JP2022505835A - 腫瘍転移を阻害するためのg12c変異体krasタンパク質の阻害剤としての2-(2-アクリロイル-2,6-ジアザスピロ[3.4]オクタン-6-イル)-6-(1h-インダゾール-4-イル)-ベンゾニトリル誘導体および関連化合物 - Google Patents
腫瘍転移を阻害するためのg12c変異体krasタンパク質の阻害剤としての2-(2-アクリロイル-2,6-ジアザスピロ[3.4]オクタン-6-イル)-6-(1h-インダゾール-4-イル)-ベンゾニトリル誘導体および関連化合物 Download PDFInfo
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- JP2022505835A JP2022505835A JP2021522510A JP2021522510A JP2022505835A JP 2022505835 A JP2022505835 A JP 2022505835A JP 2021522510 A JP2021522510 A JP 2021522510A JP 2021522510 A JP2021522510 A JP 2021522510A JP 2022505835 A JP2022505835 A JP 2022505835A
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- aminyl
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- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 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
- 230000002792 vascular Effects 0.000 description 1
- 230000006442 vascular tone Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine 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-CFWMRBGOSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- UGBMEXLBFDAOGL-INIZCTEOSA-N zd6126 Chemical compound C1C[C@H](NC(C)=O)C2=CC(OP(O)(O)=O)=CC=C2C2=C1C=C(OC)C(OC)=C2OC UGBMEXLBFDAOGL-INIZCTEOSA-N 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- 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
- C07D487/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
- C07D471/10—Spiro-condensed systems
Abstract
Description
技術分野
本開示の実施形態は、一般に、例えば、がんの処置のための新規の化合物ならびに治療薬または予防薬としてのその調製方法および使用方法に関する。
RASは、原形質膜と会合し、GDPまたはGTPのいずれかと結合する、189個のアミノ酸(分子質量21kDa)の密接に関連した単量体球状タンパク質群を表す。RASは分子スイッチとして作用する。RASが結合したGDPを有するときは、休止状態またはオフ側にあり、「不活性」である。一定の成長促進刺激に対する細胞の曝露に応答して、RASは、結合したGDPをGTPと交換するように誘導される。GTP結合により、RASは「スイッチオン」し、他のタンパク質(その「下流標的」)と相互作用し、活性化することができる。RASタンパク質自体はGTPを加水分解してGDPに戻し、それによってRAS自体をオフ状態にする内因性の能力は非常に低い。RASのスイッチオフには、RASと相互作用してGTPのGDPへの変換を非常に促進するGTPアーゼ活性化タンパク質(GAP)と呼ばれる外因性タンパク質が必要である。GAPと相互作用するかGTPを変換してGDPに戻す能力に影響をおよぼすRASの任意の変異により、そのタンパク質の活性化が延長され、その結果細胞に成長および分裂を継続するように指示するシグナルが延長される。これらのシグナルによって細胞が成長および分裂するので、過度に活動的なRASシグナル伝達は、最終的にがんを引き起こし得る。
簡潔に述べれば、本開示の実施形態は、G12C変異体KRAS、HRAS、および/またはNRASタンパク質を調整することができる化合物(その薬学的に許容され得る塩、同位体形態、立体異性体またはプロドラッグが含まれる)を提供する。いくつかの例では、本化合物は、KRAS、HRAS、またはNRAS G12C変異体タンパク質の12位のシステイン残基と共有結合を形成することができる求電子剤として作用する。がんなどの種々の疾患または状態の処置のためのかかる化合物の使用方法も提供する。
被験体がKRAS、HRAS、またはNRASのG12C変異を有するかどうかを決定する工程;および
被験体がKRAS、HRAS、またはNRASのG12C変異を有すると決定された場合、被験体に治療有効量の1つまたはそれを超える構造(I)の化合物を含む薬学的組成物を投与する工程を含む、方法に関する。
以下の説明では、本開示の種々の実施形態の完全な理解を得るために特定の具体的な細目が示される。しかし、当業者は、本開示をこれらの細目を用いることなく実施することができると理解するであろう。
1つの態様では、本開示は、G12C変異体KRAS、HRAS、またはNRASタンパク質に選択的に結合し、および/またはこれらを調整することができる化合物を提供する。化合物は、アミノ酸との反応によってG12C変異体KRAS、HRAS、またはNRASタンパク質を調整することができる。理論に拘束されるものではないが、本出願者らは、いくつかの実施形態では、G12C変異体KRAS、HRAS、またはNRASタンパク質の12位のシステインとの共有結合の形成によって、本開示の化合物がG12C変異体KRAS、HRAS、またはNRASタンパク質と選択的に反応すると考える。システイン12への結合により、本開示の化合物は、G12C変異体KRAS、HRAS、またはNRASのスイッチIIを不活性段階に閉じ込めることができる。この不活性段階は、GTPおよびGDPに結合したKRAS、HRAS、またはNRASで認められるものと異なり得る。いくつかの本開示の化合物はまた、スイッチIの高次構造を乱すことができる。いくつかの本開示の化合物は、GTPよりもむしろGDPに結合したKRAS、HRAS、またはNRASへの結合を優先し、したがって、KRAS、HRAS、またはNRASを不活性なKRAS、HRAS、またはNRASのGDP結合状態に隔離し得る。KRAS、HRAS、またはNRASへのエフェクター結合がスイッチIおよびIIの高次構造に高度に影響を受けやすいので、これらの化合物の不可逆的結合がKRAS、HRAS、またはNRASの下流シグナル伝達を破壊し得る。
A1、A2、A3およびA4は、各出現において独立して、CR4aR4b、OまたはNR5であり;
G1およびG2は、それぞれ独立して、CHまたはNであり、但し、L1が-O-、-S-もしくは-NR5-である場合、または隣接するA1もしくはA2が-NR5-もしくは-O-である場合、G1はCHであり、但し、L2が-NR5-である場合、または隣接するA3もしくはA4が-NR5-もしくは-O-である場合、G2はCHであり;
L1は、結合、-CR4aR4b-、-O-、-S-、-SO2-または-NR5-であり;
G2がCHである場合、L2は、結合、C1~C6アルキレンまたは-NR5-であり;
L3は、結合、-CR4aR4b-、-O-、-S-、-SO2-または-NR5-であり;
R1は、アリール、シクロアルキル、ヘテロシクリルまたはヘテロアリールであり;
R2は、H、シアノ、ヒドロキシル、ハロ、C1~C6アルキル、C2~C6アルケニル、C2~C6アルキニル、C1~C6ヒドロキシルアルキル、C1~C6シアノアルキル、C1~C6アルコキシ、C1~C6ハロアルコキシ、C1~C6ハロアルキル、アミニルアルキル、アルキルアミニル、アミニルカルボニル、C3~C8シクロアルキル、C3~C8ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、アリールまたはヘテロアリールであり;
R3a、R3bおよびR3cは、各出現において独立して、H、ハロ、ヒドロキシル、シアノ、アミノ、アルキル、シクロアルキル、シクロアルケニル、ヘテロシクレニル、ハロアルキル、アルキニル、アルケニル、アルコキシ、ハロアルコキシ、アミニルカルボニル、アミニルカルボニルアルコキシ、アミニルスルホニル、アルキルスルホニルアミニル、アルキルカルボニル、アミニルアルキルカルボニル、シクロアルキルカルボニル、ヘテロシクリルカルボニル、ヘテロシクリルカルボニルアルコキシ、アルキルスルホニル、アミニルアルキルスルホニル、シクロアルキルスルホニル、ヘテロシクリルスルホニル、アルキルチオエーテル、アミニルアルキルチオエーテル、シクロアルキルチオエーテル、ヘテロシクリルチオエーテル、アミニルアルキル、アミニルアルキニル、アミニルアルキルアミニル、アミニルアルコキシ、アルキルカルボニルアミニル、ヘテロシクリル、ヘテロシクリルアミニル、ヘテロシクリルオキシ、ヘテロシクリルアルキル、ヘテロシクリルアルキルアミニル、ヘテロシクリルアルコキシ、ヘテロシクリルカルボニルアミニル、アリール、アリールアルキル、アリールアルキルアミニル、アリールアルコキシ、アリールアミニル、アリールカルボニルアミニル、ヘテロアリール、ヘテロアリールアミニル、ヘテロアリールオキシ、ヘテロアリールアルキル、ヘテロアリールアルキルアミニル、ヘテロアリールアルコキシまたはヘテロアリールカルボニルアミニルであり;
R4aおよびR4bは、各出現において独立して、H、-OH、-NH2、-CO2H、ハロ、シアノ、C1~C6アルキル、シクロアルキル、ヘテロシクリル、C2~C6アルケニル、C2~C6アルキニル、C1~C6ハロアルキル、C1~C6ハロアルコキシ、C1~C6ヒドロキシルアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、C1~C6シアノアルキル、C1~C6カルボキシアルキル、アミニルカルボニルアルキル、アリール、ヘテロアリールもしくはアミニルカルボニルであるか、またはR4aとR4bとは、同じ炭素に結合する場合、一緒になってオキソもしくは炭素環式もしくは複素環式環を形成するか、またはR3aとR3bとは、異なる炭素に結合する場合、一緒になって炭素環式もしくは複素環式環を形成し;
R5は、各出現において独立して、H、C1~C6アルキル、C2~C6アルケニル、C2~C6アルキニル、C1~C6ヒドロキシルアルキル、C1~C6シアノアルキル、C1~C6ハロアルキルまたはC3~C8シクロアルキルアルキルであり;
m1、m2、n1およびn2は、各出現において独立して、1、2または3であり;そして
Eは、求電子部分である)
またはその薬学的に許容され得る塩、同位体形態、立体異性体もしくはプロドラッグを有する。
Qは、-C(=O)-、-C(=NR8’)-、-NR8C(=O)-、-S(=O)2-または-NR8S(=O)2-であり;
R8は、H、C1~C6アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、C3~C8シクロアルキルまたはヘテロシクリルアルキルであり;
R8’は、H、-OH、-CNまたはC1~C6アルキルであり;
ここで、アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、シクロアルキル、ヘテロシクリルアルキル、アルコキシカルボニル、ヘテロアリールならびに炭素環式、複素環式およびヘテロアリール環の各出現は、他で指定しない限り、1つまたはそれを超える置換基で必要に応じて置換される)
のうちの1つを有する。
Qは、-C(=O)-、-C(=NR8’)-、-NR8C(=O)-、-S(=O)2-または-NR8S(=O)2-であり;
R8は、H、C1~C6アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、C3~C8シクロアルキルまたはヘテロシクリルアルキルであり;
R8’は、H、-OH、-CNまたはC1~C6アルキルであり;
ここで、アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、シクロアルキル、ヘテロシクリルアルキル、アルコキシカルボニル、ヘテロアリールならびに炭素環式、複素環式およびヘテロアリール環の各出現は、他で指定しない限り、1つまたはそれを超える置換基で必要に応じて置換される)
のうちの1つを有する。
Qは、-C(=O)-、-C(=NR8’)-、-NR8C(=O)-、-S(=O)2-または-NR8S(=O)2-であり;
R8は、H、C1~C6アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、C3~C8シクロアルキルまたはヘテロシクリルアルキルであり;
R8’は、H、-OH、-CNまたはC1~C6アルキルであり;
ここで、アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、シクロアルキル、ヘテロシクリルアルキル、アルコキシカルボニル、ヘテロアリールならびに炭素環式、複素環式およびヘテロアリール環の各出現は、他で指定しない限り、1つまたはそれを超える置換基で必要に応じて置換される)
のうちの1つを有する。
Qは、-C(=O)-、-C(=NR8’)-、-NR8C(=O)-、-S(=O)2-または-NR8S(=O)2-であり;
R8は、H、C1~C6アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、C3~C8シクロアルキルまたはヘテロシクリルアルキルであり;
R8’は、H、-OH、-CNまたはC1~C6アルキルであり;
ここで、アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、シクロアルキル、ヘテロシクリルアルキル、アルコキシカルボニル、ヘテロアリールならびに炭素環式、複素環式およびヘテロアリール環の各出現は、他で指定しない限り、1つまたはそれを超える置換基で必要に応じて置換される)
のうちの1つを有する。
Qは、-C(=O)-、-C(=NR8’)-、-NR8C(=O)-、-S(=O)2-または-NR8S(=O)2-であり;
R8は、H、C1~C6アルキルまたはヒドロキシルアルキルであり;
R8’は、H、-OH、-CNまたはC1~C6アルキルであり;そして
R9およびR10は、それぞれ独立して、H、ハロ、シアノ、カルボキシル、C1~C6アルキル、アルコキシカルボニル、アミニルアルキル、アルキルアミニルアルキル、アリール、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールもしくはヒドロキシルアルキルであるか、またはR9とR10とは一緒になって、炭素環式、複素環式もしくはヘテロアリール環を形成する)
を有する。
Qは、-C(=O)-、-NR8C(=O)-、-S(=O)2-または-NR8S(=O)2-であり;
R8は、H、C1~C6アルキルまたはヒドロキシルアルキルであり;そして
R10は、H、C1~C6アルキル、アミニルアルキル、アルキルアミニルアルキルまたはヒドロキシルアルキルである)
を有する。
表1.構造(I)の代表的な化合物
一般的な反応スキーム1(「方法A」)
一般的な反応スキーム2(「方法B」)
他の実施形態は、薬学的組成物に関する。薬学的組成物は、前述の化合物のうちのいずれか1つ(または複数)および薬学的に許容され得るキャリアを含む。いくつかの実施形態では、薬学的組成物は経口投与のために製剤化されている。他の実施形態では、薬学的組成物は注射のために製剤化されている。なおさらなる実施形態では、薬学的組成物は、本明細書中に開示の化合物およびさらなる治療薬(例えば、抗がん剤)を含む。かかる治療薬の非限定的な例を、本明細書中の以下に記載する。
本明細書中に記載の治療適用で用いるために、キットおよび製品も提供する。いくつかの実施形態では、かかるキットは、キャリア、パッケージ、または容器を含み、該容器は、バイアルおよびチューブなどの1つまたはそれを超える容器(各容器は本明細書中に記載の方法で使用すべき個別の要素のうちの1つを含む)を入れるために区画化されている。適切な容器には、例えば、ボトル、バイアル、シリンジ、および試験管が含まれる。容器は、ガラスまたはプラスチックなどの種々の材料から形成されている。
本開示の実施形態は、RAS媒介細胞のシグナル伝達を阻害する方法であって、細胞を有効量の1つまたはそれを超える本明細書中に開示の化合物と接触させる工程を含む方法を提供する。RAS媒介シグナル伝達の阻害を、当該分野で公知の広範な種々の方法によって評価および実証することができる。非限定的な例には、以下を示すことが含まれる:(a)RASのGTPアーゼ活性の減少;(b)GTP結合親和性の減少またはGDP結合親和性の増加;(c)GTPのKoffの増加またはGDPのKoffの減少;(d)RAS経路の下流のシグナル伝達分子レベルの減少(pMEKレベルの減少など);および/または(e)下流シグナル伝達分子(Rafが含まれるが、これらに限定されない)へのRAS複合体の結合の減少。キットおよび市販のアッセイを、1つまたは複数の上記の決定のために利用することができる。
実施例1
化合物の生化学アッセイ
・最終化合物濃度を32μMにするために、化合物を1600μM(3μLの10mM化合物原液+15.75μLのDMSO)に希釈し、ピペッティングによって十分に混合した。
・最終化合物濃度を8μMにするために、化合物を400μM(2μLの10mM化合物原液+48μLのDMSO)に希釈し、ピペッティングによって十分に混合した。
RapidFire/TOFアッセイ:
Q-Exactiveアッセイ:
RSLCナノシステム(Thermo Scientific)を使用して測定した。
本発明の化合物がRAS媒介細胞成長を阻害する能力を、以下のように評価し、実証する。野生型RASまたは変異体RASを発現する細胞を、白色透明底96ウェルプレート中に5,000細胞/ウェルの密度でプレートする。細胞を、プレート後約2時間付着させ、その後、本明細書中に開示の化合物を添加する。一定時間後(例えば、24時間、48時間、または72時間の細胞成長後)、細胞増殖を、製造者の指示にしたがってCell Titer Glo試薬(Promega)を使用して総ATP含有量を測定することによって決定する。増殖EC50を、100μMからハーフログ間隔で減少する8点の化合物用量応答の分析によって決定する。
本明細書中に開示の化合物がRAS媒介シグナル伝達を阻害する能力を、以下のように評価し、実証する。野生型RASまたは変異体RAS(G12C、G12V、もしくはG12Aなど)を発現する細胞を、本発明の化合物を用いるか、用いずに(コントロール細胞)処理する。1つまたはそれを超える本発明の化合物によるRASシグナル伝達の阻害を、コントロール細胞と比較した場合の1つまたはそれを超える本発明の化合物で処理した細胞におけるリン酸化MEK、リン酸化ERK、リン酸化RSKの定常状態レベルおよび/またはRaf結合の減少によって実証する。
表2.代表的な化合物の修飾活性*
-は、化合物を試験しなかったことを示す
+は、0%を超える最大50%の結合活性を示す
++は、50~75%の結合活性を示す
+++は、75%を超える結合活性を示す
‡8μMの濃度で試験した
実施例2
化合物I-7の合成
tert-ブチル6-(3-クロロ-2-シアノ-5-モルホリノフェニル)-2,6-ジアザスピロ[3.4]オクタン-2-カルボキシレート
tert-ブチル6-(2-シアノ-3-(5-メチル-1H-インダゾール-4-イル)-5-モルホリノフェニル)-2,6-ジアザスピロ[3.4]オクタン-2-カルボキシレート
2-(2-アクリロイル-2,6-ジアザスピロ[3.4]オクタン-6-イル)-6-(5-メチル-1H-インダゾール-4-イル)-4-モルホリノベンゾニトリル
実施例3
化合物I-14の合成
2,6-ジクロロ-4-メトキシベンゾニトリル
tert-ブチル6-(3-クロロ-2-シアノ-5-メトキシフェニル)-2,6-ジアザスピロ[3.4]オクタン-2-カルボキシレート
tert-ブチル6-(2-シアノ-5-メトキシ-3-(5-メチル-1-(テトラヒドロ-2H-ピラン-2-イル)-1H-インダゾール-4-イル)フェニル)-2,6-ジアザスピロ[3.4]オクタン-2-カルボキシレート
4-メトキシ-2-(5-メチル-1H-インダゾール-4-イル)-6-(2,6-ジアザスピロ[3.4]オクタン-6-イル)ベンゾニトリル
2-(2-アクリロイル-2,6-ジアザスピロ[3.4]オクタン-6-イル)-4-メトキシ-6-(5-メチル-1H-インダゾール-4-イル)ベンゾニトリル
実施例4
化合物I-2の合成
tert-ブチル6-(2-メトキシ-3-(5-メチル-1H-インダゾール-4-イル)フェニル)-2,6-ジアザスピロ[3.4]オクタン-2-カルボキシレート
4-(2-メトキシ-3-(2,6-ジアザスピロ[3.4]オクタン-6-イル)フェニル)-5-メチル-1H-インダゾール
1-(6-(2-メトキシ-3-(5-メチル-1H-インダゾール-4-イル)フェニル)-2,6-ジアザスピロ[3.4]オクタン-2-イル)プロパ-2-エン-1-オン
実施例5
化合物I-25の合成
2-ブロモ-6-フルオロ-3-メチルベンゾニトリル
tert-ブチル6-(3-ブロモ-2-シアノ-4-メチルフェニル)-2,6-ジアザスピロ[3.4]オクタン-2-カルボキシレート
tert-ブチル6-(2-シアノ-4-メチル-3-(5-メチル-1H-インダゾール-4-イル)フェニル)-2,6-ジアザスピロ[3.4]オクタン-2-カルボキシレート
3-メチル-2-(5-メチル-1H-インダゾール-4-イル)-6-(2,6-ジアザスピロ[3.4]オクタン-6-イル)ベンゾニトリル
6-(2-アクリロイル-2,6-ジアザスピロ[3.4]オクタン-6-イル)-3-メチル-2-(5-メチル-1H-インダゾール-4-イル)ベンゾニトリル
実施例6
化合物I-50の合成
2,6-ジクロロ-4-ヒドロキシベンズアルデヒド
2,6-ジクロロ-4-(ピリジン-2-イルメトキシ)ベンズアルデヒド
(E)-2,6-ジクロロ-4-(ピリジン-2-イルメトキシ)ベンズアルデヒドオキシム
2,6-ジクロロ-4-(ピリジン-2-イルメトキシ)ベンゾニトリル
tert-ブチル7-(3-クロロ-2-シアノ-5-(ピリジン-2-イルメトキシ)フェニル)-2,7-ジアザスピロ[3.5]ノナン-2-カルボキシレート
tert-ブチル7-(2-シアノ-3-(5-メチル-1H-インダゾール-4-イル)-5-(ピリジン-2-イルメトキシ)フェニル)-2,7-ジアザスピロ[3.5]ノナン-2-カルボキシレート
2-(5-メチル-1H-インダゾール-4-イル)-4-(ピリジン-2-イルメトキシ)-6-(2,7-ジアザスピロ[3.5]ノナン-7-イル)ベンゾニトリル
2-(2-アクリロイル-2,7-ジアザスピロ[3.5]ノナン-7-イル)-6-(5-メチル-1H-インダゾール-4-イル)-4-(ピリジン-2-イルメトキシ)ベンゾニトリル
実施例7
化合物I-84の合成
2,4-ジクロロ-6-フルオロ-3-メトキシベンズアルデヒド
2,4-ジクロロ-6-フルオロ-3-メトキシベンゾニトリル
tert-ブチル7-(3,5-ジクロロ-2-シアノ-4-メトキシフェニル)-2,7-ジアザスピロ[3.5]ノナン-2-カルボキシレート
tert-ブチル7-(3-クロロ-2-シアノ-4-メトキシ-5-モルホリノフェニル)-2,7-ジアザスピロ[3.5]ノナン-2-カルボキシレート
tert-ブチル7-(2-シアノ-4-メトキシ-3-(5-メチル-1H-インダゾール-4-イル)-5-モルホリノフェニル)-2,7-ジアザスピロ[3.5]ノナン-2-カルボキシレート
3-メトキシ-2-(5-メチル-1H-インダゾール-4-イル)-4-モルホリノ-6-(2,7-ジアザスピロ[3.5]ノナン-7-イル)ベンゾニトリル
6-(2-アクリロイル-2,7-ジアザスピロ[3.5]ノナン-7-イル)-3-メトキシ-2-(5-メチル-1H-インダゾール-4-イル)-4-モルホリノベンゾニトリル
Claims (65)
- 以下の構造(I):
A1、A2、A3およびA4は、各出現において独立して、CR4aR4b、OまたはNR5であり;
G1およびG2は、それぞれ独立して、CHまたはNであり、但し、L1が-O-、-S-もしくは-NR5-である場合、または隣接するA1もしくはA2が-NR5-もしくは-O-である場合、G1はCHであり、但し、L2が-NR5-である場合、または隣接するA3もしくはA4が-NR5-もしくは-O-である場合、G2はCHであり;
L1は、結合、-CR4aR4b-、-O-、-S-、-SO2-または-NR5-であり;
L2は、結合、C1~C6アルキレンまたは-NR5-であり;
L3は、結合、-CR4aR4b-、-O-、-S-、-SO2-または-NR5-であり;
R1は、アリール、シクロアルキル、ヘテロシクリルまたはヘテロアリールであり;
R2は、H、シアノ、ヒドロキシル、ハロ、C1~C6アルキル、C2~C6アルケニル、C2~C6アルキニル、C1~C6ヒドロキシルアルキル、C1~C6シアノアルキル、C1~C6アルコキシ、C1~C6ハロアルコキシ、C1~C6ハロアルキル、アミニルアルキル、アルキルアミニル、アミニルカルボニル、C3~C8シクロアルキル、C3~C8ヘテロシクロアルキル、アリールアルキル、ヘテロアリールアルキル、アリールまたはヘテロアリールであり;
R3a、R3bおよびR3cは、各出現において独立して、H、ハロ、ヒドロキシル、シアノ、アミノ、アルキル、シクロアルキル、シクロアルケニル、ヘテロシクレニル、ハロアルキル、アルキニル、アルケニル、アルコキシ、ハロアルコキシ、アミニルカルボニル、アミニルカルボニルアルコキシ、アミニルスルホニル、アルキルスルホニルアミニル、アルキルカルボニル、アミニルアルキルカルボニル、シクロアルキルカルボニル、ヘテロシクリルカルボニル、ヘテロシクリルカルボニルアルコキシ、アルキルスルホニル、アミニルアルキルスルホニル、シクロアルキルスルホニル、ヘテロシクリルスルホニル、アルキルチオエーテル、アミニルアルキルチオエーテル、シクロアルキルチオエーテル、ヘテロシクリルチオエーテル、アミニルアルキル、アミニルアルキニル、アミニルアルキルアミニル、アミニルアルコキシ、アルキルカルボニルアミニル、ヘテロシクリル、ヘテロシクリルアミニル、ヘテロシクリルオキシ、ヘテロシクリルアルキル、ヘテロシクリルアルキルアミニル、ヘテロシクリルアルコキシ、ヘテロシクリルカルボニルアミニル、アリール、アリールアルキル、アリールアルキルアミニル、アリールアルコキシ、アリールアミニル、アリールカルボニルアミニル、ヘテロアリール、ヘテロアリールアミニル、ヘテロアリールオキシ、ヘテロアリールアルキル、ヘテロアリールアルキルアミニル、ヘテロアリールアルコキシまたはヘテロアリールカルボニルアミニルであり;
R4aおよびR4bは、各出現において独立して、H、-OH、-NH2、-CO2H、ハロ、シアノ、C1~C6アルキル、シクロアルキル、ヘテロシクリル、C2~C6アルケニル、C2~C6アルキニル、C1~C6ハロアルキル、C1~C6ハロアルコキシ、C1~C6ヒドロキシルアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、C1~C6シアノアルキル、C1~C6カルボキシアルキル、アミニルカルボニルアルキル、アリール、ヘテロアリールもしくはアミニルカルボニルであるか、またはR4aとR4bとは、同じ炭素に結合する場合、一緒になってオキソもしくは炭素環式もしくは複素環式環を形成するか、またはR3aとR3bとは、異なる炭素に結合する場合、一緒になって炭素環式もしくは複素環式環を形成し;
R5は、各出現において独立して、H、C1~C6アルキル、C2~C6アルケニル、C2~C6アルキニル、C1~C6ヒドロキシルアルキル、C1~C6シアノアルキル、C1~C6ハロアルキルまたはC3~C8シクロアルキルアルキルであり;
m1、m2、n1およびn2は、各出現において独立して、1、2または3であり;そして
Eは、求電子部分である]
を有する化合物またはその薬学的に許容され得る塩、同位体形態、立体異性体もしくはプロドラッグ。 - G1またはG2のうちの少なくとも1つの出現がCHである、請求項1に記載の化合物。
- G1およびG2が両方ともNである、請求項1または2のいずれか1項に記載の化合物。
- A1、A2、A3およびA4のうちの少なくとも1つの出現がCR4aR4bである、請求項1~3のいずれか1項に記載の化合物。
- Eが、標的タンパク質のシステイン残基と共有結合を形成することができる求電子部分である、請求項1~5のいずれか1項に記載の化合物。
- Eが、KRAS、HRASまたはNRAS G12C変異体タンパク質の12位のシステイン残基と共有結合を形成することができる求電子部分である、請求項6に記載の化合物。
- 前記化合物が、以下の構造(I’a)、(I’b)、(I’c)、(I’d)、(I’e)、(I’f)、(I’g)、(I’h)、(I’i)、(I’j)、(I’k)または(I’l):
Qは、-C(=O)-、-C(=NR8’)-、-NR8C(=O)-、-S(=O)2-または-NR8S(=O)2-であり;
R8は、H、C1~C6アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、C3~C8シクロアルキルまたはヘテロシクリルアルキルであり;
R8’は、H、-OH、-CNまたはC1~C6アルキルであり;
ここで、アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、シクロアルキル、ヘテロシクリルアルキル、アルコキシカルボニル、ヘテロアリールならびに炭素環式、複素環式およびヘテロアリール環の各出現は、他で指定しない限り、1つまたはそれを超える置換基で必要に応じて置換される]
のうちの1つを有する、請求項1または3~7のいずれか1項に記載の化合物。 - 前記化合物が、以下の構造(I’a1)、(I’b1)、(I’c1)、(I’d1)、(I’e1)、(I’f1)、(I’g1)、(I’h1)、(I’i1)、(I’j1)、(I’k1)または(I’l1):
Qは、-C(=O)-、-C(=NR8’)-、-NR8C(=O)-、-S(=O)2-または-NR8S(=O)2-であり;
R8は、H、C1~C6アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、C3~C8シクロアルキルまたはヘテロシクリルアルキルであり;
R8’は、H、-OH、-CNまたはC1~C6アルキルであり;
ここで、アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、シクロアルキル、ヘテロシクリルアルキル、アルコキシカルボニル、ヘテロアリールならびに炭素環式、複素環式およびヘテロアリール環の各出現は、他で指定しない限り、1つまたはそれを超える置換基で必要に応じて置換される]
のうちの1つを有する、請求項8に記載の化合物。 - R1がアリールである、請求項1~9のいずれか1項に記載の化合物。
- R1がフェニルまたはナフチルである、請求項1~10のいずれか1項に記載の化合物。
- R1が1つまたはそれを超える置換基で置換される、請求項10または11のいずれか1項に記載の化合物。
- R1が、ハロ、アミノ、ヒドロキシル、C1~C6アルキル、シアノ、C1~C6ハロアルキル、C1~C6アルコキシ、アルキルアミニル、シクロアルキル、ヘテロシクリルアルキル、アリール、ヘテロアリール、ホスフェート、ホスホアルコキシ、ボロン酸、ボロン酸エステル、-OC(=O)RもしくはC1~C6アルキルカルボニルオキシまたはそれらの組み合わせで置換され、RがC1~C6アルキルである、請求項12に記載の化合物。
- R1が、フルオロ、クロロ、ヒドロキシル、メチル、イソプロピル、シクロプロピル、トリフルオロメチルもしくはメトキシまたはそれらの組み合わせで置換される、請求項13に記載の化合物。
- R1がヘテロアリールである、請求項1~9のいずれか1項に記載の化合物。
- R1が、インダゾリル、インドリル、ベンゾイミダゾリル、ベンゾトリアゾリル、ピロロピリジルまたはキノリニルである、請求項1~9または17のいずれか1項に記載の化合物。
- R1が1つまたはそれを超える置換基で置換される、請求項17または18のいずれか1項に記載の化合物。
- R1が、シアノ、ニトロ、-NH2、-(C=O)NH2、ヒドロキシル、アルキルヒドロキシ、ハロもしくはC1~C6アルキルまたはそれらの組み合わせで置換される、請求項19に記載の化合物。
- R1がヘテロシクリルである、請求項1~9のいずれか1項に記載の化合物。
- R1が置換される、請求項23に記載の化合物。
- R1が、ヒドロキシル、ヒドロキシルアルキル、オキソおよびアミニルカルボニルから選択される1つまたはそれを超える置換基で置換される、請求項24に記載の化合物。
- R2が、H、シアノ、ヒドロキシル、ハロ、C1~C6アルキル、C1~C6シアノアルキル、C1~C6アルコキシ、C1~C6ハロアルコキシ、C1~C6ハロアルキル、C1~C6ヒドロキシルアルキル、C3~C8シクロアルキル、アミニルアルキル、アルキルアミニルまたはアミニルカルボニルである、請求項1~26のいずれか1項に記載の化合物。
- R2がHである、請求項27に記載の化合物。
- R2がシアノである、請求項29に記載の化合物。
- R2がフルオロである、請求項29に記載の化合物。
- R2がメトキシである、請求項29に記載の化合物。
- R3aがHである、請求項1~32のいずれか1項に記載の化合物。
- R3bがHである、請求項1~33のいずれか1項に記載の化合物。
- R3cがHである、請求項1~34のいずれか1項に記載の化合物。
- R3bまたはR3cが、それぞれ独立して、H、アルキル、ハロ、ヘテロシクリル、アルコキシ、ヘテロアリールアルコキシ、ヘテロシクリルアルコキシまたはアミニルアルコキシである、請求項1~33のいずれか1項に記載の化合物。
- R3bが、アルコキシ、ヘテロシクリル、ヘテロアリールアルコキシ、ヘテロシクリルアルコキシまたはアミニルアルコキシである、請求項36に記載の化合物。
- R3cが、アルキル、ハロ、アルコキシまたはアミニルアルコキシである、請求項36に記載の化合物。
- 少なくとも1つのR4aがHではない、請求項1~40のいずれか1項に記載の化合物。
- 少なくとも2つのR4aがHではない、請求項1~41のいずれか1項に記載の化合物。
- 少なくとも1つのR4aがC1~C6アルキルである、請求項1~42のいずれか1項に記載の化合物。
- C1~C6アルキルがメチルである、請求項43に記載の化合物。
- R4aおよびR4bのうちの少なくとも1つの出現が一緒になってオキソを形成する、請求項1~44のいずれか1項に記載の化合物。
- Qが-C(=O)-である、請求項8~45のいずれか1項に記載の化合物。
- Qが-S(=O)2-である、請求項8~45のいずれか1項に記載の化合物。
- Qが-NR8C(=O)-である、請求項8~45のいずれか1項に記載の化合物。
- Qが-NR8S(=O)2-である、請求項8~45のいずれか1項に記載の化合物。
- L2が結合である、請求項1~53のいずれか1項に記載の化合物。
- L3が結合である、請求項1~54のいずれか1項に記載の化合物。
- 前記化合物が、表1の化合物から選択される、請求項1に記載の化合物。
- 請求項1~56のいずれか1項に記載の実質的に精製されたアトロプ異性体。
- 請求項1~57のいずれか1項に記載の化合物と、薬学的に許容され得る担体とを含む、薬学的組成物。
- がんの処置のための方法であって、前記方法が、有効量の請求項58に記載の薬学的組成物をそれを必要とする被験体に投与することを含む、方法。
- 前記がんが、KRAS G12C、HRAS G12CまたはNRAS G12C変異によって媒介される、請求項59に記載の方法。
- 前記がんが、血液がん、膵臓がん、MYH関連ポリポーシス、結腸直腸がんまたは肺がんである、請求項59または60に記載の方法。
- 腫瘍転移を阻害するための方法であって、前記方法が、有効量の請求項58に記載の薬学的組成物をそれを必要とする被験体に投与することを含む、方法。
- がんの処置を必要とする被験体におけるがんを処置するための方法において使用するための、請求項58に記載の薬学的組成物。
- 前記がんが、KRAS G12C、HRAS G12CまたはNRAS G12C変異によって媒介される、請求項63に記載の薬学的組成物。
- 前記がんが、血液がん、膵臓がん、MYH関連ポリポーシス、結腸直腸がんまたは肺がんである、請求項63または64に記載の薬学的組成物。
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US10975071B2 (en) | 2015-09-28 | 2021-04-13 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
US10875842B2 (en) | 2015-09-28 | 2020-12-29 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
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