JP6568926B2 - 癌の治療のためのerbbチロシンキナーゼ阻害剤としてのベンゾイミダゾール誘導体 - Google Patents
癌の治療のためのerbbチロシンキナーゼ阻害剤としてのベンゾイミダゾール誘導体 Download PDFInfo
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- JP6568926B2 JP6568926B2 JP2017501113A JP2017501113A JP6568926B2 JP 6568926 B2 JP6568926 B2 JP 6568926B2 JP 2017501113 A JP2017501113 A JP 2017501113A JP 2017501113 A JP2017501113 A JP 2017501113A JP 6568926 B2 JP6568926 B2 JP 6568926B2
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- 239000003558 transferase inhibitor Substances 0.000 description 1
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- 229960001288 triamterene Drugs 0.000 description 1
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- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000005558 triazinylene group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000005559 triazolylene group Chemical group 0.000 description 1
- 229960004813 trichlormethiazide Drugs 0.000 description 1
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- FQCQGOZEWWPOKI-UHFFFAOYSA-K trisalicylate-choline Chemical compound [Mg+2].C[N+](C)(C)CCO.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O FQCQGOZEWWPOKI-UHFFFAOYSA-K 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
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- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
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- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
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- 229960002703 undecylenic acid Drugs 0.000 description 1
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- 229940120293 vaginal suppository Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
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- 208000024523 vestibulocochlear nerve neoplasm Diseases 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- 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
- 229960004528 vincristine 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
- 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
- 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
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229960001522 ximelagatran Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本願は、2014年3月20日に出願された米国仮特許出願第61/968,243号の優先権の利益を主張し、その開示をその全体として引用により本明細書に組み込む。
ベンゾイミダゾール誘導体及びその医薬組成物が本明細書に提供される。増殖性疾患の1つ以上の症状を治療し、予防し、又は寛解させるためのそれらの使用方法も本明細書に提供される。
ヒト受容体型チロシンキナーゼスーパーファミリーにおいて、ERBBファミリーは4つのメンバー:ERBB1(上皮成長因子受容体又はEGFR)、ERBB2(HER2)、ERBB3(HER3)、及びERBB4(HER4)を含む。ERBB受容体は、リガンド結合細胞外ドメイン、一回貫膜通型ドメイン、及び細胞内キナーゼドメインを有する全体的に類似の構造を共有し、それは、ERBB1、HER2、及びERBB4では活性であるが、ERBB3では機能しない。多種多様なリガンドが、ERBB1、ERBB3、及びERBB4の細胞外ドメインに対して特定されてきたが、HER2には特定されていない。リガンド結合は受容体にコンフォメーション変化を起こして、ホモ二量体及びヘテロ二量体化を形成する。リガンド結合なしで、HER2の細胞外ドメインは、リガンドにより活性化される他のERBBメンバーに似ているコンフォメーションで既に固定されており、リガンドに結合された他のERBBにとって好ましい二量体化パートナーになっている。二量体化された受容体は固有のキナーゼ活性を活性化し、細胞質尾部でのチロシンのリン酸化をもたらす。ERBB受容体は、キナーゼ効力、リン酸化部位、及び基質特異性が様々である。リン酸化されたチロシンは下流エフェクターを動員するドッキング部位として機能し、抗アポトーシス性/生存PI3K/AKT及びマイトジェンによるRAS/RAF/MEK/ERK経路を含む細胞内シグナル伝達経路の複数のカスケードを活性化させる。正常な細胞では、ERBB受容体の活性は、成長、増殖、発生及び分化、生存及びアポトーシス、細胞の形状及び接着、移動、並びに血管新生などの種々の細胞プロセスを調節する厳しい制御下にある。Yardenらの文献(Nat. Rev. Mol. Cell. Biol. 2001, 2, 127-137);Hynesらの文献(Nat. Rev. Cancer 2005, 5, 341-354)。
式Iの化合物、又はその単一のエナンチオマー、ラセミ混合物、ジアステレオマーの混合物、若しくは同位体変種;又はその医薬として許容し得る塩、溶媒和物、若しくはプロドラッグが本明細書に提供される:
R2は、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-10シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであり;
L1は、結合、-O-、-S-、-N(R1A)-、又は-C(R1AR1B)-であり(ここで、各R1A及びR1Bは、独立に、水素、ハロ、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルである);
L2は、C3-10シクロアルキレン、C6-14アリーレン、C7-15アラルキレン、ヘテロアリーレン、又はヘテロシクリレンであり;
Tは、結合、-O-、-S-、-N=、-N(R4)-、又は-C(R4)=であり;
Uは、結合、-O-、-S-、-N=、-N(R5)-、又は-C(R5)=であり;
Vは、結合、-O-、-S-、-N=、-N(R6)-、又は-C(R6)=であり;
Wは、結合、-O-、-S-、-N=、-N(R7)-、又は-C(R7)=であり;
X及びYは、それぞれ独立に、C又はNであり;
Zは、NR2A又はCR2AR2Bであり(ここで、各R2A及びR2Bは、独立に、水素、ハロ、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルである);
各R4、R5、R6、及びR7は、それぞれ独立に、(a)水素、シアノ、ハロ、若しくはニトロ;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-10シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、若しくはヘテロシクリル;又は(c)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c、若しくは-S(O)2NR1bR1cであり;但し、R4、R5、R6、及びR7の少なくとも2つが水素でないことを条件とし;且つ、R4とR5、R5とR6、又はR6とR7とが結合して、ヘテロアリール又はヘテロシクリルを形成することを条件とし;
各R1a、R1b、R1c、及びR1dは、独立に、水素、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、R1aとR1cとは、それらが結合しているC及びN原子と共に、ヘテロシクリルを形成するか;或いは、R1bとR1cとは、それらが結合するN原子と共に、ヘテロシクリルを形成し;
各R1e、R1f、及びR1gは、独立に、水素、ハロ、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであり;
但し、T、U、V、及びWの1つ以下が結合であることを条件とし;
ここで、各アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルキレン、アリール、アリーレン、アラルキル、アラルキレン、ヘテロアリール、ヘテロアリーレン、ヘテロシクリル、及びヘテロシクリレンは、1つ以上、一実施態様において、1、2、3、又は4つの置換基Qにより任意に置換されており、ここで、各Qは、(a)オキソ、シアノ、ハロ、及びニトロ;(b)それぞれ、1つ以上、一実施態様において、1、2、3、又は4つの置換基Qaにより任意にさらに置換されている、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、及びヘテロシクリル;並びに(c)-C(O)Ra、-C(O)ORa、-C(O)NRbRc、-C(NRa)NRbRc、-ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRbRc、-OC(=NRa)NRbRc、-OP(O)(ORa)2、-OS(O)Ra、-OS(O)2Ra、-OS(O)NRbRc、-OS(O)2NRbRc、-NRbRc、-NRaC(O)Rd、-NRaC(O)ORd、-NRaC(O)NRbRc、-NRaC(=NRd)NRbRc、-NRaS(O)Rd、-NRaS(O)2Rd、-NRaS(O)NRbRc、-NRaS(O)2NRbRc、-SRa、-S(O)Ra、-S(O)2Ra、-S(O)NRbRc、及び-S(O)2NRbRcから独立に選択され(ここで、各Ra、Rb、Rc、及びRdは、独立に、(i)水素;(ii)それぞれ、1つ以上、一実施態様において、1、2、3、又は4つの置換基Qaにより任意に置換されている、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、(iii)RbとRcとは、それらが結合しているN原子と共に、1つ以上、一実施態様において、1、2、3、又は4つの置換基Qaにより任意に置換されているヘテロシクリルを形成する);
ここで、各Qaは、(a)オキソ、シアノ、ハロ、及びニトロ;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、及びヘテロシクリル;並びに(c)-C(O)Rf、-C(O)ORf、-C(O)NRgRh、-C(NRf)NRgRh、-ORf、-OC(O)Rf、-OC(O)ORf、-OC(O)NRgRh、-OC(=NRf)NRgRh、-OP(O)(ORf)2、-OS(O)Rf、-OS(O)2Rf、-OS(O)NRgRh、-OS(O)2NRgRh、-NRgRh、-NRfC(O)Rk、-NRfC(O)ORk、-NRfC(O)NRgRh、-NRfC(=NRk)NRgRh、-NRfS(O)Rk、-NRfS(O)2Rk、-NRfS(O)NRgRh、-NRfS(O)2NRgRh、-SRf、-S(O)Rf、-S(O)2Rf、-S(O)NRgRh、及び-S(O)2NRgRhからなる群から独立に選択され;ここで、各Rf、Rg、Rh、及びRkは、独立に、(i)水素;(ii)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、(iii)RgとRhとは、それらが結合しているN原子と共に、ヘテロシクリルを形成する)。
本明細書に述べられる開示の理解を容易にするために、いくつかの術語が以下に定義される。
一実施態様において、式Iの化合物、又はその単一のエナンチオマー、ラセミ混合物、ジアステレオマーの混合物、若しくは同位体変種;又はその医薬として許容し得る塩、溶媒和物、若しくはプロドラッグが本明細書に提供される:
R2は、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-10シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであり;
L1は、結合、-O-、-S-、-N(R1A)-、又は-C(R1AR1B)-であり(ここで、各R1A及びR1Bは、独立に、水素、ハロ、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルである);
L2は、C3-10シクロアルキレン、C6-14アリーレン、C7-15アラルキレン、ヘテロアリーレン、又はヘテロシクリレンであり;
Tは、結合、-O-、-S-、-N=、-N(R4)-、又は-C(R4)=であり;
Uは、結合、-O-、-S-、-N=、-N(R5)-、又は-C(R5)=であり;
Vは、結合、-O-、-S-、-N=、-N(R6)-、又は-C(R6)=であり;
Wは、結合、-O-、-S-、-N=、-N(R7)-、又は-C(R7)=であり;
X及びYは、それぞれ独立に、C又はNであり;
Zは、NR2A又はCR2AR2Bであり(ここで、各R2A及びR2Bは、独立に、水素、ハロ、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルである);
各R4、R5、R6、及びR7は、それぞれ独立に、(a)水素、シアノ、ハロ、若しくはニトロ;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-10シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、若しくはヘテロシクリル;又は、(c)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c、若しくは-S(O)2NR1bR1cであり;但し、R4、R5、R6、及びR7の少なくとも2つが水素でないことを条件とし;且つ、R4とR5、R5とR6、又はR6とR7とが結合して、ヘテロアリール又はヘテロシクリルを形成することを条件とし;
各R1a、R1b、R1c、及びR1dは、独立に、水素、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、R1aとR1cとは、それらが結合しているC及びN原子と共に、ヘテロシクリルを形成するか;或いはR1bとR1cとは、それらが結合するN原子と共に、ヘテロシクリルを形成し;且つ
各R1e、R1f、及びR1gは、独立に、水素、ハロ、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであり;
但し、T、U、V、及びWの1つ以下が結合であることを条件とし;
ここで、各アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルキレン、アリール、アリーレン、アラルキル、アラルキレン、ヘテロアリール、ヘテロアリーレン、ヘテロシクリル、及びヘテロシクリレンは、1つ以上、一実施態様において、1、2、3、又は4つの置換基Qにより任意に置換されており、ここで、各Qは、(a)オキソ、シアノ、ハロ、及びニトロ;(b)それぞれ、1つ以上、一実施態様において、1、2、3、又は4つの置換基Qaにより任意にさらに置換されている、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、及びヘテロシクリル;並びに、(c)-C(O)Ra、-C(O)ORa、-C(O)NRbRc、-C(NRa)NRbRc、-ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRbRc、-OC(=NRa)NRbRc、-OP(O)(ORa)2、-OS(O)Ra、-OS(O)2Ra、-OS(O)NRbRc、-OS(O)2NRbRc、-NRbRc、-NRaC(O)Rd、-NRaC(O)ORd、-NRaC(O)NRbRc、-NRaC(=NRd)NRbRc、-NRaS(O)Rd、-NRaS(O)2Rd、-NRaS(O)NRbRc、-NRaS(O)2NRbRc、-SRa、-S(O)Ra、-S(O)2Ra、-S(O)NRbRc、及び-S(O)2NRbRcから独立に選択され(ここで、各Ra、Rb、Rc、及びRdは、独立に、(i)水素;(ii)それぞれ、1つ以上、一実施態様において、1、2、3、又は4つの置換基Qaにより任意に置換されている、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、(iii)RbとRcとは、それらが結合しているN原子と共に、1つ以上、一実施態様において、1、2、3、又は4つの置換基Qaにより任意に置換されているヘテロシクリルを形成する);
ここで、各Qaは、(a)オキソ、シアノ、ハロ、及びニトロ;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、及びヘテロシクリル;並びに(c)-C(O)Rf、-C(O)ORf、-C(O)NRgRh、-C(NRf)NRgRh、-ORf、-OC(O)Rf、-OC(O)ORf、-OC(O)NRgRh、-OC(=NRf)NRgRh、-OP(O)(ORf)2、-OS(O)Rf、-OS(O)2Rf、-OS(O)NRgRh、-OS(O)2NRgRh、-NRgRh、-NRfC(O)Rk、-NRfC(O)ORk、-NRfC(O)NRgRh、-NRfC(=NRk)NRgRh、-NRfS(O)Rk、-NRfS(O)2Rk、-NRfS(O)NRgRh、-NRfS(O)2NRgRh、-SRf、-S(O)Rf、-S(O)2Rf、-S(O)NRgRh、及び-S(O)2NRgRhからなる群から独立に選択され;ここで、各Rf、Rg、Rh、及びRkは、独立に、(i)水素;(ii)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、(iii)RgとRhとは、それらが結合しているN原子と共に、ヘテロシクリルを形成する)。
nは、0、1、2、3、4、5、又は6の整数であり;
各RLは、独立に、(i)水素;又は(ii)それぞれ、1つ以上の置換基Qにより任意に置換されている、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-10シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、若しくはヘテロシクリル;又は(iii)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c、若しくは-S(O)2NR1bR1cであるか;或いは
同じ環に結合する2つ以上のRLがある場合、2つのRLは結合して、(i)結合、-O-、-NRN-、若しくは-S-;又は(ii)それぞれ、1つ以上の置換基Qにより任意に置換されている、C1-6アルキレン、C1-6ヘテロアルキレン、C2-6アルケニレン、若しくはC2-6ヘテロアルケニレンを形成し;
RNは、(a)水素;(b)それぞれ、1つ以上の置換基Qにより任意に置換されている、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、若しくはヘテロシクリル;(c)-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c、若しくは-S(O)2NR1bR1cであり;且つ
R1、R2、R4、R5、R6、R7、R1a、R1b、R1c、R1d、及びQは、本明細書に定義される通りであり;且つ、R4とR5、R5とR6、及びR6とR7の組の1つは結合して、それぞれ、1つ以上の置換基Qにより任意に置換されている、C3-7シクロアルキル、C6-14アリール、ヘテロアリール、又はヘテロシクリルを形成する)。
その単一のエナンチオマー、ラセミ混合物、ジアステレオマーの混合物、若しくは同位体変種;又はその医薬として許容し得る塩、溶媒和物、若しくはプロドラッグを含む、有効成分としての本明細書に提供される化合物、例えば、式Iの化合物;及び医薬として許容し得るビヒクル、担体、希釈剤、若しくは賦形剤、又はその混合物を含む医薬組成物が本明細書に提供される。
経口投与用の本明細書に提供される医薬組成物は、経口投与用の固体、半固体、又は液体剤形で提供できる。本明細書で使用される通り、経口投与は、頬側投与、舌投与、及び舌下投与も含む。好適な経口剤形には、錠剤、速溶錠(fastmelts)、チュアブル錠、カプセル剤、丸剤、ストリップ剤(strips)、トローチ剤、ロゼンジ剤、香錠、カシェ剤、ペレット剤、薬用チューイングガム、原末、発泡性又は非発泡性の散剤又は顆粒剤、オーラルミスト、液剤、乳剤、懸濁剤、ウェハー剤、スプリンクル剤(sprinkles)、エリキシル剤、及びシロップ剤があるが、これらに限定されない。有効成分(複数可)に加えて、医薬組成物は、結合剤、充填剤、希釈剤、崩壊剤、湿潤剤、滑沢剤、流動促進剤、着色剤、移染阻害剤(dye-migration inhibitors)、甘味剤、着香剤、乳化剤、懸濁化剤及び分散化剤、保存剤、溶媒、非水性液体、有機酸、並びに二酸化炭素の源を含むがこれらに限定されない1種以上の医薬として許容し得る担体又は賦形剤を含み得る。
本明細書に提供される医薬組成物は、局所又は全身投与のために、注射、注入、又は移植により非経口投与できる。非経口投与には、本明細書で使用される通り、静脈内、動脈内、腹腔内、髄腔内、心室内、尿道内、胸骨内、頭蓋内、筋肉内、関節滑液嚢内、膀胱内、及び皮下投与がある。
本明細書に提供される医薬組成物は、皮膚、開口部、又は粘膜に局所投与できる。局所投与は、本明細書で使用される通り、皮膚(内)、結膜、角膜内、眼内、眼、耳、経皮、鼻腔内、膣内、尿道、呼吸器、及び直腸投与を含む。
本明細書に提供される医薬組成物は、調整放出剤形として製剤できる。本明細書で使用される通り、用語「調整放出」は、有効成分(複数可)の放出の速度又は場所が、同じ経路により投与される場合、即時の剤形のものとは異なる剤形を指す。調整放出剤形には、遅延放出、延長放出、長期放出、持続放出、パルス放出、制御放出、加速放出及び高速放出、標的化放出、プログラム化放出、並びに胃内滞留剤形があるが、これらに限定されない。調整放出剤形中の医薬組成物は、マトリックス制御放出装置、浸透制御放出装置、多粒子制御放出装置、イオン交換樹脂、腸溶性コーティング、多層コーティング、微小球、リポソーム、及びこれらの組み合わせを含むがこれらに限定されない当業者に公知である種々の調整放出装置及び方法を利用して製造できる。有効成分(複数可)の放出速度は、有効成分(複数可)の粒径及び多形を変えることによっても調整できる。
調整放出剤形中の本明細書に提供される医薬組成物は、当業者に公知であるマトリックス制御放出装置を利用して製造できる。Takadaらの文献(「制御薬物送達の事典(Encyclopedia of Controlled Drug Delivery)」;Mathiowitz編;Wiley: 1999;Vol 2中)を参照されたい。
調整放出剤形中の本明細書に提供される医薬組成物は、1チャンバー系、2チャンバー系、非対称膜技術(AMT)、及び押出コア系(extruding core system)(ECS)を含むがこれらに限定されない浸透制御放出装置を使用して製造できる。一般に、そのような装置は少なくとも2成分:(a)有効成分を含むコア;及び(b)少なくとも1つの送達口を有する、コアを包み込む半透膜を有する。半透膜は、送達口(複数可)を通る押出しにより薬物放出を起こすように、使用水性環境からのコアへの水の流入を制御する。
調整放出剤形中の本明細書に提供される医薬組成物は、直径が、約10μm〜約3mm、約50μm〜約2.5mm、又は約100μm〜約1mmの範囲である多数の粒子、顆粒、又はペレットを含む多粒子制御放出装置として製造できる。そのような多粒子は、湿式及び乾式造粒、押出/球形化、ローラー圧縮、溶融凝固(melt-congealing)を含む当業者に公知であるプロセスにより、及びシードコアの噴霧被覆により製造できる。例えば、「多粒子経口薬物送達(Multiparticulate Oral Drug Delivery)」;Ghebre-Sellassie編;Marcel Dekker: 1994;及び「医薬ペレット化技術(Pharmaceutical Pelletization Technology)」;Ghebre-Sellassie編;Marcel Dekker: 1989を参照されたい。
本明細書に提供される医薬組成物は、リポソーム-、再封入赤血球-、及び抗体系送達系を含む、治療すべき対象の体の特定の組織、受容体、又は他の部分に標的化するようにも製剤できる。例には、米国特許第5,709,874号;同第5,759,542号;同第5,840,674号;同第5,900,252号;同第5,972,366号;同第5,985,307号;同第6,004,534号;同第6,039,975号;同第6,048,736号;同第6,060,082号;同第6,071,495号;同第6,120,751号;同第6,131,570号;同第6,139,865号;同第6,253,872号;同第6,271,359号;同第6,274,552号;同第6,316,652号;及び同第7,169,410号に開示のものがあるが、これらに限定されない。
一実施態様において、対象におけるERBB媒介性の病態、障害、又は疾患の1つ以上の症状を治療し、予防し、又は寛解させる方法であって、該対象に、本明細書に開示される化合物、例えば、式Iの化合物、又はその単一のエナンチオマー、ラセミ混合物、ジアステレオマーの混合物、若しくは同位体変種;又はその医薬として許容し得る塩、溶媒和物、若しくはプロドラッグを投与することを含む方法が本明細書に提供される。
本明細書で使用される通り、これらのプロセス、スキーム、及び実施例で使用される記号及び慣例は、特定の略語が具体的に定義されているか否かにかかわらず、現代の科学文献、例えば、the Journal of the American Chemical Society又はthe Journal of Biological Chemistryに使用されているものと一致する。具体的だが非限定的に、以下の略語が実施例及び明細書全体で使用され得る:g(グラム);mg(ミリグラム);mL(ミリリットル);μL(マイクロリットル);L(リットル);mM(ミリモラー);μM(マイクロモラー);Hz(ヘルツ);MHz(メガヘルツ);mmol(ミリモル);eq.(当量);hr又はhrs(時間);min(分);MS(質量分析法);NMR(核磁気共鳴);ESI(エレクトロスプレーイオン化);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);ACN(アセトニトリル);CDCl3(重水素化クロロホルム);DCM(ジクロロメタン);DMF(N,N-ジメチルホルムアミド);DMSO(ジメチルスルホキシド);DMSO-d6(重水素化ジメチルスルホキシド);EtOAc(酢酸エチル);Et2O(ジエチルエーテル);EtOH(エタノール);MeOH(メタノール);PE(石油エーテル);THF(テトラヒドロフラン);DIPEA(N,N-ジイソプロピルエチルアミン);TEA(トリエチルアミン);TFA(トリフルオロ酢酸);BOP(ベンゾトリアゾール-1-イル-オキシ-トリス-(ジメチルアミノ)-ホスホニウムヘキサフルオロホスフェート);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);TBTU(O-ベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウムテトラフルオロボラート);DIPC(1,3-ジイソプロピルカルボジイミド);Me(メチル);Et(エチル);iPr(イソプロピル);tBu(tert-ブチル);Boc(tert-ブトキシルカルボニ(butoxylcarbony));Bn(ベンジル);Ph(フェニル);及びAcO(アセタート)。
(細胞増殖アッセイ)
試験化合物の生物学的活性を、細胞増殖アッセイを利用して決定した。野生型ERBB1に対する活性を、A431ヒト類表皮癌細胞(ATCC)及びヒト新生児表皮角化細胞、又はHEKn細胞(ATCC)を利用して決定した。変異したERBB1に対する活性を、HCC827ヒトNSCLC腺癌細胞(ATCC)を使用して決定したが、それは、エクソン19中のE746-A759の欠失を有する。薬剤耐性変異ERBB1に対する活性を、H1975ヒトNSCLC腺癌細胞(ATCC)を使用して決定したが、それは、L858R突然変異とシスのT790M突然変異を有する。
表1.細胞増殖の阻害
((R)-tert-ブチル3-(2-アミノ-7,8-ジヒドロ-1H-[1,4]ジオキシノ[2',3':3,4]ベンゾ[1,2-d]イミダゾール-1-イル)アゼパン-1-カルボキシラート5の合成)
(R)-tert-ブチル3-(2-アミノ-7,8-ジヒドロ-1H-[1,4]ジオキシノ[2',3':3,4]ベンゾ[1,2-d]イミダゾール-1-イル)アゼパン-1-カルボキシラート5の合成をスキーム1に示す。
スキーム1
((R)-N-(1-(1-アクリロイルアゼパン-3-イル)-7,8-ジヒドロ-1H-[1,4]ジオキシノ[2',3':3,4]ベンゾ[1,2-d]イミダゾール-2-イル)-2-メチルイソニコチンアミドC1の合成)
(R)-N-(1-(1-アクリロイルアゼパン-3-イル)-7,8-ジヒドロ-1H-[1,4]ジオキシノ[2',3':3,4]ベンゾ[1,2-d]イミダゾール-2-イル)-2-メチルイソニコチンアミドC1の合成をスキーム2に示す。
スキーム2
((R)-N-(1-(1-アクリロイルアゼパン-3-イル)-7,8-ジヒドロ-1H-[1,4]ジオキシノ[2',3':3,4]ベンゾ[1,2-d]イミダゾール-2-イル)-2-(トリフルオロメチル)イソニコチンアミドB1の合成)
((R)-N-(1-(1-アクリロイルアゼパン-3-イル)-7,8-ジヒドロ-1H-[1,4]ジオキシノ[2',3':3,4]ベンゾ[1,2-d]イミダゾール-2-イル)-2-メトキシイソニコチンアミドC2の合成)
((R,E)-N-(1-(1-(4-(ジメチルアミノ)ブタ-2-エノイル)アゼパン-3-イル)-7,8-ジヒドロ-1H-[1,4]ジオキシノ[2',3':3,4]ベンゾ[1,2-d]イミダゾール-2-イル)-2-(トリフルオロメチル)イソニコチンアミドC3の合成)
本件出願は、以下の構成の発明を提供する。
(構成1)
式Iの化合物、又はその単一のエナンチオマー、ラセミ混合物、ジアステレオマーの混合物、若しくは同位体変種;又はその医薬として許容し得る塩、溶媒和物、若しくはプロドラッグ:
(化1)
(式中、R 1 は、(a)水素、シアノ、ハロ、若しくはニトロ;(b)C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-10 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、若しくはヘテロシクリル;(c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O) 2 R 1a 、-OS(O)NR 1b R 1c 、-OS(O) 2 NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O) 2 R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O) 2 NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O) 2 R 1a 、-S(O)NR 1b R 1c 、若しくは-S(O) 2 NR 1b R 1c ;又は(d)-C(O)CR 1e =CR 1f CR 1g 、
(化2)
-N 1a C(O)CR 1e =CR 1f CR 1g 、
(化3)
-S(O)CR 1e =CR 1f CR 1g 、
(化4)
-S(O 2 )CR 1e =CR 1f CR 1g 、
(化5)
-NR 1a S(O)CR 1e =CR 1f CR 1g 、
(化6)
-NR 1a S(O 2 )CR 1e =CR 1f CR 1g 、又は
(化7)
であり;
R 2 は、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-10 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、又はヘテロシクリルであり;
L 1 は、結合、-O-、-S-、-N(R 1A )-、又は-C(R 1A R 1B )-であり(ここで、各R 1A 及びR 1B は、独立に、水素、ハロ、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-7 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、又はヘテロシクリルである);
L 2 は、C 3-10 シクロアルキレン、C 6-14 アリーレン、C 7-15 アラルキレン、ヘテロアリーレン、又はヘテロシクリレンであり;
Tは、結合、-O-、-S-、-N=、-N(R 4 )-、又は-C(R 4 )=であり;
Uは、結合、-O-、-S-、-N=、-N(R 5 )-、又は-C(R 5 )=であり;
Vは、結合、-O-、-S-、-N=、-N(R 6 )-、又は-C(R 6 )=であり;
Wは、結合、-O-、-S-、-N=、-N(R 7 )-、又は-C(R 7 )=であり;
X及びYは、それぞれ独立に、C又はNであり;
Zは、NR 2A 又はCR 2A R 2B であり(ここで、各R 2A 及びR 2B は、独立に、水素、ハロ、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-7 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、又はヘテロシクリルである);
各R 4 、R 5 、R 6 、及びR 7 は、それぞれ独立に、(a)水素、シアノ、ハロ、若しくはニトロ;(b)C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-10 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、若しくはヘテロシクリル;又は(c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O) 2 R 1a 、-OS(O)NR 1b R 1c 、-OS(O) 2 NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O) 2 R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O) 2 NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O) 2 R 1a 、-S(O)NR 1b R 1c 、若しくは-S(O) 2 NR 1b R 1c であり;但し、R 4 、R 5 、R 6 、及びR 7 の少なくとも2つが水素でないことを条件とし;且つ、R 4 とR 5 、R 5 とR 6 、又はR 6 とR 7 とが結合して、ヘテロアリール又はヘテロシクリルを形成することを条件とし;
各R 1a 、R 1b 、R 1c 、及びR 1d は、独立に、水素、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-7 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、R 1a とR 1c とは、それらが結合しているC及びN原子と共に、ヘテロシクリルを形成するか;或いはR 1b とR 1c とは、それらが結合するN原子と共に、ヘテロシクリルを形成し;且つ
各R 1e 、R 1f 、及びR 1g は、独立に、水素、ハロ、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-7 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、又はヘテロシクリルであり;
但し、T、U、V、及びWの1つ以下が結合であることを条件とし;
ここで、各アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルキレン、アリール、アリーレン、アラルキル、アラルキレン、ヘテロアリール、ヘテロアリーレン、ヘテロシクリル、及びヘテロシクリレンは、1つ以上、一実施態様において、1、2、3、又は4つの置換基Qにより任意に置換されており、ここで、各Qは、(a)オキソ、シアノ、ハロ、及びニトロ;(b)それぞれ、1つ以上、一実施態様において、1、2、3、又は4つの置換基Q a により任意にさらに置換されている、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-7 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、及びヘテロシクリル;並びに、(c)-C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-C(NR a )NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(=NR a )NR b R c 、-OP(O)(OR a ) 2 、-OS(O)R a 、-OS(O) 2 R a 、-OS(O)NR b R c 、-OS(O) 2 NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(=NR d )NR b R c 、-NR a S(O)R d 、-NR a S(O) 2 R d 、-NR a S(O)NR b R c 、-NR a S(O) 2 NR b R c 、-SR a 、-S(O)R a 、-S(O) 2 R a 、-S(O)NR b R c 、及び-S(O) 2 NR b R c から独立に選択され(ここで、各R a 、R b 、R c 、及びR d は、独立に、(i)水素;(ii)それぞれ、1つ以上、一実施態様において、1、2、3、又は4つの置換基Q a により任意に置換されている、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-7 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、(iii)R b とR c とは、それらが結合しているN原子と共に、1つ以上、一実施態様において、1、2、3、又は4つの置換基Q a により任意に置換されているヘテロシクリルを形成する);
ここで、各Q a は、(a)オキソ、シアノ、ハロ、及びニトロ;(b)C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-7 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、及びヘテロシクリル;並びに、(c)-C(O)R f 、-C(O)OR f 、-C(O)NR g R h 、-C(NR f )NR g R h 、-OR f 、-OC(O)R f 、-OC(O)OR f 、-OC(O)NR g R h 、-OC(=NR f )NR g R h 、-OP(O)(OR f ) 2 、-OS(O)R f 、-OS(O) 2 R f 、-OS(O)NR g R h 、-OS(O) 2 NR g R h 、-NR g R h 、-NR f C(O)R k 、-NR f C(O)OR k 、-NR f C(O)NR g R h 、-NR f C(=NR k )NR g R h 、-NR f S(O)R k 、-NR f S(O) 2 R k 、-NR f S(O)NR g R h 、-NR f S(O) 2 NR g R h 、-SR f 、-S(O)R f 、-S(O) 2 R f 、-S(O)NR g R h 、及び-S(O) 2 NR g R h からなる群から独立に選択され;ここで、各R f 、R g 、R h 、及びR k は、独立に、(i)水素;(ii)C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-7 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、(iii)R g とR h とは、それらが結合しているN原子と共に、ヘテロシクリルを形成する)。
(構成2)
Tが-N=である、構成1記載の化合物。
(構成3)
Tが-C(R 4 )=である、構成1記載の化合物。
(構成4)
Uが-N=である、構成1〜3のいずれか一項記載の化合物。
(構成5)
Uが-C(R 5 )=である、構成1〜3のいずれか一項記載の化合物。
(構成6)
Vが-N=である、構成1〜5のいずれか一項記載の化合物。
(構成7)
Vが-C(R 6 )=である、構成1〜5のいずれか一項記載の化合物。
(構成8)
Wが-N=である、構成1〜7のいずれか一項記載の化合物。
(構成9)
Wが-C(R 7 )=である、構成1〜7のいずれか一項記載の化合物。
(構成10)
XがNである、構成1〜9のいずれか一項記載の化合物。
(構成11)
XがCである、構成1〜9のいずれか一項記載の化合物。
(構成12)
YがNである、構成1〜11のいずれか一項記載の化合物。
(構成13)
YがCである、構成1〜11のいずれか一項記載の化合物。
(構成14)
式IIの構造を有する、構成1記載の化合物、又はその単一のエナンチオマー、ラセミ混合物、ジアステレオマーの混合物、若しくは同位体変種;又はその医薬として許容し得る塩、溶媒和物、若しくはプロドラッグ:
(化8)
。
(構成15)
式IIIの構造を有する、構成1記載の化合物、又はその単一のエナンチオマー、ラセミ混合物、ジアステレオマーの混合物、若しくは同位体変種;又はその医薬として許容し得る塩、溶媒和物、若しくはプロドラッグ:
(化9)
(式中、記号
(化10)
は、該6員環が、該環中に1つのN原子を含むことを表す)。
(構成16)
L 1 が、結合、-O-、-N(R 1A )-、又は-C(R 1A R 1B )-である、構成1〜15のいずれか一項記載の化合物。
(構成17)
L 1 が結合である、構成16記載の化合物。
(構成18)
L 1 が-O-である、構成16記載の化合物。
(構成19)
L 1 が、-NH-又は-CH 2 -である、構成16記載の化合物。
(構成20)
L 2 が、それぞれ、1つ以上の置換基Qにより任意に置換されている、C 3-10 シクロアルキレン、ヘテロアリーレン、又はヘテロシクリレンである、構成1〜19のいずれか一項記載の化合物。
(構成21)
L 2 が、それぞれ、1つ以上の置換基Qにより任意に置換されている、ヘテロアリーレン又はヘテロシクリレンである、構成20記載の化合物。
(構成22)
L 2 が
(化11)
である、構成20記載の化合物
(式中、rは、0、1、2、3、4、5、又は6の整数であり;
sは、0、1、2、3、4、5、6、7、8、9、又は10の整数であり;且つ
各R L は、独立に、(i)水素;又は(ii)それぞれ、1つ以上の置換基Qにより任意に置換されている、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-10 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、若しくはヘテロシクリル;又は(iii)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O) 2 R 1a 、-OS(O)NR 1b R 1c 、-OS(O) 2 NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O) 2 R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O) 2 NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O) 2 R 1a 、-S(O)NR 1b R 1c 、若しくは-S(O) 2 NR 1b R 1c であるか;或いは
同じ環に結合する2つ以上のR L がある場合に、2つのR L は結合して、(i)結合、-O-、-NR N -、若しくは-S-;又は(ii)それぞれ、1つ以上の置換基Qにより任意に置換されている、C 1-6 アルキレン、C 1-6 ヘテロアルキレン、C 2-6 アルケニレン、若しくはC 2-6 ヘテロアルケニレンを形成する)。
(構成23)
L 2 が
(化12)
である、構成20記載の化合物
(式中、rは、0、1、2、3、4、5、又は6の整数であり;
sは、0、1、2、3、4、5、6、7、8、9、又は10の整数であり;且つ
各R L は、独立に、(i)水素;又は(ii)それぞれ、1つ以上の置換基Qにより任意に置換されている、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-10 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、若しくはヘテロシクリル;又は(iii)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O) 2 R 1a 、-OS(O)NR 1b R 1c 、-OS(O) 2 NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O) 2 R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O) 2 NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O) 2 R 1a 、-S(O)NR 1b R 1c 、若しくは-S(O) 2 NR 1b R 1c であるか;或いは
同じ環に結合する2つ以上のR L がある場合に、2つのR L は結合して、(i)結合、-O-、-NR N -、若しくは-S-;又は(ii)それぞれ、1つ以上の置換基Qにより任意に置換されている、C 1-6 アルキレン、C 1-6 ヘテロアルキレン、C 2-6 アルケニレン、若しくはC 2-6 ヘテロアルケニレンを形成する)。
(構成24)
L 2 が
(化13)
である、構成20記載の化合物
(式中、rは、0、1、2、3、4、5、又は6の整数であり;
tは、0、1、2、3、4、5、又は6の整数であり;且つ
各R L は、独立に、(i)水素;又は(ii)それぞれ、1つ以上の置換基Qにより任意に置換されている、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-10 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、若しくはヘテロシクリル;又は(iii)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O) 2 R 1a 、-OS(O)NR 1b R 1c 、-OS(O) 2 NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O) 2 R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O) 2 NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O) 2 R 1a 、-S(O)NR 1b R 1c 、若しくは-S(O) 2 NR 1b R 1c であるか;或いは
同じ環に結合する2つ以上のR L がある場合に、2つのR L は結合して、(i)結合、-O-、-NR N -、若しくは-S-;又は(ii)それぞれ、1つ以上の置換基Qにより任意に置換されている、C 1-6 アルキレン、C 1-6 ヘテロアルキレン、C 2-6 アルケニレン、若しくはC 2-6 ヘテロアルケニレンを形成する)。
(構成25)
L 2 が
(化14)
である、構成20記載の化合物
(式中、rは、0、1、2、3、4、5、又は6の整数であり;
tは、0、1、2、3、4、5、又は6の整数であり;且つ
各R L は、独立に、(i)水素;又は(ii)それぞれ、1つ以上の置換基Qにより任意に置換されている、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-10 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、若しくはヘテロシクリル;又は(iii)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O) 2 R 1a 、-OS(O)NR 1b R 1c 、-OS(O) 2 NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O) 2 R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O) 2 NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O) 2 R 1a 、-S(O)NR 1b R 1c 、若しくは-S(O) 2 NR 1b R 1c であるか;或いは
同じ環に結合する2つ以上のR L がある場合に、2つのR L は結合して、(i)結合、-O-、-NR N -、若しくは-S-;又は(ii)それぞれ、1つ以上の置換基Qにより任意に置換されている、C 1-6 アルキレン、C 1-6 ヘテロアルキレン、C 2-6 アルケニレン、若しくはC 2-6 ヘテロアルケニレンを形成する)。
(構成26)
rが0である、構成22〜25のいずれか一項記載の化合物。
(構成27)
L 1 -L 2 が
(化15)
である、構成20記載の化合物
(式中、記号
(化16)
は、該6員環が、該環中に1〜3つのN原子を含むことを表し、各硫黄は任意にスルホキシド又はスルホンとして酸化されている)。
(構成28)
L 1 -L 2 が
(化17)
である、構成20記載の化合物。
(構成29)
式IVの構造を有する、構成1記載の化合物、又はその単一のエナンチオマー、ラセミ混合物、ジアステレオマーの混合物、若しくは同位体変種;又はその医薬として許容し得る塩、溶媒和物、若しくはプロドラッグ:
(化18)
(式中、mは、0、1、2、3、4、5、6、7、8、9、又は10の整数であり;
nは、0、1、2、3、4、5、又は6の整数であり;
各R L は、独立に、(i)水素;又は(ii)それぞれ、1つ以上の置換基Qにより任意に置換されている、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-10 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、若しくはヘテロシクリル;又は(iii)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O) 2 R 1a 、-OS(O)NR 1b R 1c 、-OS(O) 2 NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O) 2 R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O) 2 NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O) 2 R 1a 、-S(O)NR 1b R 1c 、若しくは-S(O) 2 NR 1b R 1c であるか;或いは
同じ環に結合するR L が2つ以上ある場合に、2つのR L は結合して、(i)結合、-O-、-NR N -、若しくは-S-;又は(ii)それぞれ、1つ以上の置換基Qにより任意に置換されている、C 1-6 アルキレン、C 1-6 ヘテロアルキレン、C 2-6 アルケニレン、若しくはC 2-6 ヘテロアルケニレンを形成し;且つ
R N は(a)水素;(b)それぞれ、1つ以上の置換基Qにより任意に置換されている、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-7 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、若しくはヘテロシクリル;(c)-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O) 2 R 1a 、-OS(O)NR 1b R 1c 、-OS(O) 2 NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O) 2 R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O) 2 NR 1b R 1c 、-S(O)R 1a 、-S(O) 2 R 1a 、-S(O)NR 1b R 1c 、若しくは-S(O) 2 NR 1b R 1c である)。
(構成30)
式Vの構造を有する、構成1記載の化合物、又はその単一のエナンチオマー、ラセミ混合物、ジアステレオマーの混合物、若しくは同位体変種;又はその医薬として許容し得る塩、溶媒和物、若しくはプロドラッグ:
(化19)
。
(構成31)
式VIの構造を有する、構成1記載の化合物、又はその単一のエナンチオマー、ラセミ混合物、ジアステレオマーの混合物、若しくは同位体変種;又はその医薬として許容し得る塩、溶媒和物、若しくはプロドラッグ:
(化20)
。
(構成32)
式VIIの構造を有する、構成1記載の化合物、又はその単一のエナンチオマー、ラセミ混合物、ジアステレオマーの混合物、若しくは同位体変種;又はその医薬として許容し得る塩、溶媒和物、若しくはプロドラッグ:
(化21)
。
(構成33)
R 1 が、-C(O)CR 1e =CR 1f CR 1g 又は
(化22)
である、構成1〜32のいずれか一項記載の化合物。
(構成34)
R 1 が
(化23)
から選択される、構成33記載の化合物。
(構成35)
R 1 が、-N 1a C(O)CR 1e =CR 1f CR 1g 又は
(化24)
である、構成1〜32のいずれか一項記載の化合物。
(構成36)
R 1 が
(化25)
から選択される、構成35記載の化合物。
(構成37)
R 2 が、それぞれ、1つ以上の置換基Qにより任意に置換されている、C 6-14 アリール、ヘテロアリール、又はヘテロシクリルである、構成1〜36のいずれか一項記載の化合物。
(構成38)
R 2 が、1つ以上の置換基Qにより任意に置換されている6員〜10員の単環式又は二環式のアリールである、構成37記載の化合物。
(構成39)
R 2 が、N、O、及びSから選択される1〜4つのヘテロ原子を含み、1つ以上の置換基Qにより任意に置換されている、5員〜10員の単環式又は二環式のヘテロアリールである、構成37記載の化合物。
(構成40)
R 2 が、N、O、及びSから選択される1〜4つのヘテロ原子を含み、1つ以上の置換基Qにより任意に置換されている、5員〜10員の単環式又は二環式の複素環である、構成37記載の化合物。
(構成41)
R 2 が、それぞれ、1つ以上の置換基Qにより任意に置換されている、フェニル、ピリジニル、ピリダジニル、ベンゾ[c][1,2,5]オキソジアゾリル、又はベンゾ[c][1,2,5]チオジアゾリルである、構成37記載の化合物。
(構成42)
R 4 が水素である、構成1〜41のいずれか一項記載の化合物。
(構成43)
R 5 とR 6 とが結合して、1つ以上の置換基Qにより任意に置換されているヘテロシクリルを形成する、構成1〜42のいずれか一項記載の化合物。
(構成44)
R 5 とR 6 とが結合して、下記から選択されるヘテロシクリルを形成する、構成44記載の化合物:
(化26)
。
(構成45)
R 7 が水素である、構成1〜44のいずれか一項記載の化合物。
(構成46)
R 7 が、クロロ、メチル、又はメトキシである、構成1〜44のいずれか一項記載の化合物。
(構成47)
R 6 とR 7 とが結合して、1つ以上の置換基Qにより任意に置換されているヘテロシクリルを形成する、構成1〜42のいずれか一項記載の化合物。
(構成48)
R 6 とR 7 とが結合して、下記から選択されるヘテロシクリルを形成する、構成47記載の化合物:
(化27)
(式中、pは、1、2、3、4、5、又は6の整数である)。
(構成49)
R 5 が水素である、構成1〜42、47、及び48のいずれか一項記載の化合物。
(構成50)
ZがNHである、構成1〜49のいずれか一項記載の化合物。
(構成51)
下記から選択される、構成1記載の化合物、並びにその単一のエナンチオマー、ラセミ混合物、ジアステレオマーの混合物、及び同位体変種;並びにその医薬として許容し得る塩、溶媒和物、及びプロドラッグ:
(化28)
。
(構成52)
下記から選択される、構成1記載の化合物、並びにその単一のエナンチオマー、ラセミ混合物、ジアステレオマーの混合物、及び同位体変種;並びにその医薬として許容し得る塩、溶媒和物、及びプロドラッグ:
(化29)
。
(構成53)
R 1a が、水素又はメチルである、構成51又は52記載の化合物。
(構成54)
R 1f が、水素、ジメチルアミノメチル、ピロリジン-1-イルメチル、又はピペリジン-1-イルメチルである、構成51〜53のいずれか一項記載の化合物。
(構成55)
下記から選択される、構成1記載の化合物、及びその同位体変種;並びにその医薬として許容し得る塩、溶媒和物、及びプロドラッグ:
(化30)
。
(構成56)
下記から選択される、構成1記載の化合物、及びその同位体変種;並びにその医薬として許容し得る塩、溶媒和物、及びプロドラッグ:
(化31)
。
(構成57)
構成1〜56のいずれか一項記載の化合物及び医薬として許容し得る賦形剤を含む医薬組成物。
(構成58)
経口、鼻腔内、気管支、又は局所投与のために製剤される、構成57記載の医薬組成物。
(構成59)
単一の剤形として製剤される、構成57又は58記載の医薬組成物。
(構成60)
経口、非経口、鼻腔内、呼吸器、経肺、又は静脈内剤形として製剤される、構成57〜59のいずれか一項記載の医薬組成物。
(構成61)
経口剤形である、構成60記載の医薬組成物。
(構成62)
前記経口剤形が、錠剤又はカプセル剤である、構成61記載の医薬組成物。
(構成63)
第二の治療剤をさらに含む、構成57〜62のいずれか一項記載の医薬組成物。
(構成64)
対象におけるERBB媒介性の病態、障害、又は疾患の1つ以上の症状を治療し、予防し、又は寛解させる方法であって、該対象に、構成1〜56のいずれか一項記載の化合物又は構成57〜63のいずれか一項記載の医薬組成物を投与することを含む、前記方法。
(構成65)
前記ERBB媒介性の病態、障害、又は疾患が増殖性疾患である、構成64記載の方法。
(構成66)
対象における増殖性疾患(a proliferative or disease)の1つ以上の症状を治療し、予防し、又は寛解させる方法であって、該対象に、構成1〜56のいずれか一項記載の化合物又は構成57〜63のいずれか一項記載の医薬組成物を投与することを含む、前記方法。
(構成67)
前記増殖性疾患が癌である、構成65又は66記載の方法。
(構成68)
前記癌が薬剤耐性である、構成67記載の方法。
(構成69)
前記癌がERBBバリアントを含む、構成67又は68記載の方法。
(構成70)
前記ERBBバリアントがEGFRバリアントである、構成69記載の方法。
(構成71)
前記EGFRバリアントが、689、700、709、715、719、720、746-759、761-765、767-775、783、784、790、796、826、839、846、858、861、及び863のアミノ酸位置で、1つ以上の欠失、挿入、又は置換を含む、構成70記載の方法。
(構成72)
前記EGFRバリアントが、719、746-751、790、及び858のアミノ酸位置で、1つ以上の欠失、挿入、又は置換を含む、構成70記載の方法。
(構成73)
前記EGFRバリアントが、G719C、G719S、G719A、ΔE746-A750、ΔE746-T751、ΔE746-A750(ins RP)、ΔD761-E762(ins EAFQ)、ΔS768-D770(dup SVD)、ΔV769-D770(ins ASV)、ΔD770-N771(ins SVQ)、ΔP772-H773(ins PR)、ΔH773-V774(ins NPH)、ΔH773-V774(ins H)、ΔH773-V774(ins PH)、及びΔH773-V774(ins GNPH)、T790M、並びにL858Rからそれぞれ独立に選択される、1、2、又はそれ以上の欠失、挿入、及び/又は置換を含む、構成70記載の方法。
(構成74)
前記EGFRバリアントが、T790M、L858R、又はこれらの組み合わせを含む、構成70記載の方法。
(構成75)
前記ERBBバリアントがHER2バリアントである、構成69記載の方法。
(構成76)
前記HER2が前記癌中で過剰発現されている、構成67〜75のいずれか一項記載の方法。
(構成77)
前記癌が、EGFR阻害剤に耐性である、構成68〜76のいずれか一項記載の方法。
(構成78)
前記癌が、アファチニブ、カネルチニブ、ダコミチニブ、エルロチニブ、ゲフィチニブ、イコチニブ、ラパチニブ、ネラチニブ、ペリチニブ、バルリチニブ、又はこれらの組み合わせに耐性である、構成77記載の方法。
(構成79)
前記癌が、膀胱癌、脳腫瘍、乳癌、口及び喉の癌、大腸癌、肺癌、又は膵臓癌、前立腺癌、胃癌、又は子宮癌である、構成67〜78のいずれか一項記載の方法。
(構成80)
前記癌が肺癌である、構成79記載の方法。
(構成81)
前記癌が非小細胞肺癌である、構成79記載の方法。
(構成82)
前記癌が、再発性又は不応性である、構成67〜81のいずれか一項記載の方法。
(構成83)
前記対象がヒトである、構成64〜82のいずれか一項記載の方法。
(構成84)
細胞の成長を阻害する方法であって、該細胞を、構成1〜56のいずれか一項記載の化合物と接触させることを含む、前記方法。
(構成85)
前記細胞が癌細胞である、構成84記載の方法。
(構成86)
前記細胞がERBBバリアントを含む、構成84又は85記載の方法。
(構成87)
前記ERBBバリアントがEGFRバリアントである、構成86記載の方法。
(構成88)
前記EGFRバリアントが、689、700、709、715、719、720、746-759、761-765、767-775、783、784、790、796、826、839、846、858、861、及び863のアミノ酸位置で、1つ以上の欠失、挿入、又は置換を含む、構成87記載の方法。
(構成89)
前記EGFRバリアントが、719、746-751、790、及び858のアミノ酸位置で、1つ以上の欠失、挿入、又は置換を含む、構成87記載の方法。
(構成90)
前記EGFRバリアントが、G719C、G719S、G719A、ΔE746-A750、ΔE746-T751、ΔE746-A750(ins RP)、ΔD761-E762(ins EAFQ)、ΔS768-D770(dup SVD)、ΔV769-D770(ins ASV)、ΔD770-N771(ins SVQ)、ΔP772-H773(ins PR)、ΔH773-V774(ins NPH)、ΔH773-V774(ins H)、ΔH773-V774(ins PH)、及びΔH773-V774(ins GNPH)、T790M、並びにL858Rからそれぞれ独立に選択される、1、2、又はそれ以上の欠失、挿入、及び/又は置換を含む、構成87記載の方法。
(構成91)
前記EGFRバリアントが、T790M、L858R、又はこれらの組み合わせを含む、構成87記載の方法。
(構成92)
ERBBの活性を調節する方法であって、該ERBBを、構成1〜56のいずれか一項記載の化合物と接触させることを含む、前記方法。
(構成93)
前記ERBBがERBBバリアントである、構成92記載の方法。
(構成94)
前記ERBBバリアントがEGFRバリアントである、構成93記載の方法。
(構成95)
前記EGFRバリアントが、689、700、709、715、719、720、746-759、761-765、767-775、783、784、790、796、826、839、846、858、861、及び863のアミノ酸位置で、1つ以上の欠失、挿入、又は置換を含む、構成94記載の方法。
(構成96)
前記EGFRバリアントが、719、746-751、790、及び858のアミノ酸位置で、1つ以上の欠失、挿入、又は置換を含む、構成94記載の方法。
(構成97)
前記EGFRバリアントが、G719C、G719S、G719A、ΔE746-A750、ΔE746-T751、ΔE746-A750(ins RP)、ΔD761-E762(ins EAFQ)、ΔS768-D770(dup SVD)、ΔV769-D770(ins ASV)、ΔD770-N771(ins SVQ)、ΔP772-H773(ins PR)、ΔH773-V774(ins NPH)、ΔH773-V774(ins H)、ΔH773-V774(ins PH)、及びΔH773-V774(ins GNPH)、T790M、並びにL858Rからそれぞれ独立に選択される、1、2、又はそれ以上の欠失、挿入、及び/又は置換を含む、構成94記載の方法。
(構成98)
前記EGFRバリアントが、T790M、L858R、又はこれらの組み合わせを含む、構成94記載の方法。
Claims (45)
- 式IVの化合物、又はその単一のエナンチオマー、ラセミ混合物、ジアステレオマーの混合物、若しくは同位体変種;又はその医薬として許容し得る塩、若しくは溶媒和物:
mは、0、1、2、3、4、5、6、7、8、9、又は10の整数であり;
nは、0、1、2、3、4、5、又は6の整数であり;
R 1 は、-C(O)CH=CHR 1f であり、ここで、R 1f は、水素、ジメチルアミノメチル、ピロリジン-1-イルメチル、又はピペリジン-1-イルメチルであるか;又はR 1 は:
R 2 は、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-10 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、又はヘテロシクリルであり;
R 4 、R 5 、R 6 、及びR 7 は、それぞれ独立に、(a)水素、シアノ、ハロ、若しくはニトロ;(b)C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-10 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、若しくはヘテロシクリル;又は(c)-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(=NR 1a )NR 1b R 1c 、-OS(O)R 1a 、-OS(O) 2 R 1a 、-OS(O)NR 1b R 1c 、-OS(O) 2 NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(=NR 1d )NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O) 2 R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O) 2 NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O) 2 R 1a 、-S(O)NR 1b R 1c 、若しくは-S(O) 2 NR 1b R 1c であり;但し、R 5 とR 6 、又はR 6 とR 7 とが結合して、ヘテロアリール又はヘテロシクリルを形成することを条件とし;
各RLは、独立に、(i)水素;又は(ii)C 1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-10シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、若しくはヘテロシクリル;又は(iii)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c、若しくは-S(O)2NR1bR1cであるか;或いは
同じ環に結合するRLが2つ以上ある場合に、2つのRLは結合して、(i)結合、-O-、-NRN-、若しくは-S-;又は(ii)C 1-6アルキレン、C1-6ヘテロアルキレン、C2-6アルケニレン、若しくはC2-6ヘテロアルケニレンを形成し;
RNは(a)水素;(b)C 1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、若しくはヘテロシクリル;(c)-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c、若しくは-S(O)2NR1bR1cであり;かつ
各R 1a 、R 1b 、R 1c 、及びR 1d は、独立に、水素、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-7 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、R 1a とR 1c とは、それらが結合しているC及びN原子と共に、ヘテロシクリルを形成するか;或いはR 1b とR 1c とは、それらが結合するN原子と共に、ヘテロシクリルを形成し;
ここで、各アルキル、アルキレン、ヘテロアルキレン、アルケニル、アルケニレン、ヘテロアルケニレン、アルキニル、シクロアルキル、シクロアルキレン、アリール、アリーレン、アラルキル、アラルキレン、ヘテロアリール、ヘテロアリーレン、ヘテロシクリル、及びヘテロシクリレンは、1つ以上の置換基Qにより任意に置換されており、ここで、各Qは、(a)オキソ、シアノ、ハロ、及びニトロ;(b)それぞれ、1つ以上の置換基Q a により任意にさらに置換されている、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-7 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、及びヘテロシクリル;並びに、(c)-C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-C(NR a )NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(=NR a )NR b R c 、-OP(O)(OR a ) 2 、-OS(O)R a 、-OS(O) 2 R a 、-OS(O)NR b R c 、-OS(O) 2 NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(=NR d )NR b R c 、-NR a S(O)R d 、-NR a S(O) 2 R d 、-NR a S(O)NR b R c 、-NR a S(O) 2 NR b R c 、-SR a 、-S(O)R a 、-S(O) 2 R a 、-S(O)NR b R c 、及び-S(O) 2 NR b R c から独立に選択され(ここで、各R a 、R b 、R c 、及びR d は、独立に、(i)水素;(ii)それぞれ、1つ以上の置換基Q a により任意に置換されている、C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-7 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、(iii)R b とR c とは、それらが結合しているN原子と共に、1つ以上の置換基Q a により任意に置換されているヘテロシクリルを形成する);
ここで、各Q a は、(a)オキソ、シアノ、ハロ、及びニトロ;(b)C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-7 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、及びヘテロシクリル;並びに、(c)-C(O)R f 、-C(O)OR f 、-C(O)NR g R h 、-C(NR f )NR g R h 、-OR f 、-OC(O)R f 、-OC(O)OR f 、-OC(O)NR g R h 、-OC(=NR f )NR g R h 、-OP(O)(OR f ) 2 、-OS(O)R f 、-OS(O) 2 R f 、-OS(O)NR g R h 、-OS(O) 2 NR g R h 、-NR g R h 、-NR f C(O)R k 、-NR f C(O)OR k 、-NR f C(O)NR g R h 、-NR f C(=NR k )NR g R h 、-NR f S(O)R k 、-NR f S(O) 2 R k 、-NR f S(O)NR g R h 、-NR f S(O) 2 NR g R h 、-SR f 、-S(O)R f 、-S(O) 2 R f 、-S(O)NR g R h 、及び-S(O) 2 NR g R h からなる群から独立に選択され;ここで、各R f 、R g 、R h 、及びR k は、独立に、(i)水素;(ii)C 1-6 アルキル、C 2-6 アルケニル、C 2-6 アルキニル、C 3-7 シクロアルキル、C 6-14 アリール、C 7-15 アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、(iii)R g とR h とは、それらが結合しているN原子と共に、ヘテロシクリルを形成する)。 - R1が、-C(O)CH=CHR1fである(ここで、R1fは、水素、ジメチルアミノメチル、ピロリジン-1-イルメチル、又はピペリジン-1-イルメチルである)、請求項1〜4のいずれか一項記載の化合物。
- R2が、それぞれ、1つ以上の置換基Qにより任意に置換されている、C6-14アリール、ヘテロアリール、又はヘテロシクリルである、請求項1〜6のいずれか一項記載の化合物。
- R2が、それぞれ、1つ以上の置換基Qにより任意に置換されている、フェニル、ピリジニル、ピリダジニル、ベンゾ[c][1,2,5]オキソジアゾリル、又はベンゾ[c][1,2,5]チオジアゾリルである、請求項7記載の化合物。
- R4が水素である、請求項1〜8のいずれか一項記載の化合物。
- R5とR6とが結合して、1つ以上の置換基Qにより任意に置換されているヘテロシクリルを形成する、請求項1〜9のいずれか一項記載の化合物。
- R7が、水素、クロロ、メチル、又はメトキシである、請求項1〜11のいずれか一項記載の化合物。
- R5が水素である、請求項1〜9のいずれか一項記載の化合物。
- R6とR7とが結合して、1つ以上の置換基Qにより任意に置換されているヘテロシクリルを形成する、請求項1〜9及び13のいずれか一項記載の化合物。
- 請求項1〜19のいずれか一項記載の化合物及び医薬として許容し得る賦形剤を含む、医薬組成物。
- 経口、鼻腔内、気管支、又は局所投与のために製剤される、請求項20記載の医薬組成物。
- 単一の剤形として製剤される、請求項20又は21記載の医薬組成物。
- 経口、非経口、鼻腔内、呼吸器、経肺、又は静脈内剤形として製剤される、請求項20〜22のいずれか一項記載の医薬組成物。
- 経口剤形である、請求項23記載の医薬組成物。
- 前記経口剤形が、錠剤又はカプセル剤である、請求項24記載の医薬組成物。
- 第二の治療剤をさらに含む、請求項20〜25のいずれか一項記載の医薬組成物。
- ERBB媒介性の病態、障害、又は疾患の1つ以上の症状を治療し、予防し、又は寛解させるための医薬の製造における、請求項1〜19のいずれか一項記載の化合物の使用。
- 前記ERBB媒介性の病態、障害、又は疾患が、増殖性疾患である、請求項27記載の使用。
- 増殖性疾患の1つ以上の症状を治療し、予防し、又は寛解させるための医薬の製造における、請求項1〜19のいずれか一項記載の化合物の使用。
- 前記増殖性疾患が、癌である、請求項28又は29記載の使用。
- 前記癌が、薬剤耐性である、請求項30記載の使用。
- 前記癌が、ERBBバリアントを含む、請求項30又は31記載の使用。
- 前記ERBBバリアントが、EGFRバリアントである、請求項32記載の使用。
- 前記EGFRバリアントが、689、700、709、715、719、720、746-759、761-765、767-775、783、784、790、796、826、839、846、858、861、及び863のアミノ酸位置で、1つ以上の欠失、挿入、又は置換を含む、請求項33記載の使用。
- 前記EGFRバリアントが、719、746-751、790、及び858のアミノ酸位置で、1つ以上の欠失、挿入、又は置換を含む、請求項33記載の使用。
- 前記EGFRバリアントが、G719C、G719S、G719A、ΔE746-A750、ΔE746-T751、ΔE746-A750(ins RP)、ΔD761-E762(ins EAFQ)、ΔS768-D770(dup SVD)、ΔV769-D770(ins ASV)、ΔD770-N771(ins SVQ)、ΔP772-H773(ins PR)、ΔH773-V774(ins NPH)、ΔH773-V774(ins H)、ΔH773-V774(ins PH)、及びΔH773-V774(ins GNPH)、T790M、並びにL858Rからそれぞれ独立に選択される、1、2、又はそれ以上の欠失、挿入、及び/又は置換を含む、請求項33記載の使用。
- 前記EGFRバリアントが、T790M、L858R、又はこれらの組み合わせを含む、請求項33記載の使用。
- 前記ERBBバリアントが、HER2バリアントである、請求項32記載の使用。
- 前記HER2が、前記癌中で過剰発現されている、請求項38記載の使用。
- 前記癌が、EGFR阻害剤に耐性である、請求項30〜39のいずれか一項記載の使用。
- 前記癌が、アファチニブ、カネルチニブ、ダコミチニブ、エルロチニブ、ゲフィチニブ、イコチニブ、ラパチニブ、ネラチニブ、ペリチニブ、バルリチニブ、又はこれらの組み合わせに耐性である、請求項40記載の使用。
- 前記癌が、膀胱癌、脳腫瘍、乳癌、口及び喉の癌、大腸癌、肺癌、膵臓癌、前立腺癌、胃癌、又は子宮癌である、請求項30〜41のいずれか一項記載の使用。
- 前記癌が、肺癌である、請求項42記載の使用。
- 前記癌が、非小細胞肺癌である、請求項42記載の使用。
- 前記癌が、再発性又は不応性である、請求項30〜44のいずれか一項記載の使用。
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JP6568926B2 (ja) | 2014-03-20 | 2019-08-28 | カペラ セラピューティクス,インコーポレーテッド | 癌の治療のためのerbbチロシンキナーゼ阻害剤としてのベンゾイミダゾール誘導体 |
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US11242352B2 (en) | 2022-02-08 |
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EP3119784B1 (en) | 2020-07-22 |
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US20210061816A1 (en) | 2021-03-04 |
US11713322B2 (en) | 2023-08-01 |
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