ−2−(2−フルオロフェニル)−7−メチル−N,N−ジ(2−プロパニル)−5−(4−(2−プロペノイル)−1−ピペラジニル)−1,6−ナフチリジン−8−カルボキサミド。
(M)−4−((2S)−4−((2E)−4−(ジメチルアミノ)−2−ブテノイル)−2−メチル−1−ピペラジニル)−6−フルオロ−7−(2−フルオロ−6−ヒドロキシフェニル)−1−(4−メチル−2−(2−プロパニル)−3−ピリジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
3−クロロ−2−(2−フルオロフェニル)−8−(2−(2−プロパニル)フェニル)−5−(4−(2−プロペノイル)−1−ピペラジニル)−1,6−ナフチリジン−7−カルボニトリル。
3−クロロ−2−(2−フルオロフェニル)−8−(2−(2−プロパニル)フェニル)−5−(4−(2−プロペノイル)−1−ピペラジニル)−1,6−ナフチリジン−7−カルボキサミド
1−(4−(3−クロロ−7−(ジフルオロメチル)−2−(2−フルオロフェニル)−8−(2−(2−プロパニル)フェニル)−1,6−ナフチリジン−5−イル)−1−ピペラジニル)−2−プロペン−1−オン
1−(4−(3−クロロ−8−(((2S,5S)−2,5−ジメチル−1−ピロリジニル)カルボニル)−2−(2−フルオロフェニル)−7−(ヒドロキシメチル)−1,6−ナフチリジン−5−イル)−1−ピペラジニル)−2−プロペン−1−オン。
1−((3S)−4−(3−クロロ−2−(2−フルオロフェニル)−7−(ヒドロキシメチル)−1,6−ナフチリジン−5−イル)−3−メチル−1−ピペラジニル)−2−プロペン−1−オン。
(M)−6−クロロ−7−(2−フルオロフェニル)−1−(4−メチル−1−オキシド−2−(2−プロパニル)−3−ピリジニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
(M)−6−クロロ−1−(4−((ジメチルアミノ)メチル)−2−(2−プロパニル)−3−ピリジニル)−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン。
1−((3S)−4−(7−アミノ−3−クロロ−2−(2−フルオロフェニル)−8−(o−トリル)−1,6−ナフチリジン−5−イル)−3−メチルピペラジン−1−イル)プロパ−2−エン−1−オン。
1−((3S)−4−(7−フルオロ−3−クロロ−2−(2−フルオロフェニル)−8−(o−トリル)−1,6−ナフチリジン−5−イル)−3−メチルピペラジン−1−イル)プロパ−2−エン−1−オン
1−(2−アミノ−6−(2−プロパニル)フェニル)−6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)ピリド[2,3−d]ピリミジン−2(1H)−オン
4−(6−クロロ−7−(2−フルオロフェニル)−4−((2S)−2−メチル−4−(2−プロペノイル)−1−ピペラジニル)−2−オキソピリド[2,3−d]ピリミジン−1(2H)−イル)−3−メチル−5−(2−プロパニル)安息香酸メチル。
4−((2S,5R)−4−アクリロイル−2,5−ジメチルピペラジン−1−イル)−1−(2−イソプロピルフェニル)−7−フェニル−5,6,7,8−テトラヒドロピリド[3,4−d]ピリミジン−2(1H)−オン
[2−(1−メチルエチル)フェニル]−ボロン酸(8.97g、54.7mmol)、[2−(1−メチルエチル)フェニル]−ボロン酸(8.97g、54.7mmol)、塩化銅(0.541g、5.47mmol)及びTEA(2.54mL、18.23mmol)の混合物を、N2でパージした後、MeOH(100mL)を加え、得られた混合物を室温で一晩撹拌した。反応物を、9:1 飽和NH4Cl/NH4OHでクエンチし、DCMで抽出した。合わせた有機物をNa2SO4で乾燥させ、濾過し、濃縮し、DCM中0〜5% MeOHを使用してシリカゲル上でクロマトグラフィーを行って、黄色固体として3−((2−イソプロピルフェニル)アミノ)イソニコチンアミド(0.97g、3.80mmol、収率10.42%)を得た。m/z(ESI、+veイオン):256(M+H)+.1H NMR(400MHz,DMSO−d6)δppm 9.65(s,1H),8.32−8.38(m,1H),8.20(s,1H),7.96(d,J=5.2Hz,1H),7.78(br s,1H),7.60(d,J=5.2Hz,1H),7.39(dd,J=7.6,1.6Hz,1H),7.28−7.32(m,1H),7.15−7.25(m,2H),3.04−3.19(m,1H),1.19(d,J=6.8Hz,6H).
MeCN(100mL)中の3−((2−イソプロピルフェニル)アミノ)イソニコチンアミド(1.51g、5.91mmol)、ピリジン(1.435mL、17.74mmol)及びCDI(2.88g、17.74mmol)の混合物を、85℃で一晩加熱した。混合物を、飽和NaHCO3でクエンチし、EtOAcで抽出した。合わせた有機物をNa2SO4で乾燥させ、濾過し、濃縮し、ヘプタン中0〜50% EtOAcを使用してシリカゲル上でクロマトグラフィーを行って、白色固体として1−(2−イソプロピルフェニル)ピリド[3,4−d]ピリミジン−2,4(1H,3H)−ジオン(1.3g、4.62mmol、収率78%)を得た。m/z(ESI、+veイオン):281.8(M+H)+.1H NMR(400MHz,DMSO−d6)δppm 12.03(s,1H),8.48(d,J=5.2Hz,1H),7.92(d,J=5.0Hz,1H),7.70(s,1H),7.54−7.66(m,2H),7.42−7.47(m,1H),7.32−7.41(m,1H),2.71−2.85(m,1H),1.13(d,J=6.8Hz,3H),1.05(d,J=6.8Hz,3H).
トルエン(3mL)中の1−(2−イソプロピルフェニル)ピリド[3,4−d]ピリミジン−2,4(1H,3H)−ジオン(0.186g、0.661mmol)の懸濁液に、1,1’−ジメチルトリエチルアミン(1.155mL、6.61mmol)及びオキシ塩化リン(0.308mL、3.31mmol)を加え、得られた混合物を80℃で加熱した。5分後、混合物が溶液になり、加熱を30分間続けた。LCMSは、所望の中間体への完全な変換を示した。反応混合物を0℃まで冷却し、10当量のDIEAを加えた後、2,5−ジメチルピペラジン−1−カルボン酸(2R,5S)−tert−ブチル(0.213mL、0.992mmol)を加えた。この混合物を室温まで温めながら1時間かけて撹拌し、その時点でLCMSは、所望の生成物への変換を示した。混合物を、冷飽和NaHCO3溶液に注ぎ、10分間激しく撹拌した。混合物をEtOAcで抽出し、合わせた有機物をNa2SO4で乾燥させ、濾過し、濃縮し、ヘプタン中0〜40% EtOAcを使用してシリカゲル上でクロマトグラフィーを行って、淡黄色フォームとして(2R,5S)−4−(1−(2−イソプロピルフェニル)−2−オキソ−1,2−ジヒドロピリド[3,4−d]ピリミジン−4−イル)−2,5−diメチルピペラジン−1−カルボン酸tert−ブチル(0.281g、0.588mmol、収率89%)を得た。m/z(ESI、+veイオン):477.8(M+H)+.1H NMR(400MHz,DMSO−d6)δppm 8.39(dd,J=5.4,2.9Hz,1H),7.72−7.80(m,2H),7.50−7.65(m,2H),7.38−7.47(m,1H),7.21−7.31(m,1H),4.72−4.85(m,1H),4.23−4.43(m,1H),4.00−4.14(m,2H),3.67−3.81(m,2H),3.40−3.60(m,1H),1.45(s,9H),1.31(dd,J=9.1,6.6Hz,3H),1.15−1.21(m,3H),1.11(dd,J=6.6,4.8Hz,3H),1.00(dd,J=6.8,4.8Hz,3H).
アセトン(20mL)中の(2R,5S)−4−(1−(2−イソプロピルフェニル)−2−オキソ−1,2−ジヒドロピリド[3,4−d]ピリミジン−4−イル)−2,5−ジメチルピペラジン−1−カルボン酸tert−ブチル(0.36g、0.754mmol)及び(ブロモメチル)ベンゼン(0.193mL、1.131mmol)の混合物を、還流まで1時間加熱した。少しの生成物が観察され、大部分は出発材料であった。さらなる(ブロモメチル)ベンゼン(0.193mL、1.131mmol)を加え、得られた混合物を還流まで一晩加熱した。混合物を室温にし、濃縮し、DCM中0〜10% MeOHを使用する少量のシリカゲル上でのクロマトグラフィーを行って、黄色固体として7−ベンジル−4−((2S,5R)−4−(tert−ブトキシカルボニル)−2,5−ジメチルピペラジン−1−イル)−1−(2−イソプロピルフェニル)−2−オキソ−1,2−ジヒドロピリド[3,4−d]ピリミジン−7−イウム(0.401g、0.705mmol、収率94%)を得た。m/z(ESI、+veイオン):567.8(M+H)+.1H NMR(400MHz,DMSO−d6)δppm 8.84(br d,J=6.8Hz,1H),8.30−8.40(m,2H),7.56−7.65(m,2H),7.34−7.48(m,6H),7.25(d,J=8.1Hz,1H),5.87−5.90(m,2H),4.66−4.76(m,1H),4.24−4.46(m,1H),4.01−4.15(m,1H),3.66−3.87(m,2H),3.41−3.61(m,1H),2.58−2.66(m,1H),1.45(s,9H),1.34(t,J=5.5Hz,3H),1.18(dd,J=14.5,6.8Hz,3H),1.08(d,J=6.8Hz,3H),0.95(dd,J=10.8,6.8Hz,3H).
7−ベンジル−4−((2S,5R)−4−(tert−ブトキシカルボニル)−2,5−ジメチルピペラジン−1−イル)−1−(2−イソプロピルフェニル)−2−オキソ−1,2−ジヒドロピリド[3,4−d]ピリミジン−7−イウムを、80%水性MeOH(20mL)中で溶解させ、0℃にした。次に、NaBH4(0.570g、15.08mmol)を加え、得られた混合物を還流まで20分間加熱した。反応が完了し、室温にし、飽和NaHCO3で注意深くクエンチし、DCMで抽出した。合わせた有機物をNa2SO4で乾燥させ、濾過し、濃縮して、(2R,5S)−4−(7−ベンジル−1−(2−イソプロピルフェニル)−2−オキソ−1,2,5,6,7,8−ヘキサヒドロピリド[3,4−d]ピリミジン−4−イル)−2,5−ジメチルピペラジン−1−カルボン酸tert−ブチルを得た。m/z(ESI、+veイオン):571.8(M+H)+.
MeOH(15mL)中の(2R,5S)−4−(7−ベンジル−1−(2−イソプロピルフェニル)−2−オキソ−1,2,5,6,7,8−ヘキサヒドロピリド[3,4−d]ピリミジン−4−イル)−2,5−ジメチルピペラジン−1−カルボン酸tert−ブチル(0.280g、0.490mmol)の溶液に、活性炭上のパラジウム 10wt.%(0.365g、0.343mmol)及びギ酸アンモニウム(0.309g、4.90mmol)を加え、得られた混合物を還流まで加熱した。20分後、出発材料が消費され、所望の質量が観測された。混合物を室温にし、celiteに通して濾過し、濃縮し、ヘプタン中0〜100% 3:1 EtOAc/EtOHを使用してシリカゲル上でクロマトグラフィーを行って、白色固体として(2R,5S)−4−(1−(2−イソプロピルフェニル)−2−オキソ−1,2,5,6,7,8−ヘキサヒドロピリド[3,4−d]ピリミジン−4−イル)−2,5−ジメチルピペラジン−1−カルボン酸tert−ブチル(0.105g、0.218mmol、収率44.5%)を得た。m/z(ESI、+veイオン):481.8(M+H)+.1H NMR(400MHz,DMSO−d6)δppm 7.39−7.51(m,2H),7.25−7.34(m,1H),7.13−7.18(m,1H),7.03−7.11(m,1H),4.38−4.53(m,1H),4.12−4.38(m,1H),3.93−4.06(m,1H),3.58−3.74(m,2H),3.40−3.49(m,2H),2.98−3.16(m,2H),2.73−2.94(m,2H),2.36−2.46(m,2H),1.41−1.47(m,9H),1.10−1.19(m,8H),1.03−1.10(m,4H).
中間体I−1
2−(1−(トリフルオロメチル)シクロプロピル)アニリン
3−シクロプロピルピリジン−2−アミン
(6−ブロモ−5−クロロピリジン−2−イル)−2−イミド二炭酸ジ−tert−ブチル
4−(1−メチルシクロプロピル)ピリミジン−5−アミン
4−イソプロピル−6−メチルピリミジン−5−アミン
3−(tert−ブチル)ピラジン−2−アミン
1−ベンジル−3−シクロプロピル−1H−ピラゾール−4−アミン
3−イソプロピル−N1,N1,5−トリメチルベンゼン−1,4−ジアミン
2−シクロプロピル−6−メチルアニリン
3−(プロパ−1−エン−2−イル)ピリジン−2−アミン
3,5−ジイソプロピル−1H−ピラゾール−4−アミン
4−メチル−3−プロピルピリジン−2−アミン
2−イソプロピル−4−(トリフルオロ−メチル)ピリジン−3−アミン
N,N,4−トリメチルピリジン−2,3−ジアミン
6−アミノ−5−エチルニコチノニトリル
4−イソプロピル−2−メチルピリジン−3−アミン
3−イソプロピル−6−メチルピリジン−2−アミン
3−(プロパ−1−エン−2−イル)ピラジン−2−アミン
3−エチルピラジン−2−アミン
1−(2−アミノピリジン−3−イル)シクロプロパンカルボニトリル
4−シクロプロピル−2−メチルピリジン−3−アミン
1−(tert−ブチル)−4−メチル−1H−ピラゾール−5−アミン
2−(tert−ブチル)ピリジン−3−アミン
2−(5−(ジフルオロメトキシ)−2−フルオロフェニル)−4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン
4,6−ジシクロプロピルピリミジン−5−アミン
2−フルオロ−6−イソプロピルアニリン
3−イソプロピルピラジン−2−アミン
4−イソプロピル−2,6−ジメチル−ピリミジン−5−アミン
4,6−ジイソプロピル−2−メチル−ピリミジン−5−アミン
4−クロロ−6−イソプロピルピリミジン−5−アミン
3−イソプロピル−N1,N1−ジメチルベンゼン−1,2−ジアミン
2−イソプロピル−6−メトキシ−4−メチルピリジン−3−アミン
6−イソプロピル−N2,N2−ビス(4−メトキシベンジル)−4−メチルピリジン−2,5−ジアミン
4−シクロプロピル−6−メチルピリミジン−5−アミン
6−イソプロピル−N4,N4−ジメチルピリミジン−4,5−ジアミン
4,6−ジ−イソプロピル−2−メトキシピリミジン−5−アミン
4−(((tert−ブチルジフェニルシリル)オキシ)メチル)−2−イソプロピル−6−メチルアニリン
2−ブロモ−4,6−ジイソプロピルピリミジン−5−アミン
4−イソプロピル−6−メトキシピリミジン−5−アミン
2−(((tert−ブチルジフェニルシリル)オキシ)メチル)−6−イソプロピルアニリン
4−イソプロピル−1H−ピロール−3−アミン
ボロン酸B−1
(2−ヒドロキシ−6−メチルフェニル)ボロン酸
(2,4−ジフルオロ−5−ヒドロキシフェニル)ボロン酸
(2,3−ジフルオロ−6−ヒドロキシフェニル)ボロン酸
(3,6−ジフルオロ−2−ヒドロキシフェニル)ボロン酸
(6−フルオロ−2−ヒドロキシ−3−メチルフェニル)ボロン酸
Claims (28)
- 薬学的に許容される塩の形態である、請求項1〜11のいずれか一項に記載の化合物。
- 請求項1〜12のいずれか一項に記載の化合物及び薬学的に許容される賦形剤を含む医薬製剤。
- 細胞中のKRAS G12Cを阻害する方法であって、前記細胞を、請求項1〜12のいずれか一項に記載の化合物又は請求項13に記載の組成物と接触させることを含む方法。
- 対象におけるがんを治療する方法であって、請求項1〜12のいずれか一項に記載の化合物又は請求項13に記載の組成物の治療有効量を前記対象に投与することを含む方法。
- 前記がんが、肺がん、膵臓がん、又は結腸直腸がんである、請求項15に記載の方法。
- 前記がんが肺がんである、請求項16に記載の方法。
- 前記肺がんが、非小細胞肺がんである、請求項17に記載の方法。
- 前記がんが、膵臓がんである、請求項16に記載の方法。
- 前記がんが、結腸直腸がんである、請求項16に記載の方法。
- 必要とする患者に治療有効量の追加の薬学的に活性な化合物を投与することをさらに含む、請求項15に記載の方法。
- 前記追加の薬学的に活性な化合物が、抗PD−1アンタゴニストである、請求項21に記載の方法。
- 前記追加の薬学的に活性な化合物が、ニボルマブである、請求項21に記載の方法。
- 前記追加の薬学的に活性な化合物が、ペムブロリズマブである、請求項21に記載の方法。
- 前記追加の薬学的に活性な化合物が、AMG 404である、請求項21に記載の方法。
- 対象におけるがんを治療するための請求項1〜24のいずれか一項に記載の化合物の使用。
- がんを治療するための医薬の作製における請求項1〜12のいずれか一項に記載の化合物。
- 前記がんが、固形腫瘍である、請求項26に記載の化合物。
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MX2020010836A (es) | 2021-01-08 |
EP3788038B1 (en) | 2023-10-11 |
JP7266043B2 (ja) | 2023-04-27 |
CA3098574A1 (en) | 2019-11-07 |
US20240050430A1 (en) | 2024-02-15 |
AU2019262589A1 (en) | 2020-10-29 |
MA52501A (fr) | 2021-03-10 |
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AU2019262589B2 (en) | 2022-07-07 |
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